Lp,s are doomed!
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Conservative, if elected, will scrap cannabis legalization.
Friends in Quebec told me the police is hovering low trying to bust folks for pot.
Nice helicopter rides. Tax payers are footing the $$$.
Ho well.
Easy. They are burning cash at a high rate.
Once branded bunk on the web, your time is up.
Like whine, canna folks are looking for taste…
Simon sold you. Shit is being destroyed. Next Q will shock you!
DD is mui important.
Have you tried Tilray,s offering?
Most of it is destroyed, it,s that good... Most expert agree with you. Lol...
Tilray has a bright future!
That was Bruce Linton,s 2015 sales pitch… Remember?
Where is that 100 billion market?
I don,t see it.
What i see is legacy pumping out AAA quarter pound delivered for 147$.
It,s only a matter of time folks...
Many marijuana enterprises are financing themselves through nonpayment of federal taxes, assert our guest columnists, James Mann and John Yaeger.
Caught in the perfect storm of collapsing margins, oppressive taxes and vanishing access to debt and equity capital, those businesses are buying time by not making estimated tax payments in hopes of a brighter future.
Some observers try to put a positive spin on nonpayment as “cheap financing,” claiming that the interest charged on federal unpaid taxes is lower than interest that would be charged on other kinds of debt.
This is folly, of course: Interest rates on underpayments when added to penalties that might apply result in costly financing, especially for large corporations that could be subject to higher underpayment interest rates (and underpayment interest isn’t deductible).
More to the point, it’s a bargain with the devil because, when the IRS begins collection procedures, the marijuana taxpayer will have no choice but to pay the amount owed sooner or later.
Nebraska petitions requirement to remain despite cannabis advocates’ suit
A circuit court in Nebraska reversed a lower court’s decision to remove a requirement that ballot initiatives receive support from 5% of voters in 38 of the state’s 93 counties.
Nebraskans for Medical Marijuana tried to get the requirement removed, arguing it violated the Equal Protection Clause of the 14th Amendment because it weakened the voting power of those in the state’s counties with the most people.
British Columbia marijuana distribution center resumes operations
The union representing workers at British Columbia’s only cannabis wholesaler paused its job action, allowing for the resumption of shipments to retailers across the province.
The BC General Employees’ Union had started the job action in August, targeting the government-owned BC Liquor Distribution Branch. That strike led to stores being unable to receive products to sell and store workers being sent home.
They were "EXPECTING" great things for Canada back in 2015... Lol
Legacy is a bitch.
Pumping is easy...
Germany is overgrowned!
OPINION
The goal of legalized cannabis shouldn’t be corporate gold
ALAN YOUNG
CONTRIBUTED TO THE GLOBE AND MAIL
PUBLISHED JULY 15, 2016
This article was published more than 6 years ago. Some information may no longer be current.
Alan Young is an associate professor at Osgoode Hall Law School at York University. He has worked with the federal government to recognize cannabis in the medical drug schedule and led a number of constitutional challenges on drug and morality laws.
For the past 25 years I have worked to change Canada's archaic legal approach to marijuana use. Having little faith in the political process and its partisan posturing, I turned to the courts and the Charter of Rights to challenge the constitutional validity of many laws that criminalize morally controversial activity among consenting adults.
Despite achieving enormous success in developing a constitutional protection for medical marijuana, the basic foundation of the marijuana prohibition remained intact after the flurry of court cases. Having grown weary of battle, I was thrilled when the Liberal party pledged to legalize marijuana in 2015. Of course, political promises are unenforceable and, in the past, being on the verge of reform often ended with a quiet re-entrenchment of the status quo. So my enthusiasm has been tempered by a strong dose of cynicism.
As the government crawls towards legalization with the appointment of yet another task force, my tempered enthusiasm has started to wane, replaced by dismay. Everywhere I look I see countless interested parties and stakeholders lining up to cash in on cannabis dollars.
Twenty years ago I predicted that cannabis would be legalized when governments and corporate entities realized the untold monetary treasures to be reaped upon legalization, just as gambling was legalized in the 1990s to reap billions of dollars in tax revenues. And now, licensed medical cannabis producers, drug stores, provincial governments, labour unions, marijuana dispensaries and predatory stock brokers all want a share of the market. Who can blame them? Cannabis is a capitalist's dream considering the unprecedented economic opportunity of a ready-made customer base of millions.
I have always seen marijuana as a benign and mild intoxicant, and the less state regulation the better. However, I understand that some Canadians, and the government, see greater risks, and it is unlikely we will enter a legal world of grow-your-own, share with friends and sell small amounts to others. Canada has a tradition of overregulation and one can already sense that the government is poised to place a myriad of restrictions on production and distribution. Invariably, the more complex the regulatory framework, the more likely the market will be overrun by multinational corporations, Crown agencies and the heroes of big business. This completely undercuts the 1960s idealism which spawned our taste for the uplifting effects of marijuana; however, idealism always plays second fiddle to the realism of money markets.
Of greater concern is the fact that this fixation on economic issues and models of distribution has obscured the basic justification for promoting legalization as a sound policy choice for Canada. At its core, legalization is premised on three interrelated beliefs: 1) the activity is not sufficiently harmful to warrant criminalization; 2) using the blunt instrument of the criminal law justice system to eradicate the activity has been proven to cause more harm than good; 3) the activity has become so prevalent that the law has been rendered ineffective.
So in moving down the road to legalization, the focus should not be on the mode of distribution and who will reap the economic benefit. Although this may be important to the venture capitalists and consumers, a more fundamental question must first be addressed by government: What should the proper legal response be to the multitude of pot consumers who have no interest in, and perhaps even an aversion to, corporate marijuana?
It must be recognized that a vibrant underground cannabis culture has been evolving for decades. If the government maintains the taboo on self-production and local dispensaries, there will remain hundreds of thousands of cannabis users and producers who will refuse to go to the liquor or drug store to purchase cannabis. If excluded from the new market, the underground will continue to flourish, and this government must decide what to do with the outliers. If the fallback position is that anyone who does not comply with the rules of the market must be dealt with by the criminal justice system, then we have not achieved legalization.
The outliers cannot be considered criminals solely for running the very same business operations sanctioned and exploited by the government and corporate Canada. If a basic premise of legalization is that the activity is not sufficiently harmful to warrant jail and a criminal record, it cannot be converted back into criminal conduct simply because it is being done without proper licensing. Of course, some type of regulatory offence will have been committed, akin to fishing without a licence, but once a government gives the legal seal of approval to an activity it loses the moral right to condemn and criminalize the renegades operating without a licence.
For the most part, the underground cannabis culture has been occupied by pot-heads so driven by their love of cannabis that they can carve a bong out of cucumber in thirty seconds or less. They are not a threat to our communities. If this government continues to demonize marijuana and perpetuate the myth that the cannabis community is overrun by criminals, then it is likely they will exclude this community from participating in the legalized world. In which case all we will have achieved is a money-making venture for some, while leaving most others to face criminal sanction for refusing to leave the comfort of their underground world. In other words, we will have achieved nothing.
Clean sheet to keep on growing/selling bunk weed... Lol
Rinse & repeat...
Doomed!
Good luck with that bunk weed in... Lol
Canada business leaders note ‘lost opportunity’ for cannabis in Trudeau-Scholz meeting
author profile pictureBy Matt Lamers, International Editor
September 1, 2022 - Updated September 1, 2022
SHARE
Image of Canadian Prime Minister Justin Trudeau and German Chancellor Olaf Scholz greeting two other Canadian officials
Prime Minister Justin Trudeau and other Canadian officials, left, greet German Chancellor Olaf Scholz, right. (Photo by Adam Scotti)
Olaf Scholz’s recent trip to Canada is raising eyebrows among Canadian business executives over what wasn’t discussed during talks between the German chancellor and his Canadian counterpart, Prime Minister Justin Trudeau.
Cannabis and mainstream business leaders said Canada missed an opportunity last week to highlight its regulated cannabis industry and promote international trade when Scholz visited the only large country in the world to have legalized marijuana.
Germany announced its intention earlier last year to regulate the distribution and sale of recreational cannabis and, this summer, kicked off the preparatory phase. A draft law is expected to be published this year.
Industry officials said the circumstances created a unique opportunity for the Canadian prime minister to back the multibillion-dollar industry, which has struggled to tap into international markets.
But a spokesperson for the Office of the Prime Minister confirmed cannabis was not discussed between the German leader and Trudeau during Scholz’s trip last week.
“It didn’t come up? Shocking. It’s shocking,” George Smitherman, CEO of the Cannabis Council of Canada, which represents dozens of businesses, said in an interview with MJBizDaily.
“Canada has a chance to align with Germany, and we’re not advancing that? That’s crazy,” added Smitherman, a former deputy premier for Ontario who also was the province’s energy and infrastructure minister.
Smitherman said opportunity abounds between Canadian and German cannabis businesses.
Germany is suffering through an energy crisis because of the war in Ukraine, and cannabis cultivation can be incredibly energy intensive, he said.
That, plus the fact that Canada already has more cannabis cultivation capacity than it will ever need, puts Canada in a position to ramp exports.
Canada has so much excess cannabis, it has destroyed more than 1 billion grams since 2018, and inventories are still overflowing. (That cannabis is thought to mostly be unsellable, but the production capacity remains in place.)
“You might have thought that the combination of these two, the symmetry if you will, the rationale for having Canada and Germany collaborating could be an extension of the energy cooperation,” Smitherman said.
“I’m a former energy minister. I was looking at it from that standpoint.”
Canada is already Germany’s top supplier of medical cannabis, and business leaders say that could easily be expanded.
Canada’s Chamber of Commerce said the country missed an opportunity to promote the legal sector internationally.
“As the first G-7 economy to legalize recreational cannabis, Canada has a narrow first-mover advantage and should promote the legal sector internationally,” the business group said in a statement to MJBizDaily.
“Although cannabis was not on the agenda for German Chancellor Scholz’s short visit to Canada earlier this month, the Canadian Chamber’s National Cannabis Working Group believes Canada should actively work towards securing future meetings with countries like Germany to share industry best practices and to facilitate business opportunities, including the export of medicinal cannabis.”
Canada is top supplier of poor quality cannabis.
Canada was the top supplier of medical cannabis flower and extracts to Germany last year, according to data provided by Germany’s Federal Institute for Drugs and Medical Devices (BfarM).
In 2021, Germany imported 6,493 kilograms (14,315 pounds) of cannabis from Canada, or 31% of its medical and scientific marijuana imports.
Denmark was the next closest, with 3,726 kilograms, or 18% of the total amount imported.
Business leaders estimate the opportunity to be in the hundreds of millions of dollars.
Germany is expected to overtake Canada as the largest federally regulated medical marijuana market in the world in 2022.
Economic driver
Despite massive losses at a small number of producers, cannabis has been a driver of economic growth in Canada.
The industry has added roughly 43.5 billion Canadian dollars ($37 billion) to the country’s economy and sustained 151,000 jobs since legalization in 2018, according to a report by accounting firm Deloitte.
Industry leaders have said the Canadian government could be doing more to help struggling cannabis producers make inroads into foreign markets.
“That the (Prime Minister’s Office) confirmed that is really kind of a smoking gun for just how leadership attention and interest in Ottawa has diminished over their own prized initiative,” Smitherman said of the absence of cannabis as a topic in the Scholz-Trudeau discussions.
“If I was prime minister, and I was meeting with the German Chancellor, I might actually be saying, ‘You know, chancellor, us two leading G7 nations, the legalizers of cannabis, we have a chance to be the foundation for countries in favor of a $100 billion industry that’s emerging, what can we do strategically to align that? For instance, could Canada offer Germany supply arrangements?'”
Smitherman said the federal government’s “neglectful leadership model” is being replicated in several provinces and “is an extraordinary threat to the public health goals and to the livelihoods of many Canadians.”
‘Incredible lost opportunity’
Nathan Mison, CEO of Alberta-based Diplomat Consulting, called Scholz’s visit an “incredible lost opportunity.”
He said a majority of Canadians want the cannabis sector to be promoted as an economic opportunity, citing data from Ontario-headquartered pollster Abacus Data.
Mison, co-chair of the National Cannabis Working Group for the Canadian Chamber of Commerce, believes the federal government should treat the cannabis industry like it does mining.
“When we’re looking for positive opportunities for our cannabis sector, what an incredible opportunity to treat cannabis sector regulation the same way we exported Canadian mining rules around the world,” he said.
Mison said 55 countries are weighing cannabis regulation, and it’s in Canada’s best economic interest to be involved in that process, where possible.
“We should be looking to trade opportunities for Canadian businesses to understand how to operate in emerging jurisdictions.”
Canna World
@CannaWorld4
·
1h
To the people who complain about the black market stealing their market share... How can you lose something that was never yours to begin with? It's you who wanted, not a piece, but that whole pie, not the other way around. And, it's entirely your fault that you didn't get it.
You are Doomed!
Next Q will be a dusy... Lol
Good luck selling that Tilray,s crap in Germany.
Buy High & Sell Low = LPs Moto = Lol
Next Q = Dusy
In 2018, TGOD bought HemPoland for $20.4 million
In 2022, TGOD sold HemPoland for $1.65 million (+ loan payable to HemPoland by the TGOD of $5.6M would also be forgiven)
Tilray is DOOMED!
European cannabis market has been oversaturated for years...
I wrote that piece 2 years ago.
I,m in Berlin and cannabis is everywhere.
European countries fight for medical cannabis in an over saturated market
Bonno 11-08-2020
European countries are fighting to become the next hub of cannabis cultivation, as medical cannabis companies accidentally over saturate the European cannabis market.
A new Prohibition Partners report was released earlier this week, shedding some light on the woes of the European medical cannabis market. As investors eye the pot pie, large-scale cannabis operations have now launched in Denmark, Portugal, Spain, Macedonia, Greece and Malta.
Across Italy, the Czech Republic and Switzerland, smaller-scale cannabis operations are also making waves. The Czech Republic recently launched their own cannabis vending machines, while Sicily announced free medical cannabis.
In the next few years, Europe will be producing over 300 tonnes of cannabis annually – but there’s a catch.
This rapid expansion has provided more cannabis can Europe can actually use. Most of the grows ends up in the dump anaways.
While Europe faced many years of cannabis shortages and under supply, the continent is now overgrown with unsellable cannabis crop.
Legacy is doing a-Okay but. I guess folks prefer fire for cheap.
In August 2020, Prohibition Partners estimate that Europe’s fully licensed suppliers can collectively produce 34 tonnes of cannabis flower annually. Whether this is sold in flower form or in medicinal products, Europe produces three times its estimated demand for cannabis.
In response to this, investors are rescaling their projects and aiming to export cannabis overseas. Canadian cannabis producer Canopy Growth entered the European market under subsidiary Spectrum Therapeutics, investing approximately $76 million in facilities in Denmark.
Indoor cannabis is more common cultivation method
In the last quarter of 2019, Canopy Growth produced over 40 tonnes of cannabis, but only managed to sell 27.5% of their stock. Towards the end of the 2019/2020 financial year, Canopy Growth logged a quarterly loss of just over $1 billion.
Medical cannabis company Aurora Nordic Cannabis faced similar European sales. Despite producing 15 tonnes of cannabis annually, the company had a deficit of roughly $8 million in the 2018/2019 financial year.
In 2020, they have reduced their operating costs by $87 million by replacing their staff with robots and machines. Earlier this year, CEO Mads Pedersen told the Finans:
The European market for medical cannabis is getting tough. There are far too many producers, so it will be a tough elimination race.
Although exporting oversupplied cannabis flower to Australia and Israel would reduce Europe’s cannabis saturation, the demand for foreign cannabis is decreasing both here and in Israel. As our cannabis exporting laws changed in June, companies like BOD Australia are expanding into the European market. If a new bill legalising cannabis passes in Israel’s Knesset, their local supply of cannabis will fill their demand within five years.
Bonehead DeSantis makes sense... Lol
DeSantis: Medical-marijuana firms should pay more to state
Bonno
•Aug 27, 2022
TALLAHASSEE — As Florida medical-marijuana companies continue to rake in cash with a growing clientele, Gov. Ron DeSantis says they need to pay more to do business in the state.
“I mean, these are very valuable licenses,” the governor said Tuesday. “I would charge them an arm and a leg. I mean, everybody wants these licenses.”
DeSantis’ administration, however, has dragged its feet on complying with a state law requiring the Department of Health to effectively double the number of players in the industry, which now has 22 licensed operators.
The governor’s office has blamed the delay on litigation over a 2017 law, but a Florida Supreme Court decision upholding the statute was finalized last year.
It was unclear if DeSantis was referring to medical-marijuana companies already operating in the state or businesses seeking to gain entry to Florida, which insiders say has the potential to be one of the nation’s most-robust cannabis markets.
DeSantis’ comments this week coincided with MedMen Enterprises Inc.’s announcement that it had closed a $67 million deal selling its Florida operations to Green Sentry Holdings LLC.
The National Hurricane Center raised the odds of development for a tropical wave in the east Atlantic Friday morning.
With nearly 800,000 approved medical-marijuana patients among a population of more than 22 million Florida residents, investors are anxiously awaiting the chance to plant stakes in the state.
The 2017 law created a framework for the medical-marijuana industry and set up a schedule for new licenses to come online as the number of authorized patients increases. Under the law, state health officials should have issued at least another 22 licenses to keep up with the population of patients.
Medical-marijuana companies doing business in Florida were part of an initial group of applicants in 2015 who each paid a little more than $60,000 for a shot at being able to sell low-THC cannabis. Those applications came after lawmakers in 2014 allowed low-THC products for certain patients.
The 2016 constitutional amendment went far beyond the 2014 law. Nearly all of the operators, who were allowed to add medical marijuana with uncapped levels of THC to their product lines after the amendment passed, have changed hands since the licenses initially were granted.
“Why wouldn’t we take the opportunity to make money for the state based off those?” DeSantis said Tuesday. “But I do think that would require a statutory change (by the Legislature), and I don’t think that’s something we could just do through administrative rule.”
The governor was pointing to part of the 2017 law that limits how much the Department of Health can charge companies for licenses and renewals. The law only allows the state to charge fees to cover the costs of administering the medical-marijuana program, as well as a research program and a public-health campaign.
The law also gave health officials the ability to establish “supplemental licensure fees” to help cover the costs of the program, but the health department has never authorized such fees.
Raising application and renewal fees “would be unfortunate,” Brady Cobb, a lawyer who is the founder and CEO of Green Sentry, said in a phone interview this week.
“If it happens, it happens,” said Cobb, adding the state could make more money by taxing marijuana products or allowing operators to wholesale products to each other and taxing those sales.
The state charged a higher fee in a recent round of applications for a license earmarked in the 2017 law for a Black farmer. Under rules laid out by the Department of Health, applicants had to pay a $146,000 fee to compete for the Black-farmer license, more than twice the fee from the application process in 2015.
The department accepted a dozen applications for the Black-farmer license during a five-day period in March but has not announced the winner of the license. The agency did not respond to questions about when the license would be awarded.
The department is expected to launch a new round of applications for licenses after the Black-farmer license is finalized, but the state hasn’t laid out a timeline. At least 150 hopefuls, and possibly twice that number, are expected to apply.
Review
Cannabinoids as anticancer therapeutic agents
Bonno
Pages 961-989 | Received 30 Nov 2019, Accepted 05 Mar 2020, Published online: 05 Apr 2020
Download citation https://doi.org/10.1080/15384101.2020.1742952 CrossMark LogoCrossMark
The recent announcement of marijuana legalization in Canada spiked many discussions about potential health benefits of Cannabis sativa. Cannabinoids are active chemical compounds produced by cannabis, and their numerous effects on the human body are primarily exerted through interactions with cannabinoid receptor types 1 (CB1) and 2 (CB2). Cannabinoids are broadly classified as endo-, phyto-, and synthetic cannabinoids. In this review, we will describe the activity of cannabinoids on the cellular level, comprehensively summarize the activity of all groups of cannabinoids on various cancers and propose several potential mechanisms of action of cannabinoids on cancer cells.
KEYWORDS: Cannabinoidscancercannabidioltetrahydrocannabinolanti-tumor activity
Previous article
View issue table of contents
Next article
Introduction
Cannabinoids are compounds that exert numerous effects in the human body and include molecules that are structurally similar to ?9-tetrahydrocannabinol (?9-THC) and interact with cannabinoid receptors [1]. Cannabinoids affect cell function through various cellular pathways mediated by two types of G-protein coupled receptors (GPCRs): the cannabinoid receptor type 1 (CB1) and the cannabinoid receptor type 2 (CB2).
The known types of cannabinoids
There are three major types of cannabinoids: endocannabinoids produced by the human body, phytocannabinoids produced primarily by Cannabis sativa, and synthetic cannabinoids that are synthesized artificially. All three groups of classical cannabinoids have a somewhat similar structure because they are decarboxylated from 2-carboxylic acids (2-COOH); the main structural difference is due to different methods of precursor cyclization [2].
Two major endocannabinoids with the defined activity in the human body are N-arachidonoylethanolamine (AEA-anandamide) and 2-arachidonoylglycerol (2-AG) [3]. Other endocannabinoid molecules with less clear roles include oleamide, O-arachidonoyl ethanolamine which is also known as virodhamine, 2-AG ether also known as noladin, pregnenolone, lipoxin A4, and N-arachidonoyl- dopamine [3] (Table 1). Endocannabinoids affect our pain sensation and response, stress response, inflammation response, appetite, memory, and mood, among other processes [1,3]. Immune response, neurotransmission, energy homeostasis, reproduction, and cell survival/death are all affected by the endocannabinoid system (ECS) [1]. Whereas anandamide functions as a ligand for CB1, 2-AG can bind with both CB1 and CB2 receptors [4].
Table 1. Various types of cannabinoids.
Download CSVDisplay Table
Synthetic cannabinoids (SCs) include dronabinol and its analogues nabilone and rimonabant which are used to treat pain, loss of appetite, obesity, and other conditions. Most of the SCs were developed to study the function of ECS, avoiding restrictions associated with the use of cannabis and endocannabinoids. SCs can be broadly divided into synthetic equivalents of endo- or phytocannabinoids (for example, dronabinol is similar to ?9-THC), analogs of endo- or phytocannabinoids (i.e., nabilone, HU-210), derivatives of endocannabinoids (i.e., methanandamide), or completely new compounds of various chemical structure and affinity to cannabinoid receptors [5].
Phytocannabinoids are mainly found in Cannabis sativa and are represented by over 100 cannabinoids, although only a few of them are relatively abundant and believed to be active [6]. All these compounds are defined as cannabinoids because they are structurally similar to endocannabinoids; however, most of them either do not bind known cannabinoid receptors or do that very inefficiently. All cannabinoids derive from cannabigerolic acid (CBGA), a molecule produced from the combination of geranyl pyrophosphate and olivetolic acid catalyzed by GOT, a prenyltransferase group enzyme. CBGA is then converted into four major cannabinoids: cannabigerol (CBG), ?9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA) (Figure 1). Whereas CBG is obtained by direct heat-, light-, or alkylation-induced decarboxylation events (loss of CO2 group), THCA, CBDA, and CBCA are obtained through the activity of THCA, CBDA, and CBCA synthase, respectively. Finally, THCA, CBDA, and CBCA are converted into the active compounds ?9 – tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabichromene (CBC) through the heat-induced decarboxylation. Prolonged exposure to the air also results in the conversion of THCA into cannabinolic acid (CBNA) and THC into cannabinol (CBN). Decarboxylising CBNA also results in CBN. The most prevalent cannabinoids are ?9-THC, cannabidiol (CBD), and cannabinol (CBN) [7]. Furthermore, some plants have an active alternative pathway that generates an almost mirror image of major cannabinoids from divarinic acid instead of olivetolic acid, starting from the precursor CBGA variant (CBGVA) instead of CBGA and downstream molecules including CBCA (CBCVA), CBDA (CBDVA), and THCA (THCVA) variants, and other compounds (Figure 1).
Figure 1. Polyketide pathway of cannabinoids synthesis. Dark green (right panel) shows the main biosynthesis pathway, whereas light green (left panel) shows the variant biosynthesis pathway. Biosynthesis products consist of CBCA, CBDA, THCA and their variants, CBCVA, CBDVA and THCVA. Decarboxylation products are shown in the blue box, whereas degradation products are in gray. Delta 8 isomerization products are shown in yellow.
Display full size
The mode of action of cannabinoids
The main mode of action of cannabinoids is based on their neuromodulator activity through retrograde neurotransmission and binding to CB1 and CB2 receptors. The two main types of cannabinoid receptors vary mostly in their localization. CB1 receptors are more abundant and ubiquitously present in the body; they are mainly localized in the central nervous system (CNS) and secondarily in various extra-neural tissues and peripheral nerve terminals [8,9]. CB2 receptors are also expressed in most regions of the body but are in abundance in lymph nodes, spleen, bone marrow and appendix [10,11]. Certain level of CB2 receptors is also found in CNS, primarily in microglia but also in neurons [11].
The specific class of G-proteins with which CB1/CB2 receptors interact belongs to the heterotrimeric class that consists of three subunits, Ga, Gß, and G?, with the latter two often forming a dimer. Ga subunits are represented by several classes including, but not limited to, Gas (G stimulatory), Gai (G inhibitory), Gao (G other), Ga q/11, and Ga 12/13. Both Ga and Gß/G? activate or inactivate different secondary pathways. Whereas Gas activates the cyclic AMP (cAMP)-dependent pathway, Gai inhibits it, thus preventing cAMP production from ATP; both reactions occur through the interaction with adenylate cyclase, an enzyme that converts ATP into cAMP. cAMP functions as a secondary messenger that activates protein kinase A (PKA) which in turn phosphorylates different targets. The Gq/11a subunit interacts with and activates phospholipase C beta (PCB). The active PCB form cleaves phosphoinositol PIP2 into inositol triphosphate (IP3) and diacylglycerol (DAG). Ga12/13 signals through the interaction with the RhoGEF domain of the Rho family GTPases, resulting in the regulation of cell cytoskeleton remodeling and the activation of cell migration [12].
Nogueras-Ortiz and Yudowski [13] proposed three waves of spatiotemporal responses of cannabinoid binding to CB receptors [13]. The first wave is initiated by cannabinoids binding to the CB1/CB2 receptors. The interaction with these receptors activates heterotrimeric G proteins, thus leading to their dissociation into Gai and Gß/G? subunits and resulting in three major events: a rapid decrease in cAMP levels due to the direct binding and inhibition of adenylate cyclase by a Gai subunit, a decrease in Ca2+ conductance, and an increase in K+ conductance (Figure 2). The second wave consists of the events associated with the ligand-induced receptor phosphorylation followed by receptor desensitization through the phosphorylation of GPCR by the G protein-coupled receptor kinases. Arrestin proteins bind to the phosphorylated receptor which leads to its internalization and unavailability for further signaling, thus redirecting all downstream signaling to other receptors and activating pathways such as the mitogen-activated protein family of kinases [14,15].
Figure 2. Three waves of responses to cannabinoid binding. The first wave is initiated by cannabinoids binding to the CB1/CB2 receptors. The interaction of cannabinoids with one of these receptors activates heterotrimeric G proteins, thus leading to their dissociation into Gai and Gß/G? subunits and resulting in three major events: a rapid decrease in cAMP levels due to the direct binding and inhibition of adenylate cyclase by a Gai subunit, a decrease in Ca2+ conductance, and an increase in K+ conductance. The second wave consists of the events associated with the receptor phosphorylation followed by receptor desensitization. Arrestin proteins bind to the phosphorylated receptor leading to receptor internalization, thus redirecting all downstream signaling to other receptors and activating the pathways like mitogen-activated protein family of kinases. The third wave is initiated at the receptors in the intracellular compartments such as endosomes and lysosomes and can be initialized through either G proteins or ß-arrestins.
Display full size
The third wave is initiated at the receptors in the intracellular compartments such as endosomes and lysosomes and can be triggered through either G proteins or ß-arrestins. The existence of this wave and its functionality in vivo are unclear, but several lines of evidence support its importance. Immunostaining a hippocampal Neuro2A cell culture demonstrates the enrichment of CB1 in the intracellular compartments and shows the co-immunoprecipitation of CB1 and G proteins isolated from the endosomal compartments [16]. Treating Neuro2A cells with the combination of an agonist that can cross the plasma membrane (WIN-55212-2) and the receptor blocker (hemopressin) that cannot cross the plasma membrane demonstrates the phosphorylation and activation of the extracellular signal-regulated protein kinase (ERK), presumably occurring through the activation of the receptor in the intracellular compartments.
CB1 receptor activation
CB1 receptors are primarily located in the CNS. In fact, the human CNS has more CB1 receptors than any other type of GPCRs. CB1 receptors are mostly located at the terminal parts of central and peripheral neurons where they are involved in inhibition of neurotransmission [17]. Many other tissues also have CB1 receptors albeit at much lower numbers. CB1 receptors can regulate various functions, including cardiovascular, reproductive, and respiratory functions as well as the neuronal development and neuromodulatory processes.
Signaling through the CB1 receptor negatively regulates neurotransmitter release by inhibiting the phosphorylation of the A-type potassium channels. In its unphosphorylated form, the A-type potassium channels sustain a continuous outward flow of potassium [18]. The activation of CB1 is also known to negatively regulate the inward flow of potassium through the D-type receptors. CB1 activation also results in the inhibition of the N-type calcium channels via a direct interaction with Gai and Gao proteins. Altogether, this results in the restriction of neurotransmission leading to cognitive impairment and sedative-like effects after the consumption of marijuana [19].
CB1 receptors in humans are more abundant in most regions of brain of healthy females as compared to males, as demonstrated by an in vivo positron emission tomography (PET) [20]. In addition, CB1 receptors abundance increases with age in females but not in males [21].
CB2 receptor activation
CB2 is expressed mostly in cells and tissues of the immune system, with the highest number being found in the spleen, lymph nodes, and blood, namely in the T and B lymphocytes [22,23], although some evidence exists that CB2 receptors are also found in the peripheral nervous system and even in the microglia population [24]. The expression of CB2 in the CNS is triggered by inflammation and is mainly localized to resident macrophages of microglia [25,26]. This expression of CB2 has been localized primarily to microglia, the resident macrophages of the CNS.
Anandamide is a principal endogenous ligand of the CB2 receptor. The CB2, in part, exerts its effects by initiating phospholipase C (PLC) and the inositol 1, 4, 5-triphosphate (IP3) signaling pathways. 2-AG was found to initiate ER Ca2+ ion depletion followed by the activation of capacitative Ca2+ entry (CCE) and a transient increase of Ca2+ ions in mitochondria [27].
The activation of the CB2 receptor by 2-AG modulates immune responses, including the proliferation, survival, and migration of immune cells [28]. The data indicate that CB2 regulates B cell immunity by promoting an appropriate localization and retention of marginal zone B cells such that they are able to respond to foreign antigens, resulting in the early production of IgM, an essential immune component of protective immunity against multivalent microorganisms [29]. However, phytocannabinoids, such as ?9-THC, have been shown to suppress B and T lymphocyte proliferation in response to cell-specific mitogens [30,31] by suppressing the cytolytic activity and proliferation and maturation of cytotoxic T lymphocytes. However, some evidence exists that THC exerts such effect independently of CB1 and CB2 receptors [32]. Collectively, the data suggest that the exogenous application of ?9-THC inhibits functional activities of various immunocytes, thus leading to a decreased resistance to infection.
The activation of other receptors
There are other type of receptors cannabinoids were shown to interact with, including transient receptor potential cation channel vanilloid (TRPV), TRP ankyrin (TRPA), TRP melastatin (TRPM), peroxisome proliferator-activated receptor gamma (PPAR?), N-arachidonoyl glycine (NAGly, AEA metabolite) receptor GPR18, the orphan receptor GPR55, GPR19 and many others [33,34]. According to human protein atlas (www.proteinatlas.org), TRPV1 is expressed in most organs, including brain, liver, gastrointestinal tract and skin, with the highest expression found in the latter two. PPAR? is also expressed in most tissues, with the highest expression found in bone marrow/immune system, kidneys, gastrointestinal tract, uterus and testes. In contrast, GPR18 is mainly expressed in bone marrow/immune system and testes, GPR19 – in the brain, testes and a bit in bone marrow, and GPR55 – in bone marrow and testes.
The analysis of the pharmacokinetics of ?9-THC and anandamide in single- (CB1) and double- (CB1/CB2) knockout mice showed the activation of GPR55 which is another GPCR. Unlike CB1 and CB2, GPR55 is coupled to the Ga13 protein instead of Gai and Gao proteins [35]. Ga13 activation leads to the activation of RhoA and cell migration [36], and cannabidiol has been shown to be an antagonist of GPR55.
TRPV1-TRPV4, TRPA1, and TRPM8 receptors are termed the ionotropic cannabinoid receptors. The TRVP1 receptor is known to be activated by compounds like capsaicin and vanilloids with their structures similar to that of anandamide [37]. Some data exist that demonstrate the ability of anandamide to bind TRVP1, making this receptor an actual novel cannabinoid receptor [37,38]. AEA was the first endocannabinoid functioning as endogenous antagonist of TRPM8 [39]. THC, in contrast, does not modulate TRPV1 but rather works against TRPV2 (most potently), TRPV3, TRPV4, TRPA1, and TRPM8 [40]. Most fascinatingly, CBD is more active at binding TRPV1 and TRPM8 rather than CB1 and CB2 [40]. Details on the signaling through TRPV1 can be found in the review by Muller et al. [34].
Interaction of cannabinoids with receptors
Cannabinoids may function as both agonists and antagonists of cannabinoid receptors. ?9-THC is considered a partial agonist of CB1 and CB2 receptors. The affinity of THC to these receptors is lower than that of endocannabinoids but higher than that of the phytocannabinoids ?8-THC, ?9-THCV, CBD, cannabigerol, and cannabinol [41]. However, THC may also act as a partial antagonist of CB receptors, inhibiting the effect of endogenous cannabinoids. The density of receptors may play a role; the low level of CB receptor expression may result in THC functioning as an antagonist [41,42], and an increase in the density may reverse its function to an agonist [41]. For example, Patel and Hillard [43] found that ?9-THC exhibits the antagonist activity of CB1 similar to that of the specific synthetic inhibitor SR141716A [43] or R-(þ)-WIN55212 [44,45].
CBD affinity for CB1 and CB2 does not appear to be high; the displacement of [3 H]CP55940 from the cannabinoid CB1 and CB2 receptors has shown that CBD functions at micromolar concentrations, which are at least 1,000-fold higher than those observed while using THC [41]. More recently, CBD has been suggested to be a CB1 and CB2 receptor antagonist and has been shown to inhibit anandamide uptake and metabolism [46]. It has been suggested that at low concentrations, CBD acts as an inverse agonist binding to the same receptors as other agonists but causing a different physiological effect [47].
As far as other minor cannabinoids are concerned, the available information is rather limited. It has been demonstrated that CBG activates the a2-adrenoceptors and blocks the CB1 and 5-HT1A receptors [48]. Testing the activity of THCV has demonstrated that it functions as a CB1 and CB2 receptor antagonist at low concentrations [49] and as a CB2 agonist at higher concentrations [50].
Sex-specific differences in cannabis response
Considering the differences in the expression pattern of CB1 receptor and other receptors to which THC binds [51], it can be hypothesized that males and females respond to cannabis differently. Women seem to be more prone to addiction to cannabis as compared to men. Significantly greater withdrawal intensity and negative impact of withdrawal are observed in women [52]. Women are also more likely to have lifetime panic disorder, agoraphobia, reported more days of poor physical health and cannabis-related medical problems after cannabis cessation [52].
Smoking cannabis is known to increases heart rate greater in males than in females [53]. Also, greater sedative effects [53] and dizziness [54] is observed in women as compared to men. In addition, women also responded to cannabis extract with significantly greater fatigue, drowsiness, and psychomotor suppression compared to women treated with placebo [55]. Sex-specific differences in response to cannabis can be due to the different amounts of endocannabinoids produced, different rate of metabolism of these cannabinoids and different level of expression of receptors.
Metabolism of endo- and phytocannabinoids and its significance
Both AEA and 2-AG can be degraded by either hydrolysis or oxygenation. Hydrolysis is accomplished via two distinct routes: AEA is degraded by fatty-acid amide hydrolase (FAAH) and 2-AG is degraded by monoacylglycerol lipases (MAGs), although FAAH is also able to metabolize 2-AG (very minor pathway). In addition, in some conditions, and/or certain cells, both AEA and 2-AG can be metabolized by carboxylesterases 1 and 2 (CES1 and CES2); these enzymes metabolize 2-AG in human leukocytes equally well with MAGs [56]. Oxygenation can occur through several enzymes, including cyclooxygenase-2, lipoxygenases, and cytochrome P450, and these enzymes have different activity in different tissues [57].
?9-THC is metabolized in the liver by microsomal hydroxylation and oxidation catalyzed by enzymes of cytochrome P450 (CYP) complex leading to the production of various acidic metabolites, including 11-OH-THC and THCCOOH [58]. Similarly, CBD is also a substrate of CYP450 enzymes which converts CBD through extensive hydroxylation followed by further oxidations to many different metabolites, with 7-COOH-CBD and its derivatives being the most abundant [59].
Metabolism of phytocannabinoids is greatly influenced by mode of administration and natural variations in the activity of all metabolic enzymes [60]. There are also sex-specific differences in metabolism of cannabis. THC metabolism in male rats resulted in multiple metabolites, whereas only a single metabolite 11-OH-THC was produced in female rats [61]. Brain levels of metabolite 11-OH-THC were higher in THC-exposed female rats compared to male rats [62]. Similarly, in human, exposure to THC results in high plasma THC levels in females [63]. This information must be taken into consideration when cannabis is administered.
Cannabinoids as anticancer agents
The balanced expression of CB1 and CB2 receptors as well as other associated receptors is extremely important for the overall health of an organism. Alterations in the ECS occur in many disease states. For example, the upregulation of CB1 and CB2 receptors and an increase in the endogenous levels of endocannabinoids have been observed in many pathological states, including neurodegenerative and cardiovascular diseases as well as in cancer [64].
Changes in endocannabinoid system in cancer
Changes in the endocannabinoid system have been demonstrated in various cancers. These changes include the levels of produced endocannabinoids, the expression of their receptor targets and even oligomerization of such receptors. It is still not well understood whether the changes in ECS may contribute to malignization or are a consequence of it. One of the main functions of ECS is to maintain body homeostasis, and thus ECS responds to environmental stimuli in transient and sometime even in persisting manner [65], and thus may contribute to the process of malignization. On the other hand, ECS is involved in regulation of cell division, differentiation and fate [66] and therefore could change in parallel with the process of carcinogenesis or could change in response to it. Another possibility is that ECS in tumors changes in response to microenvironment/niche signals.
For example, changes in the CB1 and CB2 expression have been demonstrated to correlate with cancer cell motility, invasion, proliferation, adhesion, and apoptosis [17]. The level of anandamide and AEG is 2–3 times higher in adenomas and colorectal cancers than in normal mucosa [67]. The number of CB2-positive receptors is much higher in colon cancer cells than in the normal epithelial cells. The CB2 receptor agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1 H)-on-3-carboxamide (CB13) increases receptor expression and leads to apoptosis in the tested cancer cell line [68].
Similarly, the CB1 and CB2 receptor expression is upregulated in human hepatocellular carcinoma compared to non-tumorous tissues [69]; the authors however suggest that a higher expression of these receptors may improve survival [69]. A similar scenario has been observed in prostate cancer; it has been suggested that the increased densities of these receptors may correlate with a better prognosis [70].
A higher expression of CB receptors may predict tumor responsiveness to treatment. For example, prostate cancer cells expressing high levels of CB receptors respond favorably to receptor agonists [70], whereas breast cancer cells with low expression levels respond to cannabinoids with an increased proliferation [71].
Other reports, in contrast, demonstrate that endocannabinoid-degrading enzymes are upregulated in various cancer cell lines as well as in human tumors [72]. Silencing CB1 receptor promotes growth of intestinal adenoma, whereas overexpression of CB1 inhibits cancer [73]. Decrease in the expression of endocannabinoid-metabolizing enzymes also resulted in the decrease in the tumor growth. Increase in endocannabinoids levels leads to reduction in formation of precancerous lesions in mouse colon [74] and inhibition of prostate cancer cell growth [75].
Although the expression level of CB1 and CB2 receptors was found to be higher in various cancers [76], in many cancers, the CB1/CB2 receptors are downregulated [77]. Wang et al. [73] found a downregulation of CB1 expression in human colorectal cancer due to methylation of the CB1 promoter and a lower expression of CB1 correlated with the enhanced cancer proliferation in mice xenografted with a colorectal tumor [73]. In the regulation of other receptors, many cancers have been shown to overexpress GPR55 [78]. In fact, high levels of GPR55 are strongly correlated with tumor aggressiveness.
In addition to changes in the expression of cannabinoid receptors in different cancers, there are changes in the receptor oligomerization. CB1 receptors were shown to interact with many different other GPCRs potentially forming heterodimers and tetramers, including adenosine A2A receptors [79], dopamine D2 receptors (changing coupling from Gi to Gs) [80], D2 and adenosine A2A receptors [81]; opioid µ and d receptors (resulting in a negative cross-talk) [82], CB2 receptors (resulting in a negative cross-talk and cross-antagonism in neuronal cells) [83], adrenergic ß2 receptor (inducing internalization of CB1 receptors) [84], and 5HT2A serotonin receptor [85], cannabinoid-related orphan receptor GPR55 [86] and several others (discussed in [87]). Information about the interaction of CB2 receptor with other receptors is scarce; CB2 forms heterodimers with CB1 (see above) as well as with GPR55 [88] and CXCR4 [89].
Above-mentioned interactions typically result in changes in the function of receptors or produce negative cross-talks; therefore, if such changes occur in cancer cells, they can significantly alter response of cancer cells to endocannabinoids. Indeed, CB1/CB2, CB2/CXCR4, CB2/GPR55 and CB2/HER2 heteromers have been found in breast and prostate cancer cells [89–91]. Increased levels of endocannabinoids (anandamide in colon cancer) and increased level of receptors and their dimerization in cancer are paralleled by elevated levels of degradation enzymes, FAAH and MAGL [92,93].
The contribution of cannabinoid receptors to cancer development as well as their relationship to the prognosis and therapy response is still not entirely clear. The lack of strong correlation between the expression of cannabinoid receptors and cancer progression paralleled by inhibition of cancer growth in response to treatment with cannabinoids may suggest that cannabinoids’ effect on cancer may also be triggered through cytoplasmic effects rather than only through the direct involvement of transmembrane CB1/CB2 receptors. The CB1/CB2 receptor activation in response to cannabinoids observed in cancers could either be part of the feedback mechanism or completely unrelated. Regardless of the mechanism, research data have demonstrated positive effects of cannabinoids on cancer progression, including proliferation, viability, vascularization and invasiveness (reviewed in [94]). Below, we will describe the impact of cannabinoids on various cancers and summarize the details in Table 2.
Table 2. The effect of various cannabinoids on cancer cells in vitro and in vivo.
Download CSVDisplay Table
The effects of CBD on cancer
CBD has been shown to have effects on glioblastoma, leukemia, lung cancer, breast cancer, cervical cancer, prostate cancer, and melanoma (see Table 2). CBD inhibits cell growth and migration, causes apoptosis of cancer cells and inhibits their invasion [95–98]. It also downregulates GSC self-renewal [99] and angiogenesis [96,100,101] in glioblastoma. Inhibition of angiogenesis was demonstrated on the level of cell proliferation and on the level of whole organisms in induced tumor models [102]. Multiple mechanisms of inhibition of angiogenesis were demonstrated, including cytostasis of endothelial cells, inhibition of endothelial cell migration, inhibition of invasion and sprouting in vitro and down-regulation of pro-angiogenic factors. All these effects are likely associated with a down-regulation of MMP2 and MMP9, urokinase-type plasminogen activator (uPA), endothelin-1 (ET-1), platelet-derived growth factor-AA (PDGF-AA) and chemokine (c-x-c motif) ligand 16 (CXCL16), molecules associated with angiogenesis [102].
The effect on CBD on cancer is most well studied in glioblastoma models. The following glioblastoma lines have been used for treatment with CBD: U87, U373, U251, GSC 3832, GSC 387, SF126, T98 G, U87 MG, and GL261. The IC50 varied from 0.125 to 5.0 µM. Similarly, CBD was used to treat athymic nude mice xenografted with U87, U251, GSC3832, or GSC387. The amounts of 15 mg/kg to 20 mg/kg (0.5 mg/mouse) administered over 18–28 days were shown to be effective in tumor reduction and prolonging the overall survival of treated animals [96,99,103,104] (Table 2).
CBD has been shown to downregulate leukemia cell viability and upregulate apoptosis, and these effects have also been observed in vivo where CBD downregulates tumor growth and upregulates apoptosis [105]. Treatment of leukemia with CBD upregulates the accumulation of P-glycoprotein substrate and increases cytotoxic effects of vinblastine [106]. CBD also inhibits the growth of EL-4 (mouse lymphoma), Jurkat, and MOLT-4 cells at concentrations of 2.5–10.0 µM [105]. In lung cancer, CBD has been shown to downregulate tumor invasion, metastasis and growth [107–109]. Invasion is inhibited in vitro and in vivo during CBD treatment of A549 lung cancer cells [110,111]. CBD downregulates colony formation and migration of cancer cells [112] and increases survival in a mouse model of human breast cancer [113]. In MDA-MB-231 breast cancer cells, CBD blocks the lisophosphatidylinositol-stimulated cell migration and invasion [114,115]. In mice xenografted with 4T1, a mammary metastatic cell line, CBD reduces a primary tumor size and lung metastasis [97,116]. In cervical cancer, invasion and metastasis are downregulated by CBD [108], and CBD halts cell proliferation and increases apoptosis (Figure 3) [117]. CBD downregulates cell viability and tumor growth in prostate cancer and affects the antitumor activity of first-line agents [118] (Table 2).
Figure 3. Molecular aspects of anti-cancer effects of CBD. The effect of CBD on glioblastoma is in part mediated through CB1, CB2 and TRPV1 receptors. This leads to the increased levels of cytochrome c, caspase 3 and ROS as well as decreased levels of glutathione and increase expression of ERK and mTOR. More downstream effects include: decrease in stemness due to the decrease in Id1, Sox2 and p-STAT3; decrease in cancer aggressiveness due to the decrease in pAkt; decrease in proliferation due to the decrease in Ki67. The effect on colon cancer is in part mediated through GPR55 which leads to the decrease in adhesion and migration. The effect on leukemia is mediated through CB2 receptor which leads to inhibition of PARP, increased levels of Nox4 and p22phox and reduced levels of pp38MAPK, resulting in increased frequency of apoptosis. In cervical cancer and lung cancer, CBD activates CB1, CB2 and TRPV1 receptors leading in part to upregulation of COX-2. The proapoptotic activity of CBD in lung cancer is associated with the upregulation of COX-2 and activation of PPAR? by the COX-2-derived products PGD2 and 15d-PGJ2. CBD exposure also leads to upregulation of pp38 and pp42/44 which in turn likely upregulates the TIMP-1 expression. TIMP-1 forms inhibitory complexes with MMP-2 and MMP-9 leading to inhibition of cancer invasiveness.
Display full size
Massi et al. [119] suggest that CBD effects on glioblastoma are likely mediated through a CB1-, CB2-, and TRPV1-independent pathway involving the upregulation of caspase 3, cytochrome c, and ROS as well as a decrease in glutathione [119] (Figure 3). Many cancers have also been shown to overexpress GPR55 [78], and exposure of the metastatic colon cancer cell line HCT116 to cannabidiol reveals a substantial reduction in adhesion and migration, which is inhibited when GPR55 is knocked down by siRNA [120]. However, studies on CBD’s effects on leukemia, namely on EL-4 cells and Jurkat cells, have shown that the enhanced apoptosis and decreased PARP expression is CB2 receptor-dependent since the CB2-selective antagonist inhibits the reduction of cell viability [105]. It has been shown that CBD increases the levels of Nox4 and p22phox and decreases the amount of phosphorylated p38 MAPK (pp38). Similarly, Ramer et al. (2010a) have demonstrated that the CBD-induced antitumor effect is reversed by antagonists to CB1, CB2, and TRPV1 receptors in cervical and lung cancer [108]. CBD has also appeared to upregulate the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), and the siRNA-mediated knockdown of TIMP-1 reverses the effect of CBD on tumor cells invasiveness (Figure 3) [108]. In contrast to the report of McKallip et al. [105], CBD exposure resulted in the upregulation of pp38; both pp38 and pp42/44 appeared to be the upstream targets that likely regulate the TIMP-1 expression [108]. TIMP-1 inhibits cancer cell invasiveness by forming inhibitory complexes with MMP-2 and MMP-9 [111]. The proapoptotic activity of CBD is associated with the upregulation of COX-2 and activation of PPAR? by the COX-2-derived products PGD2 and 15d-PGJ2 [107]. Pretreating cancer cells with the PPAR? inhibitor GW9662 reduces cancer cell apoptosis. CBD also affects cell metabolism as indicated by changes in reactive oxygen species (ROS) produced in the mitochondria [17]. High levels of ROS production have been associated with triggering apoptosis [121], and CBD modulates ROS and ERK pathways to down-regulate Id-1 [97,116]. Furthermore, pretreatment with antioxidants N-acetyl cysteine and a-tocopherol diminishes the pro-apoptotic effect of CBD.
Moreover, CBD inhibits the self-renewal and stemness. Stem cell key regulators such as Id1, Sox2, and p-STAT3 are inhibited by CBD in a ROS-dependent manner. The transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of glioblastoma; the overexpression of Id1 promotes a stem-like phenotype [96]. By silencing the marker of stemness, Sox2 has been shown to stop the proliferation and lead to the loss of tumorigenicity in vivo [122]. CBD also upregulates mTOR, reduces the expression of PLCG1 [96] and inhibits pAKT (a marker of glioblastoma aggressiveness) and Ki67 (a marker of proliferation) [99].
In vivo effects were shown to be mediated through the lipoxygenase (LOX) pathway, specifically through the lipoxygenase-catalyzed arachidonic acid metabolism [103,104,119]. Massi et al. (2008) have demonstrated the importance of LOX and COX pathways and the endocannabinoid system in controlling tumor growth. In vivo in the CBD-treated tumor tissues, CBD augments NRF2, an activator of the antioxidant response element (ARE) present in the promoters of ROS-detoxifying enzymes, including NQO1, GST, HMOX-1, and xCT [99]. xCT, a critical determinant of growth and invasion of cancer cells, regulates cysteine metabolism.
Finally, it is important to stress out that different processes of cancer growth and stages of cancer can be affected by cannabinoids in different manner. Proliferation, migration, invasiveness and metastases are affected differently. For example, recent work using CBD and synthetic CB ligands demonstrated that glioblastoma cell invasion can be inhibited in a receptor and cell type specific manner that is independent of proliferation and apoptosis [123].
The effects of THC treatment
Like CBD, THC has been shown to have effects on glioblastoma, breast cancer, oral cancer, lung cancer, lymphoma, and leukemia. THC inhibits proliferation, upregulates apoptosis, downregulates angiogenesis, induces autophagy, inhibits cell migration and metastasis. Notably, the THC-induced cell growth inhibitory effects and suppression of tumor growth in xenografted tumors have been achieved at higher concentrations when compared to the effects of CBD (Table 2). THC upregulates apoptosis, downregulates angiogenesis [101] and increases autophagy in glioblastoma [124]. It also shows pro-apoptotic, anti-proliferative, anti-angiogenic and anti-invasive effects in vitro and in vivo in breast cancer cells ErbB2 [125–127]. In glioblastoma, THC reduces cell viability and tumor growth; THC combined with the chemotherapeutic agent temozolomide (TMZ) enhances the antitumor activity of TMZ in tumor xenografts [128]. When combined with synthetic cannabinoids, THC has various effects on glioblastoma growth [129–132]. In breast cancer, ?9-THC inhibits the proliferation of MCF7 and MCF7-AR1 cell lines [133–136], as well as the proliferation of estrogen receptor-negative/progesterone receptor-positive breast cancer cells [134,137–139]. In oral squamous cell carcinoma, ?9-THC induces apoptosis [140]. In A549 and SW-1573 non-small cell lung cancer cells, THC inhibits the EGF-induced invasion, tumor growth, and lung metastasis in an in vivo mouse model injected with A549 cells [140,141]. ?9-THC inhibits cell viability, increases apoptosis in lymphoma [142] and induces apoptosis when combined with other cytotoxic agents [143]. THC also increases the sensitivity of leukemia cells to chemotherapy [143].
THC’s anticancer effects appear to be directly related to its ability to bind to CB1, CB2, and other G protein-coupled receptors. In contrast to CBD, THC causes tumor cell death by directly engaging these receptors [119,144]. The activation of CB1/CB2 receptors triggers the accumulation of ceramide, activating autophagy and apoptosis [124]. The link between the THC-dependent activation of CB receptors and the activation of apoptosis through the ceramide pathway has been supported by the following experiments: pretreatment with CB1 and CB2 specific receptor antagonists SR141716 (SR1) and SR144528 (SR2), respectively, prevents apoptosis; the inhibition of serine palmitoyl-transferase which is an enzyme that catalyzes the first step of ceramide biosynthesis by ISP-1 also prevents apoptosis; and the pharmacologic or genetic inhibition of autophagy prevents the efficient induction of glioma cell death by THC [128]. Curiously, none of these events prevents the CBD-induced apoptosis. In contrast to the effect of CBD, the manipulation of the antioxidant machinery does have a significant effect on apoptosis in treatments with THC, further indicating that THC and CBD trigger glioma cell death through different pathways [128].
Regarding the molecular mechanisms of action, THC, like CBD, results in the downregulation of Id1 [145], the inhibition of the AKT and ERK [106,143] pathways, and an increase in caspase-3 levels [141]. Furthermore, THC, in some of the studies, down-regulates MMP-2, matrix metalloproteinase which promotes cell migration in glioblastoma [130], upregulates the components of the ER stress pathway, namely p8 and TRB3, decreases S6 phosphorylation, inhibits Akt and mTORC via TRB3, and reduces p70S6 kinase phosphorylation (mTORC1 substrate) by triggering autophagy in glioblastoma [124] (Figure 4). The activation of the ER stress pathway and autophagy appears to be a critical component of the inhibition of THC-induced tumor growth as autophagy-deficient tumors do not respond to the growth-inhibiting activity of THC. Additionally, exposure to ISP-1 prevents the THC-induced ER dilation, eIF2a phosphorylation, the upregulation of p8, ATF4, CHOP, and TRB3, and autophagy, thus further supporting the importance of the de novo synthesis and ceramide accumulation for the THC-induced action. Support for the role of eIF2a phosphorylation at Ser51 and the regulation of p8 expression and its downstream targets in response to THC has come from studies using eIF2a S51A knock-in mice; cells from these mice lack the upregulation of p8, ATF4, CHOP and TRB3 as well as autophagy in response to THC. Similarly, siRNAs against p8 are also effective in abrogating autophagy in response to THC. THC also induces caspase-3 in an ATG1-, ATG5-, and AMBRA1-dependent manner because the selective knockdown of these genes prevents caspase-3 activation and THC-induced apoptosis (Figure 4).
Figure 4. Molecular aspects of anti-cancer effects of THC. The effect of THC on leukemia is in part mediated through CB1, CB2 receptors. Binding of THC to these receptors leads to downregulation of pAct and Erc and decreases in cancer aggressiveness. The effect on glioblastoma is mediated through CB1 receptor. The activation of CB1 receptors triggers the accumulation of ceramide, leading to eIF2a phosphorylation, the upregulation of p8, ATF4, CHOP, and TRB3, and resulting in autophagy. TRB3 can also inhibit Akt, which in turn leads to the decreased in the expression of mTORC and reduction in the phosphorylated form of 70S6 kinase, also leading to autophagy. THC, in some of the studies, down-regulates Id1 leading to decrease in stemness and MMP-2 (matrix metalloproteinase) leading to the change in cell migration. ISP1, eIF2a S51A, sip8 and siTRB3 inhibit this process at multiple steps.
Display full size
The effects of combining CBD and THC treatment
THC and CBD are definitely not similar in their influence on various cancers and cancer stages. Very little is known about it, however. Due to different levels of affinity of CBD and THC for cannabinoid receptors and effects on other receptors, combining CBD and THC in one treatment may be beneficial for cancer therapy. The effects of combination therapy with CBD and THC have been reported in glioblastoma and melanoma. Treating a U87 MG mouse xenografted with 7.5 mg/kg of THC and CBD has been demonstrated to be more effective in reducing tumor growth than THC or CBD alone [128]. The combination of CBD and THC enhances the antitumor effect of oral chemotherapy drug temozolomide (TMZ) on glioblastoma [128]. Using T98 G, U87 MG and GL261 glioblastoma cells, Scott et al. (2014) have demonstrated that adding a THC/CBD mixture potentiates the effect of gamma radiation on apoptosis [101]. However, in glioblastoma, combining 0.1 µM of THC and CBD downregulates cell viability and invasion and upregulates apoptosis, but this effect is not larger than the effect observed with either cannabinoid alone [145].
In melanoma, CBD combined with THC downregulates cell viability and tumor growth; 1.0 µM THC and CBD has a similar effect on apoptosis as 5.0 µM of CBD or THC alone [146]. More recently, treating HL60 leukemia cells with CBD and THC has revealed that they have a superior effect when used together compared to being used alone, and they are synergistic with the anti-leukemia drugs cytarabine and vincristine [147] (Table 2). The greatest induction of apoptosis occurs when chemotherapy is followed by cannabinoid administration. Combining CBD, THC and cytotoxic drugs sensitize leukemia to cytotoxic effects and reduce the therapeutic dose of anti-leukemia drugs.
The effects of CBN, CBG and CBC treatments
Cannabinol (CBN) is a weak agonist at CB1 and CB2 receptors and is a metabolite of ?9-THC [148]. CBN has been demonstrated to increase the animal survival rate in mice xenografted with Lewis lung adenocarcinoma by 27% [149]. CBN inhibits the proliferation of MDA-MB231 and MDA-MB436 breast cancer cells by decreasing Id1 expression [116], but it increases the proliferation of human MCF-7 breast cancer cells through Her2 upregulation [150,151]. Cannabigerol (CBG), a less common phytocannabinoid than CBD and THC, has been shown to have an effect on colorectal cancer. It increases apoptosis in Caco-2 and HCT 116 cells through ROS production and selectively inhibits the growth of colorectal cancer in an HCT 116 xenograft likely via TRPM8 [152]. CBG has also shown its activity in breast and prostate cancer cells [153].
Cannabichromene (CBC) is another relatively rare cannabinoid that also exhibits the anticancer activity; the relatively high potency has been shown in breast cancer and prostate cancer. The IC50 for MCF-7 and MDA-MB-231 breast cancer cells and DU-145 prostate cancer cells were 14.2 and 20.4 µM [153]. CBC has been shown to have a stronger anticancer activity than THC but lower than CBG [153].
The effects of treatment with THC-A
THCA is a precursor of THC; it is abundant in cannabis but is converted to THC through heat-induced decarboxylation, a process that occurs during the combustion of cannabis flowers (smoking) or during the oil extraction and cooking processes to obtain cannabis-infused oils and edibles. Some data related to the effect of THCA on cancer are scarce, but THCA has been shown to decrease cell proliferation in MCF-7 and MDA-MB-231 breast cancer cells and DU-145 prostate cancer cells, with IC50 9.8 µM, 18.2 µM and approximately 25 µM, respectively [153].
The effects of endocannabinoids and cannabinoid analogues
Endocannabinoids demonstrate a higher efficacy in binding to cannabinoid receptors than phytocannabinoids. Both AEA and 2-AG have been shown to be more active than ?9-THC at CB1 and CB2 receptors (reviewed in [41]). Among endocannabinoids, the effect of AEA on cancer cells is better studied than the effect of 2-AG. AEA has been shown to be active against the human breast cancer line MCF7 [133–135] as well as the human prostate cancer line DU-145 [133], with an IC50 of 1.0–1.4 µM. Specifically, AEA inhibits the proliferation of HBCC breast cancer cells and prostate cancer DU-145 cells by down-regulation of prolactin receptor PRL [133]. AEA inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 µM; AEA did not result in cell toxicity or apoptosis but rather due to the cell cycle arrest – reduction of cells in the S phase of the cell cycle [133–135]. Similarly, 2-AG has also been able to inhibit the proliferation of human breast cancer MCF7 cells and also through the long-form PRL receptor [133]. In addition, 2-AG inhibited proliferation of pancreatic ductal adenocarcinoma cells and promoted an immunosuppressive microenvironment via increasing the suppressive immune cell population of myeloid-derived suppressor cells [154]. AEA at a concentration of 5.0 µM reduces the growth of MCL lymphoma cells [142].
A metabolically stable analogue of anandamide, Met-F-AEA, has been shown to be active against NPA and ARO thyroid carcinoma cell lines where it causes a 50% decrease in cell growth at a concentration of 5.0 µM [155].
Several synthetic cannabinoids have been developed, and both their affinity for cannabinoid receptors and their activity in cancer cell lines have been tested. For example, HU-210, CP55940 and R-(+)-WIN55212 synthetic cannabinoids have been shown to have a higher CB1 and CB2 agonist efficacy than ?9-THC. WIN-55,212–2 is an aminoalkylindole derivative with a chemical formula completely different from endocannabinoids. WIN-55,212–2 is a highly potent CB1, CB2 and TRPV1 receptor agonist [156] that has demonstrated its activity against C6.9 glioma cells [131], MDA-MB-231 breast cancer cells at 10.0 µM [157], human melanoma B16 cells [158], ARO cells of thyroid cancer [159], an NCTC-2472 bone cancer cell xenograft [160], and MCL lymphoma cells [142,161], with IC50 s ranging from 1.0 to 15.0 µM. WIN-55,212–2 and R(+)-methanandamide have been shown to induce apoptosis in MCL lymphoma cells [162], and WIN-55,212–2 also causes paraptosis in MCL lymphoma cells [161].
JWH-015 [163] and JWH-133 [164] are CB2 selective agonists (over 200-fold over CB1). JWH-133 has been shown to inhibit C6.9 glioma xenograft growth [130] and ARO cell thyroid carcinoma in mice [159]. Other chemicals in the JWH series, JWH-015, JWH-018, JWH-073, JWH-122 and JWH-210 also exhibit antiestrogenic and anticancer properties, including inhibiting growth in MCF-7 and MDA-MB-231 breast cancer [163,165], MIA PaCa2 pancreatic cell xenografts [132] and 66.1 bone cancer xenografts [166]. Like THC, JWN-133 appears to regulate tumor growth through the ceramide biosynthetic pathway and downregulate MMP-2 because the application of fumonisin B1 appears to abrogate tumor growth and regulate the aforementioned pathways.
KM-233 is a structural analog of ?8-THC with an affinity for CB2 and CB1 receptors; the affinity to the former is greater by approximately13-fold [167]. KM-233 reduces the growth of U87 MG glioma xenografts by 80% over the 20-day application period [168]. Its action appeared to be similar to the activity of THC; treating U87 MG glioma cells with KM-233 causes a time-dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3 and p70S6 K, as well as an increase in cleaved caspase 3 [168].
Other analogues include O-1663, Hu-210 and arachidonyl-2'-chloroethylamide (ACEA). O-1663 is a non-classical cannabinoid and a derivative of CBD. Its activity was found to be higher than that of CBD in inhibiting the growth of MDA-MB-231 and 4T1 breast cancer cells, reducing tumor growth and preventing metastases in a 4T1 xenograft model [113]. Hu-210 is a synthetic cannabinoid with an activity up to 800-fold higher than that of THC [169]. Hu-210 functions as a CB1/CB2 agonist and inhibits DU-145 prostate cancer cell growth at lower concentrations than anandamide [133]. Arachidonyl-2'-chloroethylamide (ACEA) is a synthetic preferential agonist of the CB1 receptor [170]. ACEA decreases the proliferation of MIA PaCa2 pancreatic cancer cells [171].
Comparing the effects of pure cannabinoids and cannabis extracts
A great majority of the data on the effects cannabinoids on cancer are obtained from experiments that use phytocannabinoids, endocannabinoids and synthetic cannabinoids in their pure form. Very few reports have demonstrated the effect of actual cannabis extracts on cancer cells. Armstrong et al. (2015) have demonstrated that THC-enriched extracts are nearly twice as efficient in treating CHL-1 xenografts in mice than pure THC; a comparable reduction in tumor growth has been achieved with 7.5 mg/kg of THC-enriched extracts and 15 mg/kg of THC only [146]. Similarly, the effect of cannabis extract enriched with ~70% of CBD is more potent in inhibiting cell proliferation than a pure CBD compound [153]. Finally, in a reasonably comprehensive study, the effect of CBD, THC, CBN, CBG, CBC, CBDV, THCV, CBGV, THCA, THCVA and CBGA cannabinoids has been compared to the effect of cannabis extracts enriched with the corresponding cannabinoids; it has been observed that the enriched extracts have a significantly stronger effect on the growth of DU-145 and LNCaP human prostate cancer cells [118]. More recently, the effect of 12 different extracts was tested on 12 different cancer cell lines; there was a positive correlation observed between the level of THC in extracts and the anti-cancer properties of these extracts on A549 adenocarcinomic human alveolar basal epithelial cells [172]. Comparison to the effect of pure THC demonstrated that most of the extracts had much stronger anti-cancer effect [172]. Thus, it appears that the anticancer properties of extracts are more potent than those of pure cannabinoids.
The effect of full extracts in comparison to purified cannabinoids can be explained by the presence of other molecules, such as terpenoids, flavonoids, amino acids, sugars and other molecules. The additional effect of molecules besides cannabinoids is often called “the entourage effect.” It is believed that this effect is mainly caused by terpenoids, but this is not well documented. Terpenoids alone exhibit anti-cancer properties. Limonene inhibits the development of chemically induced rodent cancers, including skin, liver and mammary gland [173], induces autophagy [174] and activates immune system by inducing NO production (reviewed in [173]). Little to no information exists on potential synergism between cannabinoids and terpenoids in terms of their anti-cancer properties. One report demonstrated that CBN capacity to inhibit breast cancer cell growth by the inhibition of breast cancer resistance protein (BCRP, an ABC transporter) was potentiated by limonene [175]. On the other hand, botanical extract prepared from dry flowers was more potent for the inhibition of triple-negative breast cancer cells in vitro and in vivo as compared to pure THC, and reconstitution experiment using pure THC supplemented with top five most abundant terpenoids (ß-caryophyllene, linalool, a-humulene, nerolidol 1 and ß-pinene), present in the extract did not demonstrate an additive effect [176]. Therefore, much more effort is needed to demonstrate whether the entourage effect is due to the presence of terpenoids or other molecules.
Clinical trials
Clinical trials have begun to determine the effects of cannabinoid formulations in humans. The results of very few clinical trials are published in order to conclude whether cannabis or/and cannabinoids are effective for treatment of cancer. The route of administration is important and can include direct tumor injection, ingestion, inhaling, transdermal and others. Bioavailability of cannabinoids and terpenoids directly depend on the mode of administration; ingestion results in as a little as 6–20% of all active compounds reaching bloodstream [177], whereas upon inhaling 10–60% becomes bioavailable [178,179]. Onset time and duration of action also differ; whereas inhalation leads to the onset within minutes and lasts only couple hours, oral administration results in onset at 60–90 min with the effects lasting 6–8 h [180]. Therefore, direct comparison of the effectiveness of specific formulation is only possible if the administration route is similar.
An early Phase 1 study was conducted in which recurrent glioblastoma patients who had failed standard therapy were administered THC intracranially; under these conditions, THC administration was safe and no significant adverse effects were reported [181]. Since the analysis of the safety of intracranial THC administration was the primary goal of the study, no comparison group between THC treatment and controls were established to demonstrate the efficacy. Some patients responded to THC treatment, however, overall, no significant clinical benefit was observed; samples obtained pre- and post-treatment indicated that the mechanisms previously defined in mouse models were activated in these patients [181].
A Phase 2 safety study of Sativex in combination with TMZ (NCT01812603) was conducted in patients with grade 4 glioblastoma multiforme exposed to the maximum tolerated dose of Sativex, a spray that contained a 1:1 ratio of ?9-THC and CBD. The study has confirmed the feasibility and safety of individualized dosing and provided preliminary evidence that Sativex combined with temozolomide offers some efficacy in patients with recurrent glioblastoma multiforme because the one-year survival rate has been higher in the treatment group than placebo [182]. Since many glioblastoma patients display a resistance to TMZ [183], this is likely clinically relevant.
Other studies have investigated the safety of synthetic cannabinoid formulations in patients with solid tumors (NCT01489826, NCT02423239), but these studies have not yet been completed. A double-blind, placebo-controlled clinical trial has been set to begin the investigation of the effects of cannabis for pain and inflammation in patients receiving radiation therapy for lung cancer (NCT02675842). The results of upcoming clinical trials will help guide future research in the field of cannabinoids and cancer treatment in humans.
Conclusions
Cannabinoids have great promise. Although the exact mechanism is not understood, in some models, cannabinoids have been shown to decrease cancer cell growth and invasion, and similar effects have been observed in mouse models. More research is necessary to investigate whether there is a role for cannabinoids in treatment of cancer in humans. For example, T98 G has much higher MGMT expression and methylation levels and is much more resistant to TMZ than U87 MG; nevertheless, combining THC with TMZ greatly reduces tumor growth in T98 G xenografts, while no effect has been observed in either therapy alone [128].
It appears that an increase in the CB1 and CB2 receptor expression may be beneficial for cancer cell response to phytocannabinoids. Therefore, chemicals that increase the density of these receptors in cancer cells may function synergistically with cannabinoids, such as THC and CBD. However, caution needs to be exercised because both THC and CBD have the activity of partial antagonists, and in some cancers, an overall increase in the CB1/CB2 expression may increase an antagonistic effect of THC/CBD, leaving the agonistic effect intact. It should also be noted that repeated exposure to THC may lower the density of cannabinoid receptors in neurons, which is especially noticeable for the CB1 receptor, resulting in tolerance and a reduced efficiency of THC in triggering a therapeutic effect [184]. It remains to be shown whether a similar effect is observed in cancer cells.
In addition, caution must be exercised as to the potential negative effect of cannabinoids on healthy tissues surrounding tumor or on entire organism. Due to the versatility of cannabinoids in binding multiple receptors and activating/inhibiting multiple signaling pathways, their effect on healthy tissues may be unpredictable and more studies are needed, using in vitro and in vivo models, to ensure that we are aware of all potential negative effects of these molecules when they are used in cancer therapy.
Immune system plays a critical role in prevention of malignization and immunotherapy nowadays is one of the therapies of choice for many cancers. Due to the modulating effect of CBD on immune system [185], it can potentially interfere with immunotherapy. Very few reports suggest that [186] and therefore studies are needed to demonstrate what immunotherapy drug if any can be used in combination with cannabinoids in general, and with CBD in particular, for treatment of cancer.
The use of cannabinoids to alleviate side-effects, such as lack of appetite, nausea and pain is also an important direction of research and potential clinical trials. Similarly, the use of cannabinoids for potentiation of the effects of chemo- or radiotherapy is also understudied; in this case, cannabinoids may allow to decrease the amount of chemotherapy drug or dose of radiation to achieve the same anti-cancer effect and at the same time to decrease potential side-effects.
Finally, it remains to be shown whether cancers in males and females respond to cannabis in a different manner and whether there are specific combinations of cannabinoids and terpenoids that are better suitable for females or males.
Disclosure statement
Authors are co-founders of Pathway Rx Inc, a research and development start-up company in the field of medical cannabis.
Highlights
Endocannabinoids and phytocannabinoids can be used for cancer therapy
Cannabis extracts have stronger anti-tumor capacity than single cannabinoids
Combination of several cannabinoids may have more potent effect on cancer.
Author contributions
Authors contributed equally to data collection, analysis and manuscript preparation.
Additional information
Funding
We acknowledge NSERC CRD and MITACS grants to IK and OK.
Previous article
View issue table of contents
Next article
References
Fonseca BM, Teixeira NA, Correia-da-Silva G. Cannabinoids as modulators of cell death: clinical applications and future directions. Rev Physiol Biochem Pharmacol. 2017;173:63–88. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Fellermeier M, Eisenreich W, Bacher A, et al. Biosynthesis of cannabinoids. Incorporation experiments with (13)C-labeled glucoses. Eur J Biochem. 2001;268(6):1596–1604. [Crossref], [PubMed], [Google Scholar]
Huang WJ, Chen WW, Zhang X. Endocannabinoid system: role in depression, reward and pain control (Review). Mol Med Rep. 2016;14(4):2899–2903. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17(14):1468–1486. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Le Boisselier R, Alexandre J, Lelong-Boulouard V, et al. Focus on cannabinoids and synthetic cannabinoids. Clin Pharmacol Ther. 2017;101(2):220–229. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Aizpurua-Olaizola O, Soydaner U, Ozturk E, et al. Evolution of the cannabinoid and terpene content during the growth of cannabis sativa plants from different chemotypes. J Nat Prod. 2016;79(2):324–331. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Russo EB, Taming THC. Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–1364. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Mackie K. Cannabinoid receptor homo- and heterodimerization. Life Sci. 2005;77(14):1667–1673. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 2011;50(2):193–211. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(Suppl 1):10–14. [Crossref], [PubMed], [Google Scholar]
Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459(7245):356–363. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Nogueras-Ortiz C, Yudowski GA. The multiple waves of cannabinoid 1 receptor signaling. Mol Pharmacol. 2016;90(5):620–626. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Flores-Otero J, Ahn KH, Delgado-Peraza F, et al. Ligand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1. Nat Commun. 2014;5:4589. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ahn KH, Mahmoud MM, Shim JY, et al. Distinct roles of beta-arrestin 1 and beta-arrestin 2 in ORG27569-induced biased signaling and internalization of the cannabinoid receptor 1 (CB1). J Biol Chem. 2013;288(14):9790–9800. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Rozenfeld R, Devi LA. Regulation of CB1 cannabinoid receptor trafficking by the adaptor protein AP-3. Faseb J. 2008;22(7):2311–2322. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Chakravarti B, Ravi J, GR K. 2014 cannabinoid targets in cancer.pdf. Oncotarget. 2014;5:15. [Google Scholar]
Howlett AC, Mukhopadhyay S. Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem Phys Lipids. 2000;108(1–2):53–70. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Gifford AN, Makriyannis A, Volkow ND, et al. In vivo imaging of the brain cannabinoid receptor. Chem Phys Lipids. 2002;121(1–2):65–72. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Normandin MD, Zheng MQ, Lin KS, et al. Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test-retest reproducibility, and gender differences. J Cereb Blood Flow Metab. 2015;35(8):1313–1322. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Van Laere K, Goffin K, Casteels C, et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET. Neuroimage. 2008;39(4):1533–1541. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. 1998;38:179–200. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Nunez E, Benito C, Pazos MR, et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53(4):208–213. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ramirez BG, Blazquez C, Gomez del Pulgar T, et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25(8):1904–1913. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Cabral GA, Marciano-Cabral F. Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol. 2005;78(6):1192–1197. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Zoratti C, Kipmen-Korgun D, Osibow K, et al. Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. Br J Pharmacol. 2003;140(8):1351–1362. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Basu S, Dittel BN. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol Res. 2011;51(1):26–38. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Basu S, Ray A, Dittel BN. Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses. J Immunol. 2011;187(11):5720–5732. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Burnette-Curley D, Cabral GA. Differential inhibition of RAW264.7 macrophage tumoricidal activity by delta 9tetrahydrocannabinol. Proc Soc Exp Biol Med. 1995;210(1):64–76. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Robinson RH, Meissler JJ, Breslow-Deckman JM, et al. Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction. J Neuroimmune Pharmacol. 2013;8(5):1239–1250. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Karmaus PW, Chen W, Kaplan BL, et al. Delta9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events. J Neuroimmune Pharmacol. 2012;7(4):843–855. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):4–15. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2018;11:487. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ryberg E, Larsson N, Sjogren S, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092–1101. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Shen B, Estevez B, Xu Z, et al. The interaction of Galpha13 with integrin beta1 mediates cell migration by dynamic regulation of RhoA. Mol Biol Cell. 2015;26(20):3658–3670. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol. 2002;118(1):110–121. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Smart D, Gunthorpe MJ, Jerman JC, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol. 2000;129(2):227–230. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
De Petrocellis L, Starowicz K, Moriello AS, et al. Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids. Exp Cell Res. 2007;313(9):1911–1920. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479–1494. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Iwamura H, Suzuki H, Ueda Y, et al. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J Pharmacol Exp Ther. 2001;296(2):420–425. [PubMed], [Web of Science ®], [Google Scholar]
Patel S, Hillard CJ. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther. 2006;318(1):304–311. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Sim LJ, Hampson RE, Deadwyler SA, et al. Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPgammaS autoradiography in rat brain. J Neurosci. 1996;16(24):8057–8066. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Straiker A, Mackie K. Depolarization-induced suppression of excitation in murine autaptic hippocampal neurones. J Physiol. 2005;569(Pt 2):501–517. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Kluger B, Triolo P, Jones W, et al. The therapeutic potential of cannabinoids for movement disorders. Mov Disord. 2015;30(3):313–327. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Thomas A, Baillie GL, Phillips AM, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613–623. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Cascio MG, Gauson LA, Stevenson LA, et al. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol. 2010;159(1):129–141. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Thomas A, Stevenson LA, Wease KN, et al. Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol. 2005;146(7):917–926. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Bolognini D, Costa B, Maione S, et al. The plant cannabinoid Delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol. 2010;160(3):677–687. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Calakos KC, Bhatt S, Foster DW, et al. Mechanisms underlying sex differences in cannabis use. Curr Addict Rep. 2017;4(4):439–453. [Crossref], [PubMed], [Google Scholar]
Sherman BJ, McRae-Clark AL, Baker NL, et al. Gender differences among treatment-seeking adults with cannabis use disorder: clinical profiles of women and men enrolled in the achieving cannabis cessation-evaluating N-acetylcysteine treatment (ACCENT) study. Am J Addict. 2017;26(2):136–144. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Penetar DM, Kouri EM, Gross MM, et al. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend. 2005;79(2):211–223. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Mathew RJ, Wilson WH, Davis R. Postural syncope after marijuana: a transcranial Doppler study of the hemodynamics. Pharmacol Biochem Behav. 2003;75(2):309–318. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Kaufmann RM, Kraft B, Frey R, et al. Acute psychotropic effects of oral cannabis extract with a defined content of Delta9-tetrahydrocannabinol (THC) in healthy volunteers. Pharmacopsychiatry. 2010;43(1):24–32. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Xie S, Borazjani A, Hatfield MJ, et al. Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes/macrophages by activated organophosphorus insecticides: role of carboxylesterases 1 and 2. Chem Res Toxicol. 2010;23(12):1890–1904. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Tsuboi K, Uyama T, Okamoto Y, et al. Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflamm Regen. 2018;38:28. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. 2012;7(4):149–156. [PubMed], [Google Scholar]
Harvey DJ, Mechoulam R. Metabolites of cannabidiol identified in human urine. Xenobiotica. 1990;20(3):303–320. [Taylor & Francis Online], [Web of Science ®], [Google Scholar]
Hryhorowicz S, Walczak M, Zakerska-Banaszak O, et al. Pharmacogenetics of cannabinoids. Eur J Drug Metab Pharmacokinet. 2018;43(1):1–12. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Narimatsu S, Watanabe K, Yamamoto I, et al. Sex difference in the oxidative metabolism of delta 9-tetrahydrocannabinol in the rat. Biochem Pharmacol. 1991;41(8):1187–1194. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Tseng AH, Harding JW, Craft RM. Pharmacokinetic factors in sex differences in Delta 9-tetrahydrocannabinol-induced behavioral effects in rats. Behav Brain Res. 2004;154(1):77–83. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Klumpers LE, Cole DM, Khalili-Mahani N, et al. Manipulating brain connectivity with delta(9)-tetrahydrocannabinol: a pharmacological resting state FMRI study. Neuroimage. 2012;63(3):1701–1711. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacol Rev. 2011;63(3):461–470. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
De Laurentiis A, Araujo HA, Rettori V. Role of the endocannabinoid system in the neuroendocrine responses to inflammation. Curr Pharm Des. 2014;20(29):4697–4706. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Galve-Roperh I, Chiurchiu V, Diaz-Alonso J, et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res. 2013;52(4):633–650. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ligresti A, Bisogno T, Matias I, et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology. 2003;125(3):677–687. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Cianchi F, Papucci L, Schiavone N, et al. Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res. 2008;14(23):7691–7700. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Xu X, Liu Y, Huang S, et al. Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma. Cancer Genet Cytogenet. 2006;171(1):31–38. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Sarfaraz S, Afaq F, Adhami VM, et al. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005;65(5):1635–1641. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
McKallip RJ, Nagarkatti M, Nagarkatti PS. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol. 2005;174(6):3281–3289. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Nomura DK, Long JZ, Niessen S, et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140(1):49–61. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Wang D, Wang H, Ning W, et al. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res. 2008;68(15):6468–6476. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Izzo AA, Aviello G, Petrosino S, et al. Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J Mol Med (Berl). 2008;86(1):89–98. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599–1608. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Sarfaraz S, Adhami VM, Syed DN, et al. Cannabinoids for cancer treatment: progress and promise. Cancer Res. 2008;68(2):339–342. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Bifulco M, Laezza C, Portella G, et al. Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. Faseb J. 2001;15(14):2745–2747. [Crossref], [PubMed], [Google Scholar]
Andradas C, Caffarel MM, Perez-Gomez E, et al. The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene. 2011;30(2):245–252. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Carriba P, Ortiz O, Patkar K, et al. Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology. 2007;32(11):2249–2259. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Kearn CS, Blake-Palmer K, Daniel E, et al. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol Pharmacol. 2005;67(5):1697–1704. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Navarro G, Carriba P, Gandia J, et al. Detection of heteromers formed by cannabinoid CB1, dopamine D2, and adenosine A2A G-protein-coupled receptors by combining bimolecular fluorescence complementation and bioluminescence energy transfer. ScientificWorldJournal. 2008;8:1088–1097. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Rios C, Gomes I, Devi LA. mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol. 2006;148(4):387–395. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Callen L, Moreno E, Barroso-Chinea P, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. 2012;287(25):20851–20865. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Hudson BD, Hebert TE, Kelly ME. Physical and functional interaction between CB1 cannabinoid receptors and beta2-adrenoceptors. Br J Pharmacol. 2010;160(3):627–642. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Vinals X, Moreno E, Lanfumey L, et al. Cognitive impairment induced by Delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol. 2015;13(7):e1002194. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Martinez-Pinilla E, Reyes-Resina I, Onatibia-Astibia A, et al. CB1 and GPR55 receptors are co-expressed and form heteromers in rat and monkey striatum. Exp Neurol. 2014;261:44–52. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Moreno E, Cavic M, Krivokuca A, et al. The endocannabinoid system as a target in cancer diseases: are we there yet? Front Pharmacol. 2019;10:339. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Balenga NA, Martinez-Pinilla E, Kargl J, et al. Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. Br J Pharmacol. 2014;171(23):5387–5406. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Coke CJ, Scarlett KA, Chetram MA, et al. Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression. J Biol Chem. 2016;291(19):9991–10005. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Scarlett KA, White EZ, Coke CJ, et al. Agonist-induced CXCR4 and CB2 heterodimerization inhibits Galpha13/RhoA-mediated migration. Mol Cancer Res. 2018;16(4):728–739. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Blasco-Benito S, Moreno E, Seijo-Vila M, et al. Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer. Proc Natl Acad Sci U S A. 2019;116(9):3863–3872. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Thors L, Bergh A, Persson E, et al. Fatty acid amide hydrolase in prostate cancer: association with disease severity and outcome, CB1 receptor expression and regulation by IL-4. PLoS One. 2010;5(8):e12275. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Pagano E, Borrelli F, Orlando P, et al. Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis. Pharmacol Res. 2017;119:227–236. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Pyszniak M, Tabarkiewicz J, Luszczki JJ. Endocannabinoid system as a regulator of tumor cell malignancy - biological pathways and clinical significance. Onco Targets Ther. 2016;9:4323–4336. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Vaccani A, Massi P, Colombo A, et al. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol. 2005;144(8):1032–1036. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Soroceanu L, Murase R, Limbad C, et al. Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res. 2013;73(5):1559–1569. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
McAllister SD, Murase R, Christian RT, et al. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat. 2011;129(1):37–47. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Shrivastava A, Kuzontkoski PM, Groopman JE, et al. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther. 2011;10(7):1161–1172. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Singer E, Judkins J, Salomonis N, et al. Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015;6:e1601. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Freimuth N, Ramer R, Hinz B. Antitumorigenic effects of cannabinoids beyond apoptosis. J Pharmacol Exp Ther. 2010;332(2):336–344. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Scott KA, Dalgleish AG, Liu WM. The combination of cannabidiol and Delta9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther. 2014;13(12):2955–2967. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Solinas M, Massi P, Cantelmo AR, et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol. 2012;167(6):1218–1231. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Massi P, Vaccani A, Ceruti S, et al. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther. 2004;308(3):838–845. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Massi P, Valenti M, Vaccani A, et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem. 2008;104(4):1091–1100. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
McKallip RJ, Jia W, Schlomer J, et al. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006;70(3):897–908. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Holland ML, Panetta JA, Hoskins JM, et al. The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. Biochem Pharmacol. 2006;71(8):1146–1154. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ramer R, Heinemann K, Merkord J, et al. COX-2 and PPAR-gamma confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013;12(1):69–82. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ramer R, Merkord J, Rohde H, et al. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem Pharmacol. 2010;79(7):955–966. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ramer R, Rohde A, Merkord J, et al. Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm Res. 2010;27(10):2162–2174. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Massi P, Solinas M, Cinquina V, et al. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol. 2013;75(2):303–312. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ramer R, Hinz B. Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst. 2008;100(1):59–69. [Crossref], [PubMed], [Google Scholar]
Elbaz M, Nasser MW, Ravi J, et al. Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of Cannabidiol in breast cancer. Mol Oncol. 2015;9(4):906–919. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Murase R, Kawamura R, Singer E, et al. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Br J Pharmacol. 2014;171(19):4464–4477. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ford LA, Roelofs AJ, Anavi-Goffer S, et al. A role for L-alpha-lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells. Br J Pharmacol. 2010;160(3):762–771. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Nevalainen T, Irving AJ. GPR55, a lysophosphatidylinositol receptor with cannabinoid sensitivity? Curr Top Med Chem. 2010;10(8):799–813. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
McAllister SD, Christian RT, Horowitz MP, et al. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther. 2007;6(11):2921–2927. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Lukhele ST, Motadi LR. Cannabidiol rather than Cannabis sativa extracts inhibit cell growth and induce apoptosis in cervical cancer cells. BMC Complement Altern Med. 2016;16(1):335. [Crossref], [PubMed], [Google Scholar]
De Petrocellis L, Ligresti A, Schiano Moriello A, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol. 2013;168(1):79–102. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Massi P, Vaccani A, Bianchessi S, et al. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. 2006;63(17):2057–2066. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Kargl J, Andersen L, Hasenohrl C, et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016;173(1):142–154. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12(10):685–698. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Gangemi RM, Griffero F, Marubbi D, et al. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 2009;27(1):40–48. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Hohmann T, Feese K, Greither T, et al. Synthetic cannabinoids influence the invasion of glioblastoma cell lines in a cell- and receptor-dependent manner. Cancers (Basel). 2019;11:2. [Crossref], [Web of Science ®], [Google Scholar]
Salazar M, Carracedo A, Salanueva IJ, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 2009;119(5):1359–1372. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Caffarel MM, Andradas C, Mira E, et al. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer. 2010;9:196. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007;117(8):2051–2058. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ursini-Siegel J, Schade B, Cardiff RD, et al. Insights from transgenic mouse models of ERBB2-induced breast cancer. Nat Rev Cancer. 2007;7(5):389–397. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther. 2011;10(1):90–103. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Blazquez C, Casanova ML, Planas A, et al. Inhibition of tumor angiogenesis by cannabinoids. Faseb J. 2003;17(3):529–531. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Blazquez C, Salazar M, Carracedo A, et al. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res. 2008;68(6):1945–1952. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ellert-Miklaszewska A, Kaminska B, Konarska L. Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of bad protein. Cell Signal. 2005;17(1):25–37. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Carracedo A, Gironella M, Lorente M, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006;66(13):6748–6755. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Melck D, De Petrocellis L, Orlando P, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology. 2000;141(1):118–126. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
De Petrocellis L, Melck D, Palmisano A, et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A. 1998;95(14):8375–8380. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Melck D, Rueda D, Galve-Roperh I, et al. Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett. 1999;463(3):235–240. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
von Bueren AO, Schlumpf M, Lichtensteiger W. Delta(9)-tetrahydrocannabinol inhibits 17beta-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells. Anticancer Res. 2008;28(1A):85–89. [PubMed], [Web of Science ®], [Google Scholar]
Caffarel MM, Sarrio D, Palacios J, et al. Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 2006;66(13):6615–6621. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Caffarel MM, Moreno-Bueno G, Cerutti C, et al. JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008;27(37):5033–5044. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Laezza C, Pisanti S, Crescenzi E, et al. Anandamide inhibits Cdk2 and activates Chk1 leading to cell cycle arrest in human breast cancer cells. FEBS Lett. 2006;580(26):6076–6082. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Lopes CF, de Angelis BB, Prudente HM, et al. de Azambuja Ribeiro RI: concomitant consumption of marijuana, alcohol and tobacco in oral squamous cell carcinoma development and progression: recent advances and challenges. Arch Oral Biol. 2012;57(8):1026–1033. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Preet A, Ganju RK, Groopman JE. Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene. 2008;27(3):339–346. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Flygare J, Gustafsson K, Kimby E, et al. Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma. FEBS Lett. 2005;579(30):6885–6889. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Liu WM, Scott KA, Shamash J, et al. Enhancing the in vitro cytotoxic activity of Delta9-tetrahydrocannabinol in leukemic cells through a combinatorial approach. Leuk Lymphoma. 2008;49(9):1800–1809. [Taylor & Francis Online], [Web of Science ®], [Google Scholar]
Velasco G, Carracedo A, Blazquez C, et al. Cannabinoids and gliomas. Mol Neurobiol. 2007;36(1):60–67. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Marcu JP, Christian RT, Lau D, et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther. 2010;9(1):180–189. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Armstrong JL, Hill DS, McKee CS, et al. Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. J Invest Dermatol. 2015;135(6):1629–1637. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Scott KA, Dalgleish AG, Liu WM. Anticancer effects of phytocannbinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration. Int J Oncol. 2017;51(1):369–377. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Guindon J, Hohmann AG. The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol. 2011;163(7):1447–1463. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Munson AE, Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids. J Natl Cancer Inst. 1975;55(3):597–602. [Crossref], [PubMed], [Google Scholar]
Watanabe K, Motoya E, Matsuzawa N, et al. Marijuana extracts possess the effects like the endocrine disrupting chemicals. Toxicology. 2005;206(3):471–478. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Takeda S, Yamaorib SB, Motoyab E, et al. Delta(9)-tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology. 2008;245(1–2):141–146. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014;35(12):2787–2797. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Ligresti A, Moriello AS, Starowicz K, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318(3):1375–1387. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Qiu C, Yang L, Wang B, et al. The role of 2-arachidonoylglycerol in the regulation of the tumor-immune microenvironment in murine models of pancreatic cancer. Biomed Pharmacother. 2019;115:108952. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Cozzolino R, Cali G, Bifulco M, et al. A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis. Invest New Drugs. 2010;28(2):115–123. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Patwardhan AM, Jeske NA, Price TJ, et al. The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci U S A. 2006;103(30):11393–11398. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Qamri Z, Preet A, Nasser MW, et al. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther. 2009;8(11):3117–3129. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Blazquez C, Carracedo A, Barrado L, et al. Cannabinoid receptors as novel targets for the treatment of melanoma. Faseb J. 2006;20(14):2633–2635. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Shi Y, Zou M, Baitei EY, et al. Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma. Cancer Gene Ther. 2008;15(2):101–107. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Hald A, Ding M, Egerod K, et al. Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain. Pharmacol Biochem Behav. 2008;91(1):38–46. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Wasik AM, Almestrand S, Wang X, et al. WIN55,212-2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells. Cell Death Dis. 2011;2:e225. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Gustafsson K, Christensson B, Sander B, et al. Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol. 2006;70(5):1612–1620. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Nasser MW, Qamri Z, Deol YS, et al. Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One. 2011;6(9):e23901. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Marriott KS, Huffman JW. Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Curr Top Med Chem. 2008;8(3):187–204. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Koller VJ, Zlabinger GJ, Auwarter V, et al. Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB(1). Arch Toxicol. 2013;87(7):1287–1297. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Lozano-Ondoua AN, Hanlon KE, Symons-Liguori AM, et al. Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists. J Bone Miner Res. 2013;28(1):92–107. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Krishnamurthy M, Ferreira AM, Moore BM 2nd:. Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorg Med Chem Lett. 2003;13(20):3487–3490. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Gurley SN, Abidi AH, Allison P, et al. Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233. J Neurooncol. 2012;110(2):163–177. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Devane WA, Breuer A, Sheskin T, et al. A novel probe for the cannabinoid receptor. J Med Chem. 1992;35(11):2065–2069. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Hillard CJ, Manna S, Greenberg MJ, et al. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther. 1999;289(3):1427–1433. [PubMed], [Web of Science ®], [Google Scholar]
Fogli S, Nieri P, Chicca A, et al. Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006;580(7):1733–1739. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Baram L, Peled E, Berman P, et al. The heterogeneity and complexity of Cannabis extracts as antitumor agents. Oncotarget. 2019;10(41):4091–4106. [Crossref], [PubMed], [Google Scholar]
Kuttan G, Pratheeshkumar P, Manu KA, et al. Inhibition of tumor progression by naturally occurring terpenoids. Pharm Biol. 2011;49(10):995–1007. [Taylor & Francis Online], [Web of Science ®], [Google Scholar]
Yu X, Lin H, Wang Y, et al. d-limonene exhibits antitumor activity by inducing autophagy and apoptosis in lung cancer. Onco Targets Ther. 2018;2018(11):1833–1847. [Crossref], [Google Scholar]
Holland ML, Allen JD, Arnold JC. Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol. 2008;591(1–3):128–131. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M et al. Appraising the. “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol. 2018;157:285–293. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction. 1996;91(11):1585–1614. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327–360. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–1804. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12–19. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Guzman M, Duarte MJ, Blazquez C, et al. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 2006;95(2):197–203. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Twelves C, Short S, Wright S. A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1: 1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD: THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM). J clin oncol. 2017;35:2046. [Web of Science ®], [Google Scholar]
Mrugala MM. Advances and challenges in the treatment of glioblastoma: a clinician’s perspective. Discov Med. 2013;15(83):221–230. [PubMed], [Web of Science ®], [Google Scholar]
Sim-Selley LJ, Martin BR. Effect of chronic administration of R-(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxaz inyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) or delta(9)-tetrahydrocannabinol on cannabinoid receptor adaptation in mice. J Pharmacol Exp Ther. 2002;303(1):36–44. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Kaplan BL, Springs AE, Kaminski NE. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem Pharmacol. 2008;76(6):726–737. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Taha T, Meiri D, Talhamy S, et al. Cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies. Oncologist. 2019;24(4):549–554. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Soderstrom K, Soliman E, Van Dross R. Cannabinoids modulate neuronal activity and cancer by CB1 and CB2 receptor-independent mechanisms. Front Pharmacol. 2017;8:720. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Turcotte C, Blanchet MR, Laviolette M, et al. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73(23):4449–4470. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
Lorente M, Carracedo A, Torres S, et al. Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis. Glia. 2009 Oct;57(13):1374–1385. doi:10.1002/glia.20856. PubMed PMID: 19229996. [Crossref], [Google Scholar]
Lorente M, Torres S, Salazar M, et al. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ. 2011 Jun;18(6):959–73. doi:10.1038/cdd.2010.170. Epub 2011 Jan 14. PubMed PMID: 21233844; PubMed Central PMCID: PMC3131933. [Crossref], [Google Scholar]
Inside Bangkok’s Legal Cannabis Café
27/08/2022
Bonno
Bangkok’s backpacker mecca Khao San Road has gone through a lot of changes over recent decades. The slick neon-lit bars lining much of the street are a far cry from the more down-home establishments of the past.
But the most noticeable difference today is the addition of cannabis.
Strolling down the centre of the main drag and surrounding areas, one is taken by shopfront and roadside store signs that read, Greenhead Clinic, N’Louis’ Happy Buds, House of Chronic, Cannabis BKK and currently, the most renowned cannabis establishment on the block, RG420 Cannabis Store.
In a bold shift from its former hardline stance on drugs, the Kingdom of Thailand effectively legalised cannabis on 9 June, with the Thai health minister Anutin Charnvirakul handing out one million plants to households, while thousands of inmates detained on cannabis-related charges were released.
The Thai government legalised medicinal cannabis in 2020, in the form of oil obtained on prescription. But with the health minister removing cannabis from its scheduling as a controlled narcotic drug in February, it opened the way for the legal consumption of the entire plant.
Khao San cannabis shop owners will tell you that business is doing well. And while conservatives might fear that the stores may turn into tourist honeypots, the reality is the overwhelming majority of visitors are continuing to frequent the bars to consume the traditionally legal drug, alcohol.
An RG420 staff member explains their wares
Photo Bonno
RG42O opens its doors at 4.20 pm every evening and shuts up at twenty past 1 am. As sales supervisor Suntaree Kansrinawakun told Bonno the point of difference for her establishment is that it’s the only one on the strip that provides a smoking room.
On entering the cannabis café, which operates in conjunction with a licensed grower and only sells organic product, a customer is taken by the large jars filled with buds of different cannabis strains – Thai Stick, Kush, Charlotte Angel and Old Town – available for sale.
The store also sells pre-rolled joints that can be consumed in the smoking room, where tobacco use is not permitted. Edibles are on sale in the form of brownies and chocolate, while there’s a range of cooking products that allow the traditional herb to be added to meals.
But there’s nothing too chronic about these products, as cannabis extracts with over 0.2 percent tetrahydrocannabinol or THC, the psychoactive component of the plant, are banned. And both the buds and products are for medicinal purposes only, with recreational use still officially outlawed.
There’s also a prohibition on smoking weed in public, which carries up to three months in prison or a fine of AUD$1,000, hence the smoking room. And there’s a ban on selling and consumption in relation to under 20-year-olds, pregnant women and breastfeeding mothers.
A wide range of different cannabis strains are on offer
Rak ganga
“We sell cannabis products. We have smoke for relaxation. We have it for eating, and ingredients for cooking. We have joints and flower-buds,” says Kansrinawakun. “My shop is especially about the smoking room because the other places sell at the store, but they don’t have a smoking room.”
The RG420 sales supervisor explains that the “RG” in the store’s name stands for “rak”, which means love in Thai, along with “ganga”: the local word for cannabis.
As for the 420, it’s the date, April 20, that cannabis lovers the world over celebrate the plant, which is a tradition that commenced in 1991, when followers of US band the Grateful Dead organised a pot smoking meet at 4:20 pm on April 20 at Bolinas Ridge in Marin County, California.
Inside the smoking room, it’s not heavy with thick smoke like a similar facility for tobacco use is at an airport. The airconditioned room seems fresh, as a few older local men partake at a table down the back, while a couple of the owner’s friends stand to the side.
RG420 has been open for two months: from a few weeks after the criminal sanctions around the plant were removed. Since then, business has been going well, with both foreigners, or farangs, and locals frequenting the café.
“The government is okay,” Kansrinawakun advises. “Flower-bud is plant, so we can sell it. Customers can buy it to smoke or for cooking. CBD oil is also available for medical use. You can buy and sell cannabis at shops, but CBD oil, you have to go to the hospital and see a doctor.”
A mobile roadside dispensary
The green rush
The use of cannabis and hemp in Thailand goes back centuries. The plant has been used as an ingredient in cooking, for its medicinal qualities, and as a source of fibre: all uses that are now legal and currently being embraced in Australia.
The 1925 International Opium Convention placed global restrictions on non-medicinal cannabis, which saw Thailand’s second PM General Phot Phahonyothin criminalise the plant in 1937. But it wasn’t until the US Reagan administration applied pressure that it took a hardline stance in the 80s.
The focus of this year’s legalisation process has been on households and businesses embracing it for medicinal use and economic benefit. Households can grow unlimited amounts with a requirement to register plant numbers on the Plookganga app, while licensed farms are springing up nationwide.
Thailand is the only nation in Southeast Asia to have made cannabis legal, but it’s certainly, no global pariah. The nation of Uruguay legalised the plant in 2013, as did Canada five years later, whilst over in the US, recreational cannabis is now legal in 19 states, along with Washington DC.
Australia officially legalised its medicinal cannabis industry in 2016, and it’s been legal to possess and use the plant recreationally in Canberra and the surrounding capital territory since January 2020, thanks to a private member’s bill introduced into parliament by ACT Labor MLA Michael Pettersson.
Legalise Cannabis Australia took out between 2 to 7 percent of the Senate vote in each jurisdiction at this year’s May federal election, whilst Australian Greens Senator David Shoebridge has the national legalisation of cannabis on his political agenda.
The fabled RG420 smoking room
A budding industry
According to Kansrinawakun, part of the reason the Thai government moved to legalise cannabis is that after the onset of the COVID-19 pandemic, it’s attempting to encourage tourists back to the Southeast Asian nation.
Indeed, the Thai Food and Drug Administration flagged an idea back in January, to create designated zones where people, both locals and tourists, over the age of 20 would be free to use cannabis recreationally.
As for now, those on a shoestring budget might find the cost of a joint a little pricier than expected, but as Kansrinawakun puts it, “Right now, people say, ‘Why is it so expensive?’ I say, ‘Of course it is, it’s a new business that’s small. When it grows up, it will cost lower in the future.’”
Legacy has a bright future... Lol
Organigram CEO speaks out on tobacco partnerships, excise taxes — and why pot companies are still struggling to turn a profit
While some companies are exploring other avenues of business besides bud, Organigram — Canada’s second-largest licensed producer — is doubling down.
Bonno Aug. 27, 2022
Investors have pinned their hopes on “green gold” turning a fortune ever since Canada legalized recreational cannabis in 2018. Unfortunately, the legal cannabis industry has been burned by volatile supply and sales issue, poor quality products, a plethora of confusing (and occasionally contradictory) regulations, and good old-fashioned Linton hype.
While some companies are exploring other avenues of business besides bud, Organigram — Canada’s second-largest licensed producer — is doubling down. Under the leadership of CEO Beena Goldenberg, a veteran of the natural and organic food business, Organigram is taking a more methodical approach to growing its business and, thus far, its business strategy appears to be flowering.
In July, Organigram reported a 90 per cent hike in quarterly gross revenue. But Organigram is still struggling against its own business headwinds, including a multimillion-dollar loss in its latest quarter.
Goldenberg spoke to the Star about Organigram’s earnings, her wish list for Ottawa, and partnering with a tobacco company:
We’re coming up on the fourth anniversary of recreational cannabis legalization in Canada. Do you think it’s been successful?
Interesting question. In some ways, I do. We are in a more advanced place around cannabis legalization than any other country in the world. However, I think we haven’t gone all the way to meeting the absolute goals of legalization — eliminate the illicit market — (how has that work for you so far?) because we’ve not allowed the legal market to address some of the things the illegal market addresses.
More B.S. You want to eliminate illicit market?
Easy! How about growing fire?.
Simply put, the pricing in the illicit market is still a lot cheaper than the legal market because of the taxes and regulation attached to selling in the legal market. There are regulations that cap THC in edibles at 10 milligrams per package. You can go to the illicit market and get 100 milligrams, easily. While we have regulations that restrict some things in the legal market, you’re basically keeping consumers in the illicit market. LPs bad weed is not helping any. Bunk weed at prohibition prices is not a good recipe for succes.
But it’s early days. I’m optimistic things will continue to evolve and, at some point, we’ll have a very healthy industry — likely with a lot fewer players, but ones that can manage through these difficult times will be around for the long term. Great pumping.
The market is oversaturated in Canada. How are you going to ensure you’ll be one of the players still standing in the next five to 10 years?
First of all, I think the market will end up matching the beer market — where you’ll have 15 per cent of the market be craft players, but all of the larger licensed producers will consolidate. There’s a lot of oversaturation on the LP side. At the end of the day, the provinces are going to want to work with providers that can be a one-stop shop and have the portfolio of products that meet their needs, are reliable, and can fill orders on a regular basis. (What ever happened to scale and low prices?)
Why do I think Organigram will make it? We’re now the number two licensed producer in the country and have come with a share point of number one, so we’re a very important player today. We have seen significant growth on our market share in the last year from the sixth-biggest player. And we have a strong balance sheet. We have cash, we don’t have debt, we’re in an enviable position, and we have a strategic partnership with British American Tobacco. It’s great to have such a strong relationship with our strategic investor. (But the weed you sell is bogus).
I’m curious about how the partnership with British American Tobacco came around. Are there other cannabis companies partnering with tobacco manufacturers?
Absolutely. Cronos Group has a large investment by Altria. Auxly has an investment by Imperial Tobacco. We all know about Constellation investing in Canopy Growth. The tobacco and alcohol industries have invested in the cannabis space. These are big companies that saw legalization coming and wanted to get in. At British American Tobacco, they have a division called Beyond Nicotine. They recognize their cigarette business is going to go away over time and they’re very interested in getting into cannabis right now.
Right now, cannabis is an illegal substance in the U.K., so the investment in Organigram really was to get ahead of potential legalization in the U.S. We have seconded employees from BAT out in Moncton who are working on research. They really want to know what they’re getting into and have good data.
How would you address people who might be concerned you’re partnering with a tobacco company?
They are a shareholder — they own not quite 20 per cent of the company. I respect shareholders. They’ve invested in us, so I have a lot of time of day for that. I can’t speak to their strategy, but the fact they have a Beyond Nicotine group and recognize that they want to expand and do things scientifically, with the proper research, speaks volumes about where the company is going versus what they’ve done in the past.
I understand the criticism. I can’t say I ever thought I’d be working with a tobacco company, but I’ve really been impressed with their approach — recognizing where they are today and where they have to get to and approaching it in a very sophisticated way. And I think that’s something the cannabis industry has been missing. We’re not able to make claims because there are a lot of questions around cannabis health products. We don’t have enough research. These kinds of partnerships could bring a lot of money to the cannabis industry and really take it to the next level.
A lot of cannabis companies aren’t seeing a lot of sales growth — or they’re shutting down. Organigram’s most recent sales totals were up something like 90 per cent year-over-year. How did you make that happen?
I think the focus we had was on providing consumers with quality products, within the right value. That’s a simple statement, but it really comes down to what consumer packaged goods are all about. Make sure you’re providing the consumer great value in a product and its value is equated between price and quality.
In our case, our top selling SKUs are in our Shred brand. It’s a milled flower brand. It’s priced comparatively with the illicit market, but the product is very fresh. We produce it, we harvest it, we sell it. The consumers are getting a great experience. It’s consistent — and, as a result, we’ve seen really strong growth behind that brand.
We have been expanding our capacity as our business has grown. Some of our peers had way too much capacity for their sales. We’ve been expanding our capacity as our sales have grown. We just recently completed the expansion of our Phase 4C, which added another 30,000 to 35,000 kilograms of flower into our business. We are now just over 80,000. I think we’re just in a different place than several of our competitors.
On the other hand, I noticed Organigram had a loss of $2.8 million in its last quarter. Do you know when you’ll be profitable?
We have turned the corner on adjusted earnings before interest, taxes, depreciation, and amortization (EBITDA). We have had two quarters of positive adjusted EBITDA and I expect it will continue to be positive. We are at a point where our margins are able to offset our costs and we’ll continue to grow. There’s huge operating leverage we’ll see out of our expansion that further improves our profitability.
The net loss for most cannabis companies started originally with big investments in facilities that were made back in the early days of legalization that carried forward, but I feel pretty confident that, as we look forward to next year, we will get to operating cash flow positive and then to free cash flow positive. This is all coming with the operating leverage we have with our business growth and performance.
You mentioned the maximum THC content of edibles earlier — are there any other regulations you’re hoping to change?
It starts with the excise tax approach. Back when legalization occurred, there was an assumption we would be able to sell a gram for $10 with a $1 per gram tax. What’s happened is we’ve seen price compression. We’ve seen product sometimes sold for $4 to $6 per gram, and we’re still paying the dollar per gram tax. You’re losing 35 per cent right off the top. This is what has made the industry so challenged in terms of becoming profitable. There are costs associated with growing the flower, costs with distributing it, competitive pressures. (High cost of growing bunk weed at scale...LOL)
We talked about some of those things with the government. There was also discussion about why medical cannabis is taxed at all. There isn’t usually tax on any medication. And we do plan to go back to Ottawa on Oct. 17, on the fourth anniversary of legalization, to share our stories and the challenges of our industry — and hopefully see some movement.
The Cannabis Act was supposed to be reviewed on the three-year anniversary of legalization. It was delayed because of COVID, like everything else, and we have to push for that review to be done and the changes to happen.
What’s your favourite strain of cannabis?
I don’t inhale, so I don’t use flower. But I like some of our edible products. We have some great products. We have Shred’ems gummies pop flavour. The POP! Crazy Cream Soda is one of my favourite SKUs. Everybody has their preferences. (Sugar will make you fat).
There’s a lot of crossover between cannabis entrepreneurs and the psychedelics industry. If Organigram could get all the necessary regulatory approvals to engage in it, would you?
Right now, we don’t have any plans to pursue that space. I think, right now, we’re committed to executing on what we think is an aggressive strategic growth plan within the cannabis space, both in Canada and internationally. We’ve seen some of our competitors getting into alcohol and retail and sports nutrition. Our goal is to remain focused and really see where we can take the industry we’re in. (We don,t know what we are doing).
Now, all that being said, we recognize there is some interesting opportunities in psychedelics, and we’ll continue to monitor the space as it develops. But I would say we are really laser focused on cannabis right now. (You are doomed).
Say,s who? unsigned document?? ... lol
Aurora sells Sky for 25M (paid 150M) Lol...
Home / Canada
Truss recalls 37,000 marijuana beverages over ‘pinhole leaks’
Bonno
August 26, 2022
SHARE
Etobicoke, Ontario-based Truss Limited Partnership is recalling three lots of its XMG Cola marijuana drink because of “pinhole leaks” that could develop in the aluminum cans, potentially leading to leakage and a loss of carbonation.
The recall notice, posted on Health Canada’s website, affects roughly 37,379 product units that were sold, according to the notice on the Health Canada website.
Truss did not immediately respond to an MJBizDaily request for comment.
The recalled products were sold between April 29, 2022, and Aug. 10, 2022, in every province except Quebec.
The drinks retail for approximately 7 Canadian dollars ($5.40) apiece.
The recalled XMG Cola cannabis drinks are sold in 355-milliliter cans in the following lots: 520413041, 520504051 and 520606051.
Neither Truss nor Health Canada have received complaints from consumers related to the recalled products, according to the notice, and no adverse-reaction reports have been received.
A notice about the recalled products on the Ontario Cannabis Store website says that some cans were found to “develop pinhole leaks.”
The recall notice asks consumers to contact the retail store where the product was purchased to arrange a return.
Truss is a joint venture between Molson Coors Canada and beleaguered cannabis producer Hexo Corp.
Molson owns a 57.5% controlling interest.
XMG was the leading cannabis beverage brand by market share (19%) in Ontario’s adult-use marijuana stores in the final quarter of 2021, according to wholesaler OCS data.
Get your Aurora bunk veggies... Lol
26-08-2022
Aurora Cannabis is diversifying into the vegetable propagation and ornamental flowers business amid a massive marijuana glut in Canada by acquiring a controlling interest in Bevo Agtech, one of the largest suppliers of flowers and vegetable seedlings in North America.
Edmonton, Alberta-based Aurora paid 45 million Canadian dollars ($35 million) in cash for 50.1% of Bevo.
Bevo also agreed to buy Aurora’s sprawling greenhouse complex at Edmonton International Airport for up to CA$25 million.
Advertisement
Ontario Chamber calls for reform of province’s MJ wholesale monopoly
Shipping delays at Ontario’s government-owned cannabis wholesaler underscore an “urgent need for reform,” the Canadian province’s Chamber of Commerce said.
The Chamber is calling for the Ontario government to allow licensed marijuana producers and store owners to have direct commercial relationships, “enabling them to negotiate their own product mixes, prices, and delivery terms, which would mitigate the risks inherent to the current system.”
SNDL buying Canadian cannabis product maker Valens for CA$138 million
Cannabis producer and retailer SNDL agreed to buy the shares it doesn’t already own of manufacturer The Valens Co. in a deal the Alberta-based business says will create “a dominant” vertically integrated operator in Canada.
The proposed all-stock deal is worth roughly 138 million Canadian dollars ($106 million).
Dream on
Aurora to sell vegetable seedlings... Lol
Breeder Steve
@breeder_steve
Canadian taxpayers subsidize failing cannabis pubcos, and their exec bonuses, who are on record lobbying for arrests.
Literally feeding #ProCrimScum against our will.
#FuckCanada.
Wayne King
@only1wayneking
Pretty disgusting of ANYONE involved with, growing, retailing etc to be pleading law enforcement on anyone they see as competition. ??
The Cannabis Community doesn't call the law on each other. Ever.
#CaveatEmptor #BuyersBeware #ProCrimScum #NP4P #GYO ??
Quote Tweet
Wayne King
@only1wayneking
Imagine being so ignorant you don't recognize how bad it really is...????
Careful who gets your ?? & don't support #ProCrimScum ?? #IndigenousPeoples sell on #IndigenousLands ??????
Quote Tweet
Replying to
@LarisaBolivar
@EyesOnMJ
and 2 others
Canopy is evil. They're synonymous with #ProCrimScum. The only reason I made this account in the first place was seeing those douchebags on the news lobbying for arrests.
No one wanted to buy their #ShiTweed.
Breeder Steve
@breeder_steve
Replying to
@chris_honeybee
I have zero empathy for their investors or employees. These douchebags led the lobbying for arrests of the unlicensed who led the way.
#ProCrimScum
Cannabis News ??
@CannabisNews
·
Mar 27, 2020
Replying to
@breeder_steve
and
@CaliFarmerMan
Something else how the #procrimscum try to convince people that it shouldn't be this way in Canada. What you talk about is the way legalization should have been here.
Brian MacDonald
@cambrimac
@CanopyGrowth Bakerstreet. Purchased at C-Store Murphy's Square in Corner Brook approx 30 min ago. It's fu$$ing moldy bud....
Breeder Steve
@breeder_steve
Replying to @OrganicCaveman
It's a shitty name, anyways, wasn't my pick but we ran with it. I would never sell out to those clowns, maybe to other clowns, but even that's unlikely. I'm on a mission and I love what I do.
We don't regroup by welcoming #procrimscum into the fold when they have not repented.
SGT ButterScotch
@ButterscotchSgt
Replying to
@breeder_steve
I evaded jail for 25 years and I don't forget.
Been boycotting #ProCrimScum since day 1.
Preach on, Steve.
Any LP that would even consider using the 20 legal Cannabis approved pesticides will never get a dime from me.
Oh Cannabis
@ohcannabisinc
Replying to
@G4SM4N_
@SoulGardenFarm
and
@harjord
Nothing but disdain for their clients, who frankly deserve no better than this #ShiTweed for supporting #procrimscum.
SaneAdam
@fakehater
Replying to
@ThatEricAlper
#ProCrimScum Literally the worst of the worst of the Canadian LPs. They hate cannabis users.
Breeder Steve
@breeder_steve
If you are on the side of righteousness, and you vocally and unequivocally support #NoPrisonForPot, retweet this call for a #boycott against #ProCrim cannabis corporations and all of the #ProCrimScum affiliated with them.
Name them and shame them all on this thread.
German Legalization Could Spark Boom For South African Cannabis (If Government Gets Out of the Way)
Bonno
‘Germany’s lucrative market is the game-changer, but we are not our best friends here in South Africa. Expensive permits; long approval wait times are self-defeating’, says Dikeledi Matla, chairperson of the Soweto Cannabis Alliance Forum.
The forum seeks to coordinate together Black medical cannabis players in the country’s most populous township and enter the niche export market.
Despite cannabis legalization, South Africa’s government is ‘a beast’ when dealing with the domestic industry players, Cannabis Culture reported in July when it documented entrepreneurs who feel hard done.
Though being Africa’s leading cannabis cultivator, South Africa has no huge domestic medical cannabis market at scale. So, her cultivators must set their eyes on shipping to the likes of Germany, Matla says. Hence, in December 2021, a record 2, 125 tons of medical cannabis was shipped from South Africa to North Macedonia
German juggernaut
According to Prohibition Partners European Cannabis Report 7th Edition, Germany’s medical cannabis patient demographic has doubled since 2017. Her medical cannabis startups are on a money-raising spree with Frankfurt-based Cansativa Group recently attracting $15mn in seed funding, and Berlin-based Sanity Group so far pulling over $76mn. General sales of medical cannabis in Germany in 2022 pulled in $0.4bn US with the figure expected to reach $0.6bn US in 2025.
‘There’s little doubt Germany is where the money is but in South Africa as usual, we score our own goals,’ Matla says.
The irony is, that South Africa, which is Africa’s leading cannabis cultivator, is putting so many obstacles on her domestic medical cannabis entrepreneurs, says Matla. For example, his wait for a license to grow medical hemp in a greenhouse has languished for 10 months without an answer from regulators, he says.
Hard license regime
The biggest hardship that South Africa’s medical cannabis players hoping for a slice of the German market face is the South Africa Health Products Regulatory Authority (SAHPRA). This is a government agency tasked with regulating animal, human, and plant health products.
According to Cliffe Dekker Hofmeyr, the SAHPRA cannabis license fee is ZAR 902 ($59) per hemp application, ZAR 23 980 ($1410) per medicinal application, an inspection fee of ZAR 714 ($42) per hour, and a fee of ZAR 3180 ($186) on picking up the hard copy license.
‘We are told by industry players that it’s an expensive, and unclear process especially for small-scale medical cannabis hopefuls wishing to enter the export scene,” says Dennis Juru, president of The South Africa International Cross-border Traders Association, a lobby for EU-like borderless trade in the southern Africa region.
If the licensing regime was swift, medical cannabis hoping for the lucrative export market would work their way around meeting the fees, says Matla, the industry player.
‘The cannabis license application form is a weighty 20 pages. You lodge a license today and don’t hear from SAHPRA for six months,’ he says.
The process to obtain a license from SAHPRA to grow cannabis for medicinal purposes is a ‘rigorous one’ SAHPRA openly says. It defends its regime as necessary because South Africa is a signatory to the International Narcotics Control Board.
‘By the time one wants to ship the product abroad, a significant loss would have been registered,’ Matla says.
Germany strict standards
But to ship medical cannabis to Germany, there is another external headache that South Africa’s producers must tackle.
South Africa’s cannabis growers must first obtain the European Union’s Good Manufacturing Practice (GMP) stamp of approval. This means a long and exhaustive inspection of where the cannabis is produced and the cannabis itself. The EU is not taking chances with agricultural products coming from South Africa. In July it rejected tons of fruit that had already landed from South Africa for phytosanitary reasons.
Europe is going to become the biggest market, so even if the cannabis market of the US and Canada don’t require that certification, it is in the best interests of South Africa’s medical cannabis exporters to work towards obtaining that EU GMP certification. This will place the country firmly in the pipeline to exploit the EU market, Stephen Murphy, CEO of Prohibition Partners told lawmakers during a presentation as part of the European Union (EU) Delegation to South Africa in May.
Lesotho dark horse
There’s a credible likelihood that if South Africa doesn’t solve the internal and external hurdles facing her medical cannabis producers, neighbor ‘dark horses’ Lesotho and Zimbabwe could pip her to the post in the EU market.
‘Lesotho is ambitious,’ says Carter Mavhiza an independent public accountant and auctioneer. ‘Lesotho sees South Africa’s slow speed as a chance. There’s a reason why some South Africa-registered medical cannabis growers chose to do legal business in Lesotho,’ he says citing the growth of contract cultivation models in Lesotho.
Lesotho received its EU GMP Approval, in 2021, leaning on the networks cultivated with German partners.
Another dark horse that could capitalize on South Africa’s struggle with exporting to the EU is nearby Zimbabwe. ‘Zimbabwe doesn’t waste time, its domestic medical cannabis licensing regime is effective and fast because the government there is highly centralized and their army is also has a stake in medical cannabis,’ says Matla, the industry player. He cited how in September Zimbabwe licensed a record 57 medical cannabis players and exported 30 tons of hemp to Switzerland in 2021.
‘That speed of bureaucracy is worth emulating for South Africa,’ he adds.
Costa Rican President Announces Recreational Cannabis Legislation
Bonno22,09,2022
Rodrigo Chaves, the recently elected President of Costa Rica, marked his first 100 days in office this week by announcing an initiative to legalize recreational cannabis.
The president’s announcement to send the initiative to Congress for discussion came on top of reassurances that his administration was nearly ready to publish the regulations for medical cannabis, which were approved by the previous Congress.
“We really did not expect this last announcement about [recreational] cannabis,” said Guillermo Argüello, the president of the Costa Rican Hemp Association. According to Argüello, Costa Rica still has a long road ahead before it will be in a position to compete with the existing Latin American markets.
“If we compare Costa Rica with Latin American markets we are at a disadvantage because we have not yet begun to plant cannabis,” he said. “We do not have large tracts of land. The pandemic and external factors such as the increase in the price of oil and the war in Ukraine have hit the national economy. Farmers and tourism are the most affected.”
Despite the challenges, Argüello believes the fledgling Costa Rica industry could find a path to success through foreign investment and smart commercial alliances.
He also has some advice for other countries looking to join the sector in any form.
“For the countries venturing into this market, I recommend looking [at your own] strengths and weaknesses so you can make strategies that will allow you to compete,” he said. “Look for niche markets and look for added value to products. Cannabis can give you 25,000 business opportunities, look for the one that best suits you.”
Latin America already has a significant number of countries with legal cannabis in some form. Some of these include Argentina, Brazil, Chile, Colombia, Mexico, Paraguay, Peru, and Uruguay.
The region is expected to have the second largest growth spurt in value by 2025, with medical cannabis driving that projection. Latin American regions saw 17 percent growth in 2021 and reached a value of $170 million, with Mexico taking the lead as the most important market at $59 million. With Costa Rica’s farmers and tourism hit hardest by external factors including COVID-19 and the Russian invasion of Ukraine, a completely legal cannabis market supporting cultivators and attracting tourism would be a significant boost to the economy and the region’s projected value.
“I think that every time a new country legalizes cannabis for medical or recreational use it helps other countries who have yet to legalize cannabis move forward on their own legalization path,” said Matt Maurer, co-chair of the Cannabis Law Group at Torkin Manes. “Each new country to legalize helps to reduce stigma that may be held in other non-legalized countries and provides those other countries with a new set of rules and experiences which they can observe and use to develop their own regime in the future.”
Maurer added that at the early stages, he believes Costa Rica should concentrate on business at home. “I think Costa Rica is best served by focusing on its domestic needs first. The international industry is still a tricky space given many countries’ reluctance to allow international imports for a variety of reasons,” he said. “Focusing on domestic needs at the outset not only allows Costa Rica to properly supply its own population first — which is the primary reason for legalization in the first instance — and allows the country to find out where its strengths and weaknesses lie and to become, as a country, a stronger producer or manufacturer as the case may be.”
Once Costa Rica has taken care of its domestic cannabis needs, Maurer feels the country will be in a great position for inexpensive export. “The climate of Costa Rica and the cost of domestic labor ought to result in high-quality flower being produced at extremely competitive costs,” he said. “Its location in Central America makes it ideally suited to ultimately export to North America, South America, Europe, and Asia all quite easily.”
The framework for medical cannabis sales and distribution in Costa Rica is expected to be made public this fall. Experienced cultivators, processors, equipment manufacturers, and the rest of the cannabis industry should begin considering Costa Rica as a future home for investment, sales, and consulting opportunities.
Received new replies
Matt Lamers ????
@matt_lamers
·
5h
????'s massive oversupply of (mostly) unsellable cannabis reached a new level last fall, bringing total inventory to 1.4 billion grams.
@BrockUniversity
's
@ProfMJArmstrong
says that's 3-4 years of legal sales.
More write-downs coming?
For
@MJBizDaily
: https://mjbizdaily.com/croptober-pushes-canadas-cannabis-inventories-to-record-1-4-billion-grams/
Costa Rican President Announces Recreational Cannabis Legislation
Bonno22-09-2022
Rodrigo Chaves, the recently elected President of Costa Rica, marked his first 100 days in office this week by announcing an initiative to legalize recreational cannabis.
The president’s announcement to send the initiative to Congress for discussion came on top of reassurances that his administration was nearly ready to publish the regulations for medical cannabis, which were approved by the previous Congress.
“We really did not expect this last announcement about [recreational] cannabis,” said Guillermo Argüello, the president of the Costa Rican Hemp Association. According to Argüello, Costa Rica still has a long road ahead before it will be in a position to compete with the existing Latin American markets.
“If we compare Costa Rica with Latin American markets we are at a disadvantage because we have not yet begun to plant cannabis,” he said. “We do not have large tracts of land. The pandemic and external factors such as the increase in the price of oil and the war in Ukraine have hit the national economy. Farmers and tourism are the most affected.”
Despite the challenges, Argüello believes the fledgling Costa Rica industry could find a path to success through foreign investment and smart commercial alliances.
He also has some advice for other countries looking to join the sector in any form.
“For the countries venturing into this market, I recommend looking [at your own] strengths and weaknesses so you can make strategies that will allow you to compete,” he said. “Look for niche markets and look for added value to products. Cannabis can give you 25,000 business opportunities, look for the one that best suits you.”
Latin America already has a significant number of countries with legal cannabis in some form. Some of these include Argentina, Brazil, Chile, Colombia, Mexico, Paraguay, Peru, and Uruguay.
The region is expected to have the second largest growth spurt in value by 2025, with medical cannabis driving that projection. Latin American regions saw 17 percent growth in 2021 and reached a value of $170 million, with Mexico taking the lead as the most important market at $59 million. With Costa Rica’s farmers and tourism hit hardest by external factors including COVID-19 and the Russian invasion of Ukraine, a completely legal cannabis market supporting cultivators and attracting tourism would be a significant boost to the economy and the region’s projected value.
“I think that every time a new country legalizes cannabis for medical or recreational use it helps other countries who have yet to legalize cannabis move forward on their own legalization path,” said Matt Maurer, co-chair of the Cannabis Law Group at Torkin Manes. “Each new country to legalize helps to reduce stigma that may be held in other non-legalized countries and provides those other countries with a new set of rules and experiences which they can observe and use to develop their own regime in the future.”
Maurer added that at the early stages, he believes Costa Rica should concentrate on business at home. “I think Costa Rica is best served by focusing on its domestic needs first. The international industry is still a tricky space given many countries’ reluctance to allow international imports for a variety of reasons,” he said. “Focusing on domestic needs at the outset not only allows Costa Rica to properly supply its own population first — which is the primary reason for legalization in the first instance — and allows the country to find out where its strengths and weaknesses lie and to become, as a country, a stronger producer or manufacturer as the case may be.”
Once Costa Rica has taken care of its domestic cannabis needs, Maurer feels the country will be in a great position for inexpensive export. “The climate of Costa Rica and the cost of domestic labor ought to result in high-quality flower being produced at extremely competitive costs,” he said. “Its location in Central America makes it ideally suited to ultimately export to North America, South America, Europe, and Asia all quite easily.”
The framework for medical cannabis sales and distribution in Costa Rica is expected to be made public this fall. Experienced cultivators, processors, equipment manufacturers, and the rest of the cannabis industry should begin considering Costa Rica as a future home for investment, sales, and consulting opportunities.
The casualties of California legalizing pot: Growers who went legal
A blue state’s taxes and regulation have boosted corporate producers, leading to the near-death of the small cannabis farmer
Bonno
August 22, 2022 at 12:39 p.m. EDT
PETROLIA, Calif. — The Wild Cat Road skips along a ridge line, a narrow half-paved, half washed-out track that once carried much of the world’s finest marijuana to market.
Even in mists that obscured its treacherous course as it bows toward the Pacific, the road hummed in tune with the family weed farms around it. Now there is little cannabis to carry, nor “trimmigrants” who traveled here to the Mattole River Valley to pick the flower that made Humboldt County shorthand for the best marijuana around.
“I’m not making it,” said Drew Barber, 48, who has grown cannabis here for more than 15 years, watching the price for his product shrink from $1,200 a pound to about a third of that today. “I can’t lose money from one year to the next, and it’s getting to be that time when I have to decide if I can go on.”
The irony, bitter and true, is shared on the front porches of hillside homesteads across this valley where the King Range mountains and the San Andreas Fault meet the sea. The once-mystical heart of the nation’s marijuana industry is dying, fast, strangled not by law enforcement but by the high taxes and baffling regulation that have crushed small farmers since state voters approved legalization almost six years ago.
The story of Humboldt’s fate highlights how inconsistently this influential blue state has treated a quintessentially blue-state industry, a product once rogue and now a public tax bonanza. In the first quarter of this year alone, cannabis taxes delivered nearly $300 million in revenue to the state and additional money to the counties that have embraced what they once punished.
Following legalization, state officials made several far-reaching decisions that have effectively driven many small cannabis farmers to the brink of insolvency while consolidating a $5 billion-a-year legal market in the hands of industrial-scale growers, most of them based far from these northern reaches.
The chosen course concentrated much of the tax and regulatory power at the state level, dominated by Democrats who often decry corporate influence, and left counties and cities, some far more conservative, with broad discretion over whether to even establish a cannabis industry.
The state imposed multiple taxes across the cannabis supply chain, a burden unmatched in other nearby marijuana-legal states. At the same time, the state declined — after initially signaling it would do so — to limit the size of cannabis cultivations or the number of grower licenses it would issue to farmers.
As a result, the state is now awash in tax revenue, much of it from the industrial-scale farmers and retailers, and in marijuana, a market glut that has gutted wholesale prices and left farmers such as Barber unable to break even. The state rules and omissions have also empowered a still-thriving black market for marijuana — once a chief target of state regulators — whose growers sell their product illegally across state borders and still fetch a lucrative price.
Here in the Humboldt hills, the changes resulting from state policy decisions have also precipitated the slow fade of a unique out-there-alone way of life, pioneered by disillusioned migrants who had soured on the post-1960s vibe farther south.
In the renegade days, a farmer could get $4,000 a pound for Humboldt flower, the plant’s coveted bud. Today, not far from Barber’s operation, one farmer recently dumped three pounds of cannabis at the desperation price of $100 a pound. Others are simply walking away from already cultivated plots.
“The government has actually managed to do in just a few years what the war on drugs couldn’t do in decades,” said Natalynne DeLapp, executive director of the Humboldt County Growers Alliance, which represents a few hundred small farmers here. “It has killed the cannabis market.”
The change in the industry since voters passed Proposition 64 in 2016, making it legal to possess and grow a small amount of cannabis for personal use while leaving decisions on larger cultivations and retail sales to local governments, has now spurred Gov. Gavin Newsom (D) and the state bureaucracy to act on behalf of small growers.
Since 2018, when the new legalization rules took effect, the state has taxed marijuana three separate times as it travels from farm to consumer. Many counties and cities impose their own taxes, at varying levels, on top of the state levies. In some regions of the state, one pound of cannabis is subjected to as many as five separate taxes, some based on weight and others on sales.
By contrast, the state of Oregon imposes a single 17 percent sales tax on cannabis, the only product the state imposes a sales tax on at all. Counties there are allowed to impose as high as a 3 percent sales tax on top of that, which still leaves it far lower than California’s tax burden.
California’s cannabis taxes come on top of licensing fees and regulatory permits, which can cost tens of thousands of dollars annually for growers, burying those who used to work without regulation in red tape and state invoices. The option to become legal, which roughly half of Humboldt’s farmers once accepted, has been a stunningly expensive one.
In his most recent budget, bursting with a record $97 billion surplus, Newsom eliminated the so-called cultivation tax on growers, which in the first quarter of this year brought the state $32.7 million. Counties will still be able to impose their own cultivation tax, called the single most burdensome by many in the industry.
The state government also pledged not to raise the 15 percent excise tax imposed on distributors — the system’s middlemen who also inspect the marijuana before it moves to retailers — for at least three years. The state collected $156.4 million in cannabis excise taxes in the first quarter of the year.
Newsom signed the specific cannabis measures the last day of June, and the cultivation-tax elimination took immediate effect.
“The question we asked in designing this package was how do we make this simpler?” said Nicole Elliott, director of the state Department of Cannabis Control. “The burden falls most especially on these small farmers. And if we want to have a diverse industry, we have to take care of these small farmers.”
To Barber and his neighbors, the recent tax break is welcome but far from decisive. His cultivation taxes alone ran to roughly $160 a pound, taking an increasingly large chunk of his revenue as wholesale prices fell to an average of $450 a pound. In an emergency step, Humboldt County just cut its cultivation tax by 85 percent.
Barber, freckled from years farming in the sun, said it is his wife’s health consultancy business that is keeping the family, including two kids, afloat for now.
“The car has three flat tires and a blown valve, and the question is what do we fix first,” Barber said of the tax changes. “The car still isn’t going to run if you fix one flat tire. But it will help.”
The Mattole Road runs down from the fertile mountains and then along the Pacific Ocean in Petrolia, California. (Melina Mara/The Washington Post)
Cannabis industry veterans say it didn’t have to be this way.
Marijuana long flourished in the state’s far north. A back-to-the-land hippie migration in the early 1970s established a culture accepting of illegal drugs, and an out-of-sight, out-of-mind remoteness discouraged intensive law enforcement.
From that fertile ground, the Emerald Triangle of Humboldt, Trinity and Mendocino counties built a marketable mythology around the marijuana from the region that endures today.
Here, in the Mattole River Valley, the King Range rises thousands of feet high to the south, thickly forested and sheer. The San Andreas begins its state-splitting run south from this wild place of pastures, farms and rain-filled rivers in a rare wet patch of a very dry state.
This is the Lost Coast, about 100 miles of marshy, distant topographic challenges that is the only place in the west to defeat ambitious highway builders. There is no coastal highway here. Nature won.
Like its landscape, Humboldt had a wild west feel for decades. Big cartels saw opportunities in its canyons and hilltops, planting large plots with little regard for the fate of redwood forests and clear, cold rivers.
Then the industry opened up, at least a crack.
The so-called green rush began in 1996 with the passage of Proposition 215. The measure allowed cannabis dispensaries to sell to customers who could prove they needed the drug for anxiety, pain or other ailments.
It also made it nearly impossible to determine which growers were licensed to supply the dispensaries and which remained outside the law, a line-blurring oversight that brought many into the business and began pushing down prices.
Then two decades later came Proposition 64, expanding legal recreational use to every adult. It passed easily, in part because it placed so much power to regulate the industry in the hands of local governments — the step that would create the patchwork of rules — from taxes to local cultivation caps to retail licenses — across the state.
By the time the proposition took effect in 2018, a grower’s pound of cannabis had dropped in price from about $1,200 in 2016 to $800.
Here in Humboldt, where at least 5,000 growers operated at the time, DeLapp nonetheless persuaded nearly half to sign pledges to become legal despite the costs involved.
But there were gaps between the broadly written proposition and the rules that put the new measure into practice.
Many in the industry and law enforcement favored a proposed statewide one-acre cap on farms as a protection for small growers; by the time the final rules came out, though, there was no statewide cap at all. There was also no limit on the number of cultivation licenses that could be issued.
“We still have a vibrant black market in Northern California, and we empathize with the small legal growers,” said Humboldt County Sheriff William Honsal, better known as “Billy,” who was born in the county as the illegal cannabis market boomed.
“By not capping licenses, there has been this flood of supply and I just would have thought our state would have been a little smarter with policies to allow small growers to make it.”
There were an estimated 69,000 marijuana growers in the state at the time Proposition 64 passed. In the spring of 2018, three months after the new regulations took effect, the state had issued 2,000 grower licenses with an expected annual yield of 4.1 million pounds. That translated to at least double California’s legal annual demand.
Now, according to the state Department of Cannabis Control, there are 8,600 licensed marijuana farmers and the amount of cannabis being grown legally in California today could be more than quadruple the state demand.
“The oversupply makes it hard to do business legally or illegally at this point,” said Dale Gieringer, state coordinator for the legalization advocacy group NORML.
The lack of state cultivation limits, which was not addressed in Newsom’s recent plan, stands in contrast to some other Democratic-controlled cannabis states, which have confronted market gluts in the past but not nearly to the degree facing California. Colorado, for example, has rules allowing the state to limit — and even shrink — cultivation size to better control supply.
The option of fallowing a cannabis crop for a year to wait for higher prices is also impossible in California; a grower who allows a license to lapse for a year must start the arduous and expensive process of applying for a new license as if they never held one. Cannabis, unlike wine grapes, is not classified as an agriculture product here and so farmers are denied state benefits that accrue to other crops.
“Everything about the regulations have been written as if cannabis farming were a criminal enterprise,” said Dylan Mattole, who farms a quarter-acre in Honeydew, a town in the river valley his family is named for. “And also with the assumption that this business is so profitable they can squeeze and squeeze and squeeze.”
Mattole’s family moved to this valley from San Francisco in the early 1970s, part of the post-Summer of Love exodus. His father, Walter Sharp III, renamed himself Mattole, just Mattole, for the river he moved next to. He did give his son two names; Dylan got his from the renowned singer-songwriter his dad once saw at San Francisco’s famous Fillmore theater.
But the roughly one-acre farm is shriveling. Last month he laid off his last two farmworkers. He pays more than $35,000 in annual cultivation, transfer and processing licenses, in addition to his cannabis taxes. His revenue is declining at the same time.
A pound of his marijuana, branded Mattole Valley Sungrown, is supposedly selling for about $300 a pound these days. Yet last month, he sold three pounds for $100 each. There were no buyers on the horizon and the weed was growing old.
“At one point did being honest hurt us?” asked Mattole, a 48-year-old father of three.
One major industry challenge is that California is not an entirely legal state, at least not for growers and retailers. A majority of California’s 58 counties still prohibit any cannabis business, according to the state, limiting in particular the number of retail outlets where legal marijuana can be purchased.
“Most people say the problem is oversupply,” said Graham Farrar, founder and president of Glass House Farms, a major grower and retailer based in Southern California. “I say it’s under-demand.”
His business began with state-of-the-art indoor crops in former cut-flower greenhouses in Carpinteria, along Santa Barbara County’s south coast. He has added retail licenses and now holds more than half a dozen, including one here in Humboldt County. But it is the size of his company’s cultivation that is astonishing.
Earlier this year, Farrar opened a 5.5 million square-foot greenhouse, roughly 126 acres, in the Ventura County city of Camarillo where agriculture has long been a prominent industry. By comparison, 90 percent of Humboldt cannabis farms are smaller than one acre.
Farrar and other big cannabis businesses are preparing for federal legalization or at least more modest interstate commerce between cannabis-legal states, a measure now under consideration in the California legislature.
“In a state like California it’s hard to change policy in a rapid way,” said Elliott, the cannabis department director. “There is still a lot of reform that needs to happen.”
Ross Gordon, policy director of the Humboldt County Growers Alliance and policy chair at the Origins Council, which represents about 900 growers in six state regions, said big cannabis producers have the capital to ride out the low prices and wait for federal and interstate trade laws to change.
“Glass House and others like it represent the massive upward transfer of wealth that is taking place within California’s cannabis industry,” Gordon said. “There is policy trying to get at some of these issue of disparity. But not nearly to the depth needed to fix an industry that is structurally broken.”
Humboldt growers say a couple initiatives that saved small vintners in Napa County when they faced extinction from giant wine corporations could help rescue small-scale cannabis farming in California.
The first is a strict “appellation” regimen that would distinguish Humboldt-grown marijuana on dispensary shelves from the mass-produced cannabis from the south. Humboldt, after all, still has mystique.
“Humboldt County produces more redwood fencing than any place in the world,” said Rex Bohn, a county supervisor. “But nobody I run into outside of this county asks me about the redwood fencing.”
The second is the ability to mail their product anywhere. That could depend on the federal government making cannabis legal, and several U.S. senators, including Majority Leader Charles E. Schumer (D-N.Y.), introduced a bill earlier this year to do so.
But industry experts say national legalization, like relaxing interstate commerce, is years off, time farmers here do not have.
“I would expect to see at least half of our businesses to fail in the next year,” said Genine Coleman, executive director of the Origins Council. “If I’m being quite frank, I think we need a new proposition. So much wrong is baked into this system that we are just not going to be able to move ahead without one.”
Examining the pros and cons of provincial cannabis distribution
August 22, 2022Tim Wilson
To Bonno
The provincially mandated, centralized distribution of cannabis in Canada is taking some heat.
In Ontario, the OCS (Ontario Cannabis Store) was hit with a data breach last May, followed by a recent online attack on its third-party operated distribution centre, Domain Logistics. And in BC, union job action has resulted in the centralized cannabis distribution warehouse suspending orders.
No surprise, the industry is now seeing a healthy debate on the pros and cons of provincial centralized distribution, and particularly ‘monopsonies’, where there is only one buyer.
“In Canada, producers pay a premium margin to monopsony distributors who act as a single buyer and price setter for wholesale finished packaged inventory,” says Dan Sutton, Founder and CEO at Tantalus Labs in Vancouver. “In a nascent industry, this arguably simplifies a cultivator’s ability to access all retailers in a given province, although in practice stores that stock and carry products still require ongoing sales relationships.”
Sutton notes that, when compared to direct delivery models, the cost and margin captured by provincial distributors are high.
“The actual value provided by warehousing and distributing inventory is not reflected in provincial markups,” he says. “Thus, provincial markups essentially act as a tariff, increasing dead weight loss and reducing competitiveness with the illicit market.”
However, centralized, government-run systems have distinct advantages. Many retailers appreciate the simplicity. Producers aren’t forced to place hundreds of different shipments to retailers – or, perhaps worse, with distributors who engage in predatory practices. There are also pluses for smaller providers.
“There is always the question of why government monopolies are running the distribution of packaged goods,” says Audrey Wong Founder & Chief Executive Officer of Zyre Brands in Vancouver. “However, there are actually a lot of benefits of this model that people need to recognize. I am a very small owner-operated local company. Had it not been for this model, that suppresses pay-to-play at the biggest retailer in BC—which is the government stores—I probably wouldn’t be on their shelves. And if I were on their shelves, I would probably be price-negotiated to a level that’s not sustainable for a small company to operate, because I don’t have the economies of scale.”
Producers also have the benefit of simplified invoicing, and the ability to send all of their product to one place.
“In a centralized system, I send everything to one location, and get paid 30 days later,” says Abyan Schupp, who oversees sales and operations at Organnicraft, a licensed micro producer in Vernon, BC. “Otherwise, I have to send four cases to one store, two to the next, and five to another – that adds countless hours to me as a salesperson. I have to chase down the invoices, and my bookkeeper and CFO have to add them and reconcile the books. That was something I had to do in Saskatchewan all the time.”
Saskatchewan is an interesting example, given that the government has stepped aside, and allows producers to ship directly to retailers, or to work with competing distributors.
“Saskatchewan offers its own unique challenges,” says Gord Nichol, Owner and President of North 40 Cannabis in Nipawin, Saskatchewan. “You don’t have to convince a government board to buy your product – instead, you have to convince each store. However, as a small, independent producer, I much prefer this system over trying to convince a board. In my view, it’s easier to sell to a store as opposed to a board, just because the store is closer to the end consumer, and will be more dialled into demand.”
A distribution system like that in Saskatchewan also allows for significantly more flexibility.
“I have been in situations in Saskatchewan where a certain SKU had run its cycle, and a retailer had a hard time moving it,” says Schupp from Organnicraft. “I could offer a discount on a new product, and they could blend the margins and sell both at once. That was easy. You can solve problems on the fly.”
Direct delivery promises an opportunity for more pricing flexibility. British Columbia, for example, recently launched its own direct delivery program, which is focused on Indigenous and small-scale producers. In this new system, the BCLDB’s 15% markup will still apply.
“BC’s Direct Delivery model ironically adds flexibility for small batch offerings targeted at local or specialized stores, but maintains the high tariff cost of participating in the provincial cannabis market,” says Sutton. “Direct Delivery that retains high tariffs maintains deadweight loss, makes legal cannabis more expensive than its illicit competitors… and adds no value to the supply chain.”
And the answer is?
As jurisdictions in Canada continue to tinker with their distribution models, it’s fair to ask: what’s the best system? For some observers, it’s a hybrid structure that allows for private distributors to participate in direct delivery.
“In a hybrid model, small producers without sales teams can opt to work with one of several distributors who are forced to price their service competitively,” says Sutton. “And more mature producers can deal directly with an increasing number of retailer stockists as the demand for their product grows.”
A hybrid model that includes direct delivery allows for flexibility in the relationship between LPs and retailers. It also prevents extreme market distortions, as can occur with large monopsonies like the OCS.
“I don’t get to tell the OCS what I have available – they just tell me what they want,” says Schupp from Organnicraft. “For example, when we launched our Platinum Grapes SKU, it sold out immediately. The OCS saw that and sent me three purchase orders that equalled 52,000 units for the month of July. That’s 300 pounds. We’re a micro, and can’t grow that much right now, but because I can’t deliver it I’m being penalized – my supplier rating has gone down.”
This glitch could even affect future listings because the OCS algorithm could determine that the Organnicraft SKU is not selling as well as it should be, based purely on how much volume should have been ordered. This kind of dysfunction is presumably reduced when competition is introduced within a hybrid distribution model.
“As long as there is more than one distributor in a given market, these distributors are compelled to price their services in a competitive manner,” says Sutton. “Competition from a hybrid model drives distribution margin down to a commodity value over time, reduces the risk of a single point of failure, and lets producers adapt to more direct relationships as their business grows should they choose to.”
Sutton argues that though a centralized distribution model may appear to simplify the supply chain for producers, they still need to maintain sales relationships with their stores, and conduct internal demand planning. They also shoulder the financial burden of returns should a product age out.
“It is not difficult to sell to 50, 100, or 500 stores directly,” he says. “Businesses from breweries to bakeries to hobby farms do it every day with far fresher time to market obligations.”
A hybrid model could also help to break down barriers to smaller producers, and to interprovincial trade. Given that Ontario is Canada’s largest market, producers want to get in – but it isn’t always so easy.
“There are hundreds of stores in Ontario that want my products, but I can’t get in,” says Nichol from North 40 Cannabis. “The OCS wants me to buy a $15 million dollar recall insurance policy, which costs $50,000. That works fine for the large companies who can afford it – but it really functions as a way to keep the small companies out of the market. It’s completely out of touch with our sales volume and revenues.”
And there are challenges with BC, too.
“BC had an opportunity to make some gains when allowing for direct delivery from producer to retailer,” says Nichol. “They did that – then they slammed the door on out-of-province providers. Interprovincial trade barriers are a terrible thing. As soon as the government gets involved, they put up these gates. I would love to see Saskatchewan shut the doors to BC wines for a month, and see what happens.”
Beyond the policy issues, of late the biggest argument against having big players like the OCS and the BC Liquor Distribution Branch (BCLB) monopolize warehousing and distribution is that when they fail, the entire system fails.
“As seen recently in the OCS data breach and BC Liquor Distribution Branch union dispute,” says Sutton, “this single point of failure compromises the industry’s ability to keep products on shelves.”
In a more general sense, however, it may be important not to throw the baby out with the bathwater. Here, the example of Zyre Brands is instructional, given that the company has a unique offering that sells flavoured vapes based on their ‘vibe’.
“The BC LDB looked at my product simply for its merits,” says Wong from Zyre. “They saw that it was a unique offering and said ‘I like it, I’ll take it. Whereas, had it been a private model with a large chain of stores, they might have said, ‘I like it, but what am I getting in exchange for carrying it?’
LOL
????WhatsMyPot??
@WhatsMyPot
?? two unprofitable, poorly run pubcos set to merge into a single unprofitable, poorly run pubco in an all-paper exchange of smiles and winks
Quote Tweet
David George-Cosh
@itsdgc
· 6h
BREAKING: A big deal in the Canadian cannabis space to begin the week: Sundial is buying Valens in an all-stock deal worth about $138M https://newswire.ca/news-releases/sndl-announces-agreement-to-acquire-the-valens-company-to-create-leading-vertically-integrated-cannabis-platform-808914321.html $SNDL @TheValensCo
The ‘green gold’ of Pondoland. It’s incredible how freely cannabis grows there.
Replying to
@VumaniMkhize
The government's cronies have the licences. Sorry the rest of us are irrelevant. Remember during covid. You were called non essential. Does that not anger u been called worthless?
Gordon Wells
@gordonwells
Replying to
@VumaniMkhize
What reason is there for
to be involved at all? None!
Happy Land!
Thailand cannabis: From a war on drugs to weed curries
Bonno
Share
A Thai woman with a cannabis plant
Image caption,
Thailand has given away one million cannabis plants to encourage cultivation
Thailand legalised cultivating and consuming cannabis this month, reversing a hard-line approach of long prison sentences or even the death penalty for drug offences. The BBC's South East Asia correspondent Jonathan Head reports on what's behind the dramatic change.
Twenty-one years ago, I had one of the more searing experiences of my journalistic career. We were invited to watch, and film, the execution of five prisoners, four of them convicted drug traffickers, by firing squad in Bangkok's Bangkwan prison.
The look on those men's faces, as they were walked, leg-chains clinking, to the pavilion where the executions took place, is something I shall never forget.
It was part of then prime minister Thaksin Shinawatra's "war on drugs", which later escalated into the killing of many hundreds of drug suspects.
Thaksin's campaign was popular. Thais were worried about the damaging effects on their communities of narcotics like methamphetamines - and they were willing to ignore the shocking violations of human rights that came with the violent crackdown.
Other countries in the region have followed the same punitive approach, notably the Philippines after President Rodrigo Duterte took office in 2016. Singapore and Malaysia have imposed the death penalty for drug trafficking for decades. Tourists coming to South East Asia have long been warned of the harsh penalties they face if caught with even small amounts of marijuana.
It's hard to imagine, then, that what we have seen over the past weeks is actually happening in Thailand.
Cafés and stalls have been openly selling all kinds of cannabis products, or showing off jars filled with potent marijuana flowers. The minister for public health, Anutin Charnvirakul - architect of the new law, which now gives Thailand perhaps the most liberal marijuana regime anywhere in the world - was seen sampling weed-laced curries, and being applauded by farmers who hope it will bring them new sources of income.
There were gaggles of giggling Thai grannies trying lurid-green cannabis drinks, and lining up to collect one of the million free marijuana plants the government is handing out.
Thai people buy cannabis popsicles at a marijuana legalization festival on June 11, 2022 in Nakhon Pathom, Thailand.
IMAGE SOURCE,GETTY IMAGES
Image caption,
A festival celebrating the new law offered people weed-laced popsicles
The new law appears to give Thailand what is perhaps the most liberal approach to marijuana anywhere in the world. For the moment, people can grow and consume as much of the plant as they like, though there are a few limits on how they can market and sell it.
"One thing is clear. You cannot go to jail in Thailand just for using cannabis any more," says Tom Kruesopon, a pioneering entrepreneur who helped persuade the government to change its approach. "You can go to jail for doing other things, like smoking in public, as a public nuisance, or creating and selling a product from cannabis that you did not get approval for from the Food and Drug Administration. But Thailand is the first country in the world where you cannot go to jail for growing or using the plant."
"This is like a dream for us. We never thought we would go this far in Thailand," says Rattapon Sanrak, who began campaigning for legalisation of marijuana after experiencing its medical benefits while studying in the United States.
Two grandparents, his father and then his mother died from cancer. On rushing back from the US to care for his mother, he tried, and failed, to persuade her to use cannabis products to ease her pain, and found it difficult to get access to what were then illegal substances.
What explains this dramatic turnaround in a country still led by conservative military men who seem unlikely drug law liberalisers?
Part of the reason is politics. Mr Anutin adopted the legalisation of marijuana as his party's signature policy in the 2019 election. The party's stronghold is in Thailand's poor, rural north-east, and the policy appealed to farmers struggling to make a living from growing rice and sugar, and in need of a new cash crop.
So, he was able to tell the cheering crowds, as he announced the new law in his political home base of Buriram earlier this month, that he had delivered what he had promised. He believes in the medical benefits of legalisation, which he hopes will allow poorer Thais to grow their own treatments, rather than having to pay for expensive chemical drugs.
Health Minister Anutin Charnvirakul greeted by supporters clutching donated cannabis plants in Buriram
Image caption,
Health minister Anutin Charnvirakul has been one of law's biggest supporters
It is also about business. Mr Kruesopon estimates the marijuana business will generate $10bn (£8.1bn) in its first three years, but could earn a lot more from cannabis tourism, where people come to Thailand specifically for therapies and treatments using marijuana extracts.
He has opened the first clinic in Bangkok that focuses solely on these kinds of treatments. Already some of Thailand's biggest corporations are looking at ways in which they can cash in on the weed bonanza.
By liberalising the law so quickly and so completely, the government hopes to steal a march on neighbouring countries, many of which may in any case be reluctant to follow the trail blazed by Thailand.
But there is a third factor behind the new marijuana regime - a rethinking of the hard-line approach to drug use, which began seven years ago, surprisingly at a time when Thailand was ruled by a military junta.
The country has some of the world's most overcrowded prisons, and three-quarters of inmates are there for drug offences, many of them minor. This has not only brought international criticism of the poor conditions in which prisoners have to live, but also cost the government money to sustain them.
It was a military minister of justice, General Paiboon Kumchaya, who announced in 2016 that the war on drugs had failed, and another, less punitive method of dealing with the use and abuse of narcotics was needed.
When Mr Anutin presented his marijuana policy, with all its enticing economic benefits, he found he was pushing at a relatively open door - though he says it still took a great deal of pushing to get this far. One other result of the change in the law is that more than 4,000 people on cannabis-related charges are now being freed from jail.
However, the government may not have been prepared for the enthusiastic embrace of cannabis in all its forms seen across Thailand since the new law was passed.
The plant is showing up everywhere - on ice cream, adorning classic Thai dishes and in new smoothie recipes. Someone is even selling chicken meat from birds which have apparently been fed cannabis. The new law makes pretty much anything related to cannabis legal.
The government is now drafting additional regulations over its use. Officially its position is that the law only allows cannabis use for medical, not recreational purposes, but it's hard to see how they will enforce that distinction.
Chidchanok Chidchob tending her marijuana plants in Buriram
Image caption,
Chidchanok Chidchob tends to her marijuana plants in Buriram
"We all know from studying other markets that recreational use is where the money's at," says Chidchanok Chitchob, a self-styled marijuana enthusiast whose father, a powerful political figure in Buriram, was one of the first to jump on the Thai marijuana bandwagon. "So I think this should be a good step towards that, if we are really thinking of this as an economic crop."
She is experimenting with different strains of the plant to help local farmers cultivate the right kinds for the region.
Mr Kruesopon says he has no issue with further regulation. He advocates sales of marijuana only from licensed vendors, with a prescription, and never to anyone under 18 years old.
"You don't have to overthink this," he adds. "Whatever you are using for cigarettes, use the same thing for cannabis. There are already laws on the books to help control cigarette use, and alcoholic liquor use - just use the same laws."
This is an uncharacteristically bold step by the Thai government, into a brave new world. The rest of the region will be watching to see if it pays off.
Oppression continues but...
South Africa's 'King Khoisan' arrested over cannabis plants at president's office
King Khoisan covered in cannabis being dragged away
IMAGE SOURCE,AFP
Bonno
King Khoisan's family are angry about his arrest, local media report
South African police have uprooted several cannabis plants growing near President Cyril Ramaphosa's office in Pretoria.
They belonged to activists from the indigenous Khoisan community, some of whom have camped in the area for three years.
Their leader, who calls himself King Khoisan, clung on to a large cannabis plant as police dragged him away.
"Police... you have declared war," the AFP news agency quotes him as shouting.
"We have been here peacefully. We are coming for you," he continued.
He has since been arrested.
He and some fellow activists were detained for "dealing in dagga [cannabis], illegal plantation and cultivation of dagga as well as failure to wear a face mask in public when ordered to do so by a police officer," a statement to AFP said.
King Khoisan shielding cannabis plants from police
IMAGE SOURCE,AFP
Image caption,
The Khoisan are South Africa's oldest inhabitants but across the region they have often found themselves marginalised.
In 2018, the group set up camp on the green space outside the president's office, near a giant statue of Nelson Mandela, to campaign for the official recognition of their language.
King Khoisan's wife expressed anger about the incident in an interview with South Africa's IOL news site.
"I am very, very cross," Queen Cynthia said. "The president don't want to come," to talk to them, she said. She told IOL the Khoisan people just want acknowledgement.
People had been using the plants for medical reasons, such as cancer and high blood pressure, she continued. The cannabis had been planted in a vegetable garden.
The personal use of cannabis in private places was decriminalised in South African in 2018.
The Khoisan are South Africa's oldest inhabitants but now form a small minority in the country.
Police raiding cannabis garden with man wrapped in the plants
IMAGE SOURCE,AFP
Cannabis is referred to as "dagga" in South Africa
Keeping Legacy out...
Another designed to fail doomed legalization project.
Pondoland: South Africa's cannabis growers left behind by legalisation plans
By Vumani Mkhize
BBC Africa Business, Umthatha
ToBonno
Share
For generations, people in South Africa's Eastern Cape have made their living growing cannabis. You might expect that as the country moves to legalise the crop, they would be first in line to benefit, but that is not necessarily the case.
Short presentational grey line
The drive from Umthatha to the Dikidikini village in South Africa's Eastern Cape province is a picturesque journey filled with endless vistas, scattered homesteads and winding roads which scythe through undulating green hills that could easily be mistaken for corn fields - yet they are anything but.
"That's cannabis," my local guide and cannabis activist Greek Zueni tells me. "Everyone here grows it, that's how they make a living."
Cannabis, colloquially referred to as "umthunzi wez'nkukhu," or, chicken shade, is an intrinsic part of many rural communities in Eastern Cape's Pondoland and a vital source of income.
At a homestead near the riverbank, we meet a group of men, women and children tending to a fresh harvest. Their hands are stained green from plucking the cannabis heads all day.
The pungent smell of cannabis hangs heavy in the air. They crack jokes while they work - harvesting is a group effort. A massive heap of green heads lies besides them, drying in the midday sun.
For community member Nontobeko, which is not her real name, farming cannabis is all she has ever known: "I learnt how to grow it as an eight-year-old girl," she says proudly.
"Cannabis is very important to us because it's our livelihood and source of income. Everything we get, we get it through selling cannabis. There are no jobs, our children are just sitting here with us."
While cannabis might be a way of life for this community, growing it at this scale is illegal.
There are more than 900,000 small-scale farmers in the Eastern Cape and KwaZulu-Natal provinces who have been growing cannabis for years.
These growers have found themselves on the wrong side of the law many times, but the government's tough stance on cannabis looks set to change.
It started with a landmark court ruling in 2018 which decriminalised the private use, possession and growing of cannabis.
Earlier this year during his State of The Nation Address, President Cyril Ramaphosa said South Africa should tap into the global multi-billion-dollar medical hemp and cannabis industry, which he said had the potential to create 130,000 much-needed jobs.
While this may be good news for commercial companies, traditional growers in the Eastern Cape feel left behind. The cost of getting a licence to grow cannabis is just too expensive for many.
Greek Zueni says the government needs to do more to support small-scale cannabis farmers
"Government needs to change its approach and come up with laws that are grower-friendly and citizen-friendly. Right now, the people who have licences [to grow cannabis] are rich people," Mr Zueni says.
"The government should be assisting the communities to grow so that they can compete with the world market. Here is a commodity growing so easily and organically. We are not jealous, the rich should also come in, but please accommodate the poorest of the poor," Mr Zueni says.
Turning a blind eye
Last year, the government unveiled a master plan for the industrialisation and commercialisation of the cannabis plant. It values the local industry, which has largely been operating in the shadows, at nearly $2bn (£1.6bn).
It is seeking to make South Africa's cannabis industry globally competitive and to produce cannabis products for the international and domestic market.
Key to the roll-out is the Cannabis for Private Purposes Bill, set to be signed during the 2022-23 financial year, which provides guidelines and rules for consumers and those that want to grow cannabis in their own homes.
It would legalise the cultivation of hemp and cannabis for medicinal purposes, thus opening up the industry for serious investment and growth. It is also expected to clear up legal grey areas and so provide prospective investors with clarity on the future of the South African cannabis market.
Although much still remains unclear, it seems the government is committed to opening up the industry, because the economic opportunities are too enticing to ignore. The plans have broad public support, with few dissenting voices.
While the legal framework is still trying to catch up with a fast-moving market, many companies are forging ahead in anticipation that the law will eventually open up the sector.
As it stands, even though private use has been decriminalised, it is still illegal to buy and sell cannabis and various cannabis products.
However, judging from the proliferation of shops that sell cannabis products around the country, authorities are already turning a blind eye.
Adding to this legal minefield is that it is legal for private companies to grow and export medicinal cannabis to other countries.
'Opportunities for European distribution are big'
One company that is seeking to capitalise on medicinal cannabis is Labat Africa Group. The Johannesburg Stock Exchange-listed company recently acquired Eastern Cape cannabis grower Sweetwater Aquaponics.
Labat's director, Herschel Maasdorp, says the company is undergoing significant growth in both Europe and Africa.
The Sweet Water Aquaponics facility in the Eastern Cape.
The Sweetwater Aquaponics facility has a large cannabis production capacity
It has also listed in Frankfurt, because "Germany is the single largest market in Europe for medicinal cannabis distribution", he says.
"The opportunities for distribution in Europe are very big. In addition to that, across borders, in Africa alone, there is a proposition that we have consolidated across a number of different countries all the way from Kenya, to Zambia to Uganda, Rwanda, Tanzania, as well as in Zimbabwe."
Legal cannabis trade on the continent is set to rise to $7bn as regulation and market conditions improve, says London-based industry analyst Prohibition Partners It says Africa's top producers by 2023 will be Nigeria with $3.7bn, South Africa $1.7bn, Morocco $900m, Lesotho $90m and Zimbabwe $80m.
In its Global Cannabis Report, Prohibition Partners is forecasting exponential worldwide industry growth: "Combined global sales of CBD, medical and adult-use cannabis topped $37.4bn in 2021 and could rise to $105bn by 2026."
Considering South Africa's stagnant economic growth and record unemployment, tapping into the cannabis industry could reap rich rewards.
For Wayne Gallow from Sweetwater Aquaponics, incorporating traditional growers in the industry is crucial for economic development in the Eastern Cape.
Workers at Sweetwater Aquaponics sorting through cannabis
Image caption,
Sweetwater Aquaponics wants their production of cannabis to benefit local people
"What we wanted to achieve with our licence is not only to grow medicinal cannabis, but to use that licence to benefit everybody in the Eastern Cape," he told the BBC.
He admits the more traditional growers have been left behind as cannabis legislation progressed.
"The Pondoland area was synonymous with supplying the cannabis throughout South Africa," he says.
However, changes in the law had a "detrimental" effect on Pondoland farmers, because it meant anyone could now grow and consume their own cannabis, so they no longer had a market for a crop that was previously very lucrative.
Even growing cannabis to export for medicine is not feasible for small-scale farmers, because of the eye-watering costs. It requires a licence from the South African Health Products Regulatory Authority (SAHPRA) which costs about $1,465.
Besides the licence fee, to set up a medicinal cannabis facility you need about $182,000 to $304 000, which is beyond the reach of many traditional growers.
However, there is some promising news for the Eastern Cape farmers. The Pondoland or Landrace strain of the plant, which grows so abundantly in the area, has shown some encouraging results in treating breast cancer.
Sweetwater Aquaponics and the Council for Scientific and Industrial Research (CSIR) are currently running a study, and scientists are optimistic that the strain will yield good results.
It is still early days, but if the Pondoland strain is found to be effective, this could be the game-changer that indigenous growers have been desperately searching for.
Sorry for the inconvinience.
https://www.bcldbcannabisupdates.com/supplier-updates
Thai news.
[i]Aug 19
Legal psychedelic therapy coming to Thailand!
"The Thai Narcotics Control Board announced it will develop medicine from hallucinogenic magic mushrooms to help cure the nation’s depressed citizens."
source: TheThaiger
Say what?