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What makes cannabis cannabis? The aroma of flower and the physiological effects of consuming it come down largely to two things: cannabinoid ratios and terpene content. These twin factors go a long way toward shaping the user experience of a given product, and distinguishing it from myriad other options. But what is the source of these distinctions, whether sweeping or subtle? New research points to the importance of an oft-overlooked influence: cultivation.

Variations in terpene and cannabinoid profiles are typically chalked up to genetics. Individual cultivars, defined by parental inheritance, may be grouped into broad categories according to their genetic predisposition toward a particular dominant terpene — caryophyllene and limonene for “dessert” strains, ocimene for tropical/floral strains, and terpinolene for Jack/haze strains, to name a few — or cannabinoid profile — high-THC, high-CBD, or balanced THC-CBD.

While helpful, these cultivar/genetics-based classification systems obscure an important consideration: the conditions under which the actual plant is grown. To wit, a new study in the journal Molecules finds that clones with identical genetics can produce meaningfully different levels of both types of chemicals when grown “naturally” versus “artificially.” Other recent papers report similar findings under different lights at indoor grows.

Science now confirms what cannabis connoisseurs have argued for years as cultivation has become increasingly commercialized in legal markets: it’s not all nature; nurture matters, too.

A Cultivation Experiment

Published in January 2023, the Molecules1 study was performed by researchers at New York’s Columbia University along with the owners of three independent Northern California cannabis companies: John Casali of Humboldt’s Huckleberry Hill Farms; Tina Gordon of Humboldt’s Moon Made Farms; and Christine Skibola of Novato’s Cosmic View.

Small producers have long been wary of the cannabis industry coming under domination by multistate operators (MSO’s) with the worst practices of corporate America. But the revelations of Russian oligarch money in the coffers of leading MSO Curaleaf appear to vindicate even the most cynical observers. These follow a slew of controversies concerning product safety and labor rights at the company.

Now based in the Boston suburb of Wakefield, adult-use cannabis colossus Curaleaf seems to exemplify the industry’s trajectory — from its origins as a local operation for medicinal users to its current status as a globe-spanning titan generating unsavory headlines and a string of scandals.

The World’s Largest Cannabis Company

Today Curaleaf ranks as the largest cannabis company in the world. Last year, it claimed $1.2 billion in profits. Until recently it had operations in 23 US states with 147 dispensaries, 22 cultivation sites, and 30 processing facilities.

Like other big MSOs, Curaleaf has achieved a dominant position in the cannabis industry by setting up operations primarily in “limited-license states . . . with natural high barriers to entry and limited market participants,” a strategy that helps “to ensure the company’s market share is protected,” according to the company’s annual investor filing in 2020.

But these “high barriers to entry” are hardly “natural.” They are constructed and promoted by policy-makers, regulators, and some opportunistic legalization advocates who favor restricting access to lucrative cannabis business licenses to a small number of well-heeled applicants.

Anyone who has paid any attention to the cannabis “wellness” industry in recent years — whether through state medical and recreational programs or the free-for-all national CBD market — will be familiar with cannabinoid-infused topicals marketed to treat minor aches and pains. Because they’re easy to use and non-intoxicating, these products may serve as familiar, low-risk entry-points for elderly, wary, or cannabis-naive individuals into the wider world of cannabis products.

Cannabis-infused salves, lotions, and the like work because cannabinoid receptors CB1 and CB2 — as well as secondary targets including TRP (“trip”) channels, PPARs (nucleus receptors), and serotonin receptors — are abundantly expressed in skin cells.1,2 Topically applied cannabinoids can bind directly with these receptors and thus reduce local inflammation and pain.

But properly formulated cannabis topicals may be able to do more than just that. For decades, researchers have studied cannabinoids’ ability to treat clinical skin conditions like acne, ulcers, and dermatitis. In the skin, as elsewhere, the endocannabinoid system works broadly to maintain balance, proper functioning, and immune response, including through the synthesis of the endocannabinoids anandamide and 2-AG.3 It’s even possible that cannabinoids taken internally, and not simply via a localized topical, may be able to help — especially if a condition is more widespread.

While skin disease remains a relatively little-known indication for cannabis use, and certainly demands more specialized attention than your standard soothing balm, numerous recent papers suggest it’s an area well worth exploring.

Cannabinoids for Inflammatory Skin Diseases

To start, consider a recent article in the journal Pharmaceuticals4 that examines previous research into cannabis-based medicines for inflammatory skin diseases such as acne,5 eczema, dermatitis, and psoriasis. The Portugal-based authors review 29 studies published between 2003 and 2021, 13 of which used human subjects and the rest cell and animal models. None of the human studies involved oral intake of cannabinoids per se, though one did find that increased consumption of hemp seed oil, but not olive oil, was associated with reduced symptoms of atopic dermatitis. The authors of the original study attributed this to the high concentration in hemp seed oil of polyunsaturated fatty acids, which are endocannabinoid precursors.

On Jan. 26, the FDA issued a CBD policy statement that reaffirmed its longstanding unwillingness or inability to regulate nonpharmaceutical CBD products. The announcement is riddled with disingenuous doublespeak, starting with the wordy title: “FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward.”

After stonewalling for years, the Foot Dragging Administration is basically admitting that its bureaucracy is unable to scale with the scope and magnitude of popular interest in CBD. So it’s passing the buck to Congress.

Perhaps a more incisive title would be: “FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate.”

As per usual, the FDA reflexively privileges pharmaceutical CBD, which is so safe it’s not even considered a controlled substance. But as for nonpharmaceutical CBD — the FDA insists it’s too risky for public consumption.

It’s worth noting that cannabidiol (CBD), as a whole plant option or derivative has been available since 2010, and millions of people have used CBD products without apparent harm. A 2018 report by the World Health Organization concluded that CBD “is generally well-tolerated with a good safety profile [and] exhibits no effects indicative of any abuse or dependence potential.” A clinical trial by ValidCare assessing CBD’s impact on human liver function has given the compound a clean bill of health.

Heart disease is the leading cause of death globally. Millions of people treat heart disease by taking statins to regulate their cholesterol. Unfortunately, these drugs can cause muscle weakness and myopathy in some patients. Doctors once thought muscular pain was psychosomatic, but there’s more to it. Statin medications deplete cannabinoid receptor function, according to a recent study by a team of distinguished Italian scientists.

The study, released as a preprint on Research Square before peer review, suggests that simvastatin, a widely used medication, affects enzymes in the endocannabinoidome, the expanded endocannabinoid system encompassing several endogenous fatty acid compounds in addition to anandamide and 2-AG (the two most prominent endocannabinoids). More troublesome, though, is that simvastatin alters genes involved in regulating cannabinoid receptors.

Mapping cannabimimetic pathways manipulated by statins and redesigning existing medications to respect the endocannabinoidome could lead to therapeutic adjuvants that may limit adverse reactions to statins. This is critical, considering that statins are the most prescribed lipid-lowering agents worldwide — not only to lower cholesterol but also to inhibit inflammation and stabilize atherosclerotic plaques.

Statins & Lipid-Lowering Drugs

Statins reduce cholesterol by inhibiting an enzyme in the liver called HMG-CoA reductase. Overall, they lower low-density lipoprotein (bad cholesterol) and triglycerides, while increasing good cholesterol levels.

Lipid regulation helps reduce the risk of cardiovascular disease. The lipidome, however, consists of endocannabinoids and endocannabinoid-like neurotransmitters. And this could be why statin medications, such as simvastatin, while generally well tolerated, can cause serious side effects, including pain and toxic myopathies, in some people.

Could two rights make a wrong? Cannabis and immunotherapy have both gained traction in the oncology field in recent years — one to help treat symptoms and the other as a gentler alternative to chemotherapy — but there’s been some concern that for cancer patients using both, the former could interfere with the latter.1,2  A newly published study in the European Journal of Cancer,3  however, suggests there may be nothing to fear.

Drugs called immune checkpoint inhibitors are a form of immunotherapy that have transformed — with better targeting and less severe side effects — the treatment of many cancers, including non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors are routinely administered as first-line treatments for NSCLC, either alone or in combination with chemotherapy.

Cannabis, too, has become more widely used among cancer patients over the past decade, paralleling its growing societal acceptance and expanding medical use. In addition to preclinical research and anecdotal accounts indicating that cannabinoids may have anti-cancer effects, cannabis is also well known to mitigate many symptoms and side effects of cancer and cancer treatment, including nausea, pain, and suppressed appetite.

Red Flags from Earlier Studies

Worries about the potential incompatibility of these two treatments stem from the fact that the cannabinoid receptor CB2 is predominately expressed by immune cells, and its activation may suppress immune function. Immunotheraperies like immune checkpoint inhibitors depend upon a robust response to do their work. It’s at least plausible, then, that cannabis might interfere with immunotherapy: instead of helping, it may actually hurt.

In fact, that’s exactly what two previous studies from an Israeli research team in 20194  and 20205  have suggested — though, as the authors of the new paper, also based in Israel, argue right off the bat, those earlier findings come with some pretty large caveats. “These studies included patients with various cancers, treatment regimens, and lines of therapy and were given [immune checkpoint inhibitors] at advanced line shortly before death,” the authors write. “Under these circumstances, the use of cannabis is often a mere surrogate for high-burden symptomatic disease.”

Cannabis contains compounds that directly target cannabinoid receptors. Psychedelics like Lysergic Acid Diethylamide (LSD) target serotonin receptors. By acting through serotonin pathways, LSD affects endocannabinoid synthesis and function, according to a recent study published in the British Journal of Pharmacology.1

The October 2022 BJP study, featuring contributions from Dr. Vincenzo Di Marzo, Gabriella Gobbi, and several other scientists, sought to quantify serotonin and endocannabinoid-like molecules in the brains of mice that were sacrificed after a seven-day LSD regimen. Repeated 30 microgram doses of LSD per kilogram of body weight elicited anxiolytic and prosocial behavior. The researchers from Canada, Italy and Australia also examined how LSD affected the microbiome of the mice after the seven-day, 30-microgram dose routine.

The study noted anti-depressant and anti-anxiety effects triggered by LSD, which altered endocannabinoid tone and affected the serotonin metabolite, kynurenic acid, without impacting the levels of serotonin or its precursor tryptophan. Increased interaction among mice and anxiolytic behavior occurred, in part, through endocannabinoid signaling and corresponded to changes in a few key families of gut bacteria. These results were seen after repeated doses of LSD, not after a single session.

LSD Impacts Endocannabinoid Tone by Binding to Serotonin Receptors

Psilocybin, ayahuasca, mescaline, and LSD cause a psychedelic “trip” by binding to 5HT-2A, a serotonin receptor. This is one of 14 serotonin receptors, which induce a family of enzymes known as phospholipases (PLs). Various serotonin receptors induce different PLs. And two compounds (agonists) that activate the same receptor can promote different enzymes.

Serotonin receptors drive a symphony of endocannabinoid-producing PLs. Previous research has shown that serotonin facilitates the release of 2-AG, a major endocannabinoid, through a phospholipase c (PLC)- dependent mechanism.2 LSD and psilocin (the psychedelic metabolite of psilocybin) induce different PL enzymes by binding to the 5-HT2A receptor.

In recent years, psilocybin and MDMA have been explored as potential treatments for post-traumatic stress disorder, but somewhat more quietly so has cannabis. In fact, according to a few quick searches of PubMed, cannabis has a longer and richer association with PTSD in the scientific literature than any psychedelic. Though you wouldn’t know that by reading the headlines.

Setting aside for a minute how effective psychedelics may or may not be as breakthrough treatments for PTSD, there’s no doubt that cannabis is still much easier for most patients to access.

Recent research – including three new studies (from three different countries) – suggests that growing numbers of PTSD sufferers are medicating with cannabis, and truly finding it helpful.

Depression Drives Cannabis Use

First, a paper in the journal BMC Psychiatry1 from researchers based in Ontario, Canada, provides some insight into cannabis use among PTSD patients during the first wave of the coronavirus pandemic. Between April 3 and June 24 of 2020, 462 individuals with self-reported PTSD completed an online questionnaire that assessed mental health symptoms and cannabis intake both before the pandemic and in the seven days prior to filling out the survey.

Stress, anxiety, and depression worsened across the board, but by categorizing participants according to cannabis use patterns – not using, using less, using the same, or using more – the researchers discovered something interesting. PTSD sufferers who increased their cannabis use during the pandemic were more likely to also experience “meaningful perceived worsening of depression symptoms,” the authors write.

Project CBD is an independent media platform with 100,000-plus subscribers. Our educational website is visited regularly by people from more than 150 countries. We’re proud to say that we’re not backed by billion-dollar multistate operators, whose bottom line depends on stiffing labor unions and engaging in phony equity scams. We don’t make money by advertising products infused with sketchy “hemp-derived” intoxicants like delta-8, delta-10, HHC, THC-O, and other unregulated synthetic compounds. We don’t promote pay-to-play lists of “the best CBD products for (name-your disease)” that have little to do with efficacy and everything to do with which company has the deepest pockets.

At Project CBD, we favor regenerative farmers over pesticide polluters, artisanal craft mom-and-pops over bland potency cookie-cutters. We like our CBD fresh from the garden rather than synthesized in a lab – and that’s not just an aesthetic preference, as we recently warned in a special report about the dangers of non-natural “chiral” versions of lab-created CBD isolate.

We fight against the stigmatization of cannabis, as well as the snake-oil promoters that mislead consumers.

At Project CBD, we fight against the stigmatization of cannabis, as well as the snake-oil promoters that mislead consumers. When Fox News dredges up boogeyman claims that marijuana smoking causes gun violence, we counter with peer-reviewed evidence demonstrating the link between cannabis use and prosocial behavior. And when we see CBD and cannabis brands touting their products as “sleep aids” because they include CBN (cannabinol), we feel it’s our responsibility to let our readers know there’s actually no scientific basis for marketing claims that CBN has soporific properties.

At Project CBD, we understand not everyone is in a position to pay to access our content. That’s why we make our web content and weekly newsletter available free of charge. But if you are able, we really need your help.

CBD has exploded in popularity over the past decade.

Ethan Nadelmann talks about the power and promise of this cannabinoid with one of the world’s leading experts on the subject: Martin A. Lee, author of two highly acclaimed books, Acid Dreams and Smoke Signals, and cofounder and director of ProjectCBD.org. The two cover various topics including what is CBD and how does it work, what is its relationship to THC and what’s the evidence for its medical and health benefits, what role is the FDA playing in regulating hemp and what’s going on outside the United States?

Listen on Spotify

The post CBD: It’s a Molecule, Not a Miracle appeared first on Project CBD.

Think of your brain as an ocean, an ecosystem inhabited by numerous species of fish-like neurotransmitters and their receptors, with currents of electricity connecting and delicately balancing all the different components. Inflammation is like a bloom of red algae, harming everything around it and upsetting the homeostasis of the environment.

Enter our hero, Palmitoylethanolamide (PEA) – a lipid messenger kindred to the endocannabinoid system and a close cousin of anandamide (AEA), the famous endocannabinoid neurotransmitter. Sometimes referred to as “the endogenous version of CBD,” PEA is a powerhouse against inflammation and pain. Like CBD, PEA increases the levels of endocannabinoids and strengthens the endocannabinoid system. And, again like CBD, a constant theme in the scientific literature about PEA is its incredibly strong safety profile.

In our neural ocean metaphor, PEA weighs in as the “most venerable of the leviathans,” the grinning Right Whale, a stalwart fighter in our constant battle against inflammation and pain.

A Mystery

The PEA story begins with a mystery, which leads to another mystery — and ends with the next great wave of the cannabinoid revolution.

We begin during World War 2 – and indeed, geopolitics plays a significant role in our tale. Because of the war effort, we find it a prosperous time for the new-ish field known as “public health.” A healthy population of workers was essential to support the production of war materiel. Two NYC doctors named Coburn and Moore found that if they gave dried eggs to the poor children of the tenements, this helped to prevent rheumatic fever and other ills related to poor nutrition. They also discovered that egg yolks are an anti-inflammatory food.

“It’s rope, not dope!”

So went the clarion call from early activists seeking to restore the incredibly versatile hemp plant to its rightful place in U.S. industrial production. Just a few decades ago, that catchy slogan accurately summarized the distinction between hemp and cannabis. Up until recently, “hemp” referred to low-resin, non-intoxicating Cannabis Sativa L that had been bred for maximum fiber or seed oil content and grown for multiple industrial purposes, while “cannabis” typically meant plants bred and grown for maximum resin content and imbued with medicinal and recreational qualities well-suited for human consumption.

Today, though, the distinction between hemp and high-resin cannabis is muddled. A plethora of so-called hemp products are now being explicitly marketed for their intoxicating effect. In short, modern-day “hemp” looks a lot more like dope than rope, and that’s confusing to consumers and regulators.

It’s crucial to separate fact from fiction as stakeholders grapple with tricky issues regarding THC potency, CBD efficacy, and product safety. Here are seven common industry-promoted fallacies about hemp.

Fallacy #1: “0.3 percent THC is non-intoxicating.”

Contrary to popular belief, the 0.3 percent THC threshold in botanical hemp does not equate to non-intoxicating levels when applied to edibles and beverages. THC is a potent psychoactive compound. A dose is typically measured in milligrams (thousandths of a gram), not grams. A 0.3 percent threshold can result in an astonishingly high amount of THC in a finished product. In a 12-ounce beverage, for example, 0.3 percent translates into over 1,000mg of THC.1 A single, normal-sized “hemp” gummy could have 20mg of THC. For comparison, the maximum THC per serving allowed in edibles in the regulated California cannabis market is 10mg.

Dr. Andrew Weil is the founder and director of the Arizona Center for Integrative Medicine at the University of Arizona College of Medicine. His early publications (The Natural Mind and From Chocolate to Morphine) focused on exploring altered states of consciousness. He is the author of several bestselling books, including Spontaneous Healing (1995), Eating Well for Optimum Health (2000), and Healthy Aging (2007).

NM: As someone who has been researching cannabis for decades, how do you feel about the current legalization situation worldwide and in Japan, in particular?

Dr. Andrew Weil: I think the trend very clearly is that in most developed countries, cannabis is being made legal first for medical uses and then also for recreational uses. And that’s true throughout North America, in many European countries, and I think in some South American countries, as well. So, my feeling is that Japan is very out of step with other developed countries.

However, it has taken a long time to get where we are today in the United States. And cannabis is still in Schedule One of the Controlled Substances Act, making it unavailable at the federal level for therapeutic use. It’s urgent that we get it out of Schedule One. I think that’s going to happen very soon. Most U.S. states have legalized cannabis for medical use and 24 states have legalized recreational use.

NM: Please tell us about the history of cannabis use in folk medicine.

Adapted from The Cannabis Cancer Connection: How to use cannabis and hemp to kill cancer cells by Joe D. Goldstrich, MD, with Angela Bacca (Flower Valley Press, 2023).

There is a growing body of anecdotal and scientific evidence that the “major cannabinoids” tetrahydrocannabinol (THC) and cannabidiol (CBD), certain “minor cannabinoids” (some without a name), and other cannabis compounds have antineoplastic action against cancer cells. 

The vast majority of the existing research is on how specific cannabinoids kill cancer, but a growing body of work is revealing how the entourage of compounds found in whole-plant cannabis kills cancer. 

Although most of the studies presented here demonstrated the antineoplastic effects of individual or isolated cannabinoids, most of this research points to what lay healers and patients who make and use their own cannabis oil already know: the whole cannabis plant, including hemp varieties, every part of them, contain antineoplastic compounds that together kill cancer. 

How THC Kills Cancer

Until relatively recently, almost all medical studies about cannabis have been specifically on THC, as is most of the preclinical research showing the antineoplastic activity of cannabis. With a few exceptions, tumor cells throughout the body have cannabinoid receptors on their surface, and THC can bind to these receptors and induce apoptosis or programmed cell death. Put simply, when THC binds to the cancer cell, it forces the cancer cell to commit suicide.

Every five months Irvin Rosenfeld has gets a FedEx shipment, courtesy of the federal government, containing six metal canisters, each with 300 perfectly rolled joints of what today would be considered rather mediocre weed. But the quality of the government-issue reefer matters less than the fact that Uncle Sam has been supplying him with it regularly since 1982, when Rosenfeld won the right to smoke cannabis for reasons of medical necessity under the auspices of the federal government’s Compassionate Investigational New Drug (IND) program. Rosenfeld smokes cannabis every day to treat a rare and excruciatingly painful bone disease called multiple congenital cartilaginous exotosis.

Medicine in a Can

A total of 15 patients with different incurable ailments would enroll in the Compassionate IND Program to study cannabis before it was officially shut down in 1992. As one of the last living IND participants, Rosenfeld remains a forthright and energetic medical cannabis advocate, a role he takes very seriously. His personal story is compelling. He has suffered with extreme pain for most of his life. At age 10, x-rays revealed more than 200 tumors sprouting from bones in his arms and legs. He would undergo a dozen surgeries and consume a steady diet of prescription narcotics and other pharmaceuticals.

When he first smoked marijuana as a teenager at a social gathering, it was a revelation. Before long he realized that if he smoked cannabis every couple of hours, his pain eased and he didn’t have to rely as much on doctor-prescribed muscle relaxants, opiates, and benzos to get by. Although he felt no euphoric effects from cannabis, the herb somehow kept his disease in check, inhibiting tumor growth and helping him live a decent life. A walking, talking refutation of the lazy stoner myth, he went to college, played sports, married his childhood sweetheart Debbie, and became a successful stockbroker.

There’s no doubt that cannabis helps Rosenfeld’s condition, but it’s not a cure. Though he has learned to live with his pain, at times its relentlessness makes him feel depressed, trapped in a lonely prison from which there’s no escape. At least that’s how it felt until one day in 2020, when Rosenfeld’s pain management specialist, Dr. Michele Weiner, mentioned a potential jailbreak: ketamine.

Dissociation Nation

Ketamine, an FDA-approved “dissociative anesthetic,” has been around since 1962 when it was first synthesized by chemist Calvin Stevens. Employed initially as a tranquilizer in veterinary medicine, the drug was widely utilized during the Vietnam War for treating wounded troops. Ketamine kept injured soldiers conscious but cognitively disconnected from their pain, all while maintaining their vital functions.

Earlier this year, the Food & Drug Administration disclosed that it would not regulate non-pharmaceutical CBD products, thereby putting the onus on Congress to devise an appropriate regulatory framework for cannabidiol and other hemp-derived cannabinoids. Solicited by a formal Congressional Request for Information (RFI) on ideas for how to regulate hemp-derived CBD, public feedback included a diverse range of perspectives from businesses, trade associations, and other stakeholders. But today’s “hemp” market has moved way beyond CBD, as noted by several commentators who expressed concerns about the unregulated proliferation of high-dose THC consumables and novel synthetic intoxicants thanks to loopholes in the 2018 Farm Bill, which is up for revision and renewal in the coming months. What follows are comments recently submitted by Tiffany Devitt, a longtime Project CBD supporter, in response to the Congressional RFI on a potential regulatory pathway for hemp-derived CBD. A leading California cannabis industry policy influencer, Devitt is currently Director of Regulatory Affairs at CannaCraft & March and Ash.

Current Market Dynamics

Loopholes in the 2018 Farm Bill

The 2018 Farm Bill defines “hemp” as “the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.”

Within that definition, are two critical phrases: “all derivatives” and “whether growing or not.”

“All derivatives” is currently being misinterpreted to encompass any compound that can theoretically be chemically synthesized from CBD, even wholly novel compounds not found in the plant in commercially meaningful quantities (if at all).“Whether growing or not” is being misconstrued to mean that the 0.3 percent THC limit applies to the plant biomass and the final product, resulting in THC levels in consumer products labeled as “hemp” that substantially exceed THC limits set in state-regulated cannabis markets.Lastly, the omission of THCA, a natural compound that converts to THC when heated, is causing further confusion.

Collectively, this language has fostered a regulatory gap that companies are taking advantage of to sell highly intoxicating products, colloquially and misleadingly referred to in the national unregulated hemp marketplace as “legal cannabis.”1

The “Hemp” Market Has Moved Way Past CBD

In the federal discussion about hemp, “hemp” and “CBD” are often conflated. The reality is that the commercial market has largely shifted away from non-intoxicating CBD wellness products to highly intoxicating recreational products. Pseudo-hemp companies with brand names like Fuked Up2 and Clusterf*ck3 make no pretense of selling nutritional supplements. Instead, they market THC-like products that are far stronger than anything found in state-regulated cannabis markets, where the maximum dose of THC per serving is commonly capped at five to 10 milligrams.4 In the unregulated “hemp” market, brands like Chapo Extrax sell products with hundreds of milligrams of synthetic THC per serving.5 The so-called “hemp” market is no longer predominantly a wellness market. It is, in the words of Chapo Extrax, “the newest drug cartel in town.”6

I counted over 175 talks and posters at the 33rd annual gathering of the International Cannabinoid Research Society (ICRS), which convened in Toronto at the end of June. In accordance with longstanding ICRS policy, all speakers presented new findings and data that had not yet been published in a peer-reviewed journal. But this year’s 4-day ICRS conference was notable not only for its cutting-edge science. It was also the first ICRS meeting since the passing of its cofounder and guiding light Raphael Mechoulam.

Several colleagues paid homage to Mechoulam in a moving memorial session that honored his many contributions to the burgeoning field of cannabinoid science, which has grown to encompass numerous academic and clinical disciplines. The wide range of topics addressed at the conference is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD & THC

Cannabidiol (CBD) figured prominently in several noteworthy oral presentations and posters that explored the therapeutic potential of plant cannabinoids from various angles. A few highlights:

CBD for breast cancer recovery. Researchers from McGill University in Montreal reported a case study of a 52-yr-old breast cancer survivor who experienced significant improvement in neuropathy symptoms and quality of life following self-administration of 300 mg/day of CBD isolate for six weeks.

CBD for post-concussion syndrome. John Patrick Neary and a team of scientists in Western Canada examined CBD’s impact on 3 female patients who suffered from post-concussion syndrome. They found that cannabidiol helped restore blood pressure dynamics and improve cardiac function in patients who consumed doses as low as 50 mg/day or as high as 400 mg/day.

Dr. Mark A. Scialdone, a recognized expert in the field of organic chemistry who specializes in natural product chemistry, is an inventor of 37 issued US patents and the author of 17 peer-reviewed articles in science publications. From 1994 to 2013, he was employed as a principal investigator at DuPont Central Research and Development. Dr. Scialdone is a founding member of the Cannabis Chemistry Subdivision of the American Chemical Society from which he received the 2018 CANN-CHAS Heidolph Award for Excellence in Cannabis Chemistry. Scialdone is currently founder and president of BetterChem Consulting, which provides consulting services worldwide in the chemical, food, plant essential oil, and cannabis industries. He has guided clients on license applications, facility design and build out, equipment installation and optimization, and plant oil extraction for cannabis and hemp processing facilities.

Project CBD: Your presentation with Allyn Howlett at the International Cannabinoid Research Society conference in Toronto (June 2023) discussed the chemical conversion of CBD into Δ8-THC (delta-8 THC) and “numerous additional THC isomers . . . with unknown pharmacological and safety profiles.” Explain what an isomer is and why the lack of information regarding novel THC isomers is problematic.

Dr. Mark A. Scialdone: Isomers are similar molecules having different discrete arrangements of the same atoms creating molecules with different chemical and physical properties. The Δ8-THC being produced from the acid-catalyzed conversion of CBD is an unpurified reaction mixture that contains multiple, non-natural THC isomers, including Δ8-iso-THC and Δ4(8)-iso-THC. These are not present in cannabis and are only formed in the chemical conversion, whose impact on human health is unknown. What’s more, these non-natural THC isomers are difficult to measure — and they are also difficult, if not impossible, to remove from the reaction mixture to purify the Δ8-THC that’s produced. You need access to sophisticated analytical methods to discern product purity from the isomeric byproducts formed, which is why production from hemp-derived cannabinoid products needs to be done under the appropriate FDA regulations for API [active pharmaceutical ingredient] synthesis and manufacturing.

Project CBD: Are there other byproducts from CBD conversion to Δ8-THC that we should be concerned about in addition to these THC isomers?

Scialdone: In addition to the iso-isomers of THC, there are also abnormal isomers called regioisomers that are formed in the conversion reaction. Recently, degradation products such as olivetol as well as chlorinated compounds, have been found in commercial Δ8-THC products tested. The conversion of hemp-derived CBD into Δ8-THC and other synthetic compounds such as HHC (hexahydrocannabinol) occurs without proper regulatory oversight to ensure process standardization, product specification, and accurate third-party testing, all of which are mandated in state-licensed cannabis programs.

It was once a common assumption within the cannabis community that plant cannabinoids aren’t “activated” or useful until they are “decarbed” — short for decarboxylated — which refers to the process of heating cannabis before it is consumed. But that notion has proven to be way off the mark.

The major and minor cannabinoids in raw, unprocessed cannabis plants are found in their acid form: THCA, CBDA, CBGA, CBCA, and THCVA. When decarboxylated at a particular temperature, these cannabinoid acids are converted into their neutral counterparts: THC, CBD, CBG, CBC, THCV, etc. (and the ‘A’ vanishes). This process also occurs naturally, though much more slowly, as dried cannabis ages.

Jump to raw cannabis smoothie recipes.

Cannabinoid Acids

Thus far, medical scientists have focused primarily on the therapeutic properties of decarbed or neutral cannabinoids. But increasingly, researchers, physicians, and patients are recognizing the value of cannabinoid acids as well as other compounds found in the raw cannabis plant, which contains various enzymes, vitamins, minerals, protein, fiber, essential fatty acids, flavonoids, carotenoids, terpenes, and other polyphenols.

Concentrated in the resinous trichomes of raw cannabis flowers and to a lesser extent on the leaves, cannabinoid acids such as THCA and CBDA offer a robust cornucopia of health benefits without any intoxicating effect. What’s more, cannabinoid acids are more easily absorbed than their decarbed versions.

Pain, anxiety, and sleep are major drivers of medical cannabis use. But gastrointestinal symptoms, such as nausea and upset stomach, aren’t far behind.1 Even small doses of cannabis can soothe the stomach and stimulate the appetite. In fact, of the four cannabis-derived drugs approved so far by the U.S. Food and Drug Administration, three are prescribed for the treatment of chemotherapy-induced nausea and vomiting.

One gastrointestinal condition long associated with self-medication through cannabis is inflammatory bowel disease (IBD). A flurry of recent research bears this out. In a newly published survey of 162 IBD patients in Puerto Rico, where medical cannabis is legal but recreational use is punishable with prison time, about 25% anonymously reported using cannabis to treat their symptoms. Among these, nearly all said it offered relief.

Findings from another recent survey of New York and Minnesota medical cannabis dispensary patients were similar. And two new reviews aimed at physicians and researchers concur that while further study is needed, the evidence to date leaves little doubt that IBD patients are helped by cannabis.

ECS & the Gut

On a molecular level, this all makes sense. The endocannabinoid system is widely distributed throughout the gastrointestinal system, including not only CB1 and CB2 cannabinoid receptors but also other cannabinoid targets like PPARs, GPR55, and TRPV1. The job of the endocannabinoid system here, as everywhere, is to maintain order and balance, and the endogenous compounds (ligands) that interact with these receptors can be supported in this task by cannabis-derived and synthetic cannabinoids.

(The concentration of cannabinoid receptors in the gut also helps to explain cannabis hyperemesis syndrome, in which an overabundance of exogenous cannabinoids, particularly THC, triggers debilitating nausea, vomiting, and pain that typically resolves when cannabis use stops.)