Category: Minor Cannabinoids

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From MMJ to Special K

Brain & Ketamine

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.

Ketamine’s efficacy against pain is attributed to the drug’s ability to induce a dissociative state. At high doses ketamine produces anesthesia; at lower doses, it relieves pain and causes hallucinations. “Special K” acquired a reputation as a party drug in the 1970s due to its psychedelic and mood-altering effects. Favored by fashionistas and Silicon Valley bros, it’s still part of the recreational drug scene.

At high doses ketamine produces anesthesia; at lower doses, it relieves pain and causes hallucinations.

Some have attributed Elon Musk’s erratic behavior of late to ketamine benders at parties. (He says he uses it to relieve depression — proof that money can’t buy everything.) Although ketamine is potentially addictive and excessive use can cause liver damage, renal failure, and psychotic episodes, it’s classified as a Schedule III controlled substance (along with anabolic steroids and some acetaminophen-codeine combinations), indicating a relatively low risk for abuse.

Unlike LSD and psilocybin, ketamine has no natural source. Lysergic acid is present in ergot (rye fungus), psilocybin is a magic mushroom compound, mescaline comes from the peyote cactus, and for MDMA (“ecstasy”) there’s sassafras. But there’s no natural correlate for synthetic ketamine, which works through different molecular pathways than the classic, naturally sourced psychedelics. Acid and ‘shrooms deliver a full-blown psychedelic experience by binding to the 5-HT2A serotonin receptor, whereas ketamine confers its powerful dissociative and psychedelic effects by blocking the N-methyl-d-aspartate (NMDA) receptor, a glutamate ion channel that manages the ebb and flow of calcium inside the cell.

Fertilizer for the Brain

By inhibiting the NMDA receptor, ketamine triggers the production of a chemical known as brain-derived neurotrophic factor (BDNF), which has been likened to “fertilizer of the brain.” The role of BDNF in adult neurogenesis (the creation of new brain cells) and neuroplasticity (the ability to reorganize neural networks and synaptic connections in response to injury and lived experience) is the subject of many scientific papers.

According to a 2012 study by University of Bonn scientist Andras Bilkei-Gorzo: “On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis.” Subsequent reports by Brazilian investigators established that ketamine’s central and peripheral painkilling effects are mediated by the endocannabinoid system. When scientists blocked the CB1 cannabinoid receptor, ketamine did not prevent pain. The same group of researchers also found that ketamine caused anandamide (one of two major endocannabinoids) to be released in certain brain areas. And when anandamide levels increased, so did ketamine’s analgesic effect.

“CBD significantly augmented the activating effects of ketamine.”

Plant cannabinoids have also been shown to potentiate ketamine’s painkilling properties. A 2011 report on “The interplay of cannabinoid and NMDA glutamate receptor systems” examined “the interactive effects of cannabidiol and ketamine in healthy human subjects.” The report concluded that “CBD significantly augmented the activating effects of ketamine.” Other studies have noted that CBD boosts endocannabinoid levels and CB1 receptor signaling by delaying the metabolic breakdown and reuptake of anandamide.

CBD and ketamine are both neurogenic compounds, and this may factor into how they confer antidepressant effects. Impaired neurogenesis has been linked to clinical depression, substance abuse, and other mental health conditions. Ketamine’s rapid antidepressant effects involve enhanced BDNF-induced (and cannabinoid-regulated) neurogenesis and neuroplasticity. The drug is currently being administered off-label for refractory depression at numerous ketamine clinics around the country.

Common Biological Mechanisms

“Pain and depression share common biological mechanisms,” explains Dr. Michelle Weiner, a double board-certified physician who specializes in interventional pain medicine, physical medicine, and rehabilitation. In addition to her clinical practice at five locations in southern Florida, Dr. Weiner is an Assistant Professor at Nova Southeastern University College of Osteopathic Medicine.

Take a spin on her website and you’ll find a group photo picturing Dr. Weiner and her team of practitioners, a bevy of Florida beauties who look as though they could’ve been cast as the Real Housewives of Miami. There’s a lot going on behind the glamor. When interviewed by Project CBD, Dr. Weiner’s enthusiasm for her calling is obvious, her expertise backed by years of on-the-ground research and a vast knowledge rooted in pain studies and cutting-edge neuroscience.

While building her practice, Dr. Weiner grew increasingly frustrated with the limited tools available beyond conventional pain pills and injections. When medical cannabis was legalized in Florida in 2016, she became one of the first licensed physicians to include it in her treatment plans. She found that cannabis was an effective therapeutic option for helping chronic pain patients, especially seniors, decrease their dependence on opioids.

“It really changed my practice,” says Weiner, who is a member of Florida’s Medical Cannabis Advisory Committee. Weiner’s experience as a cannabis clinician encouraged her to explore other mind-body healing modalities, including psychedelic drugs. Today she is vice president of Mr. Psychedelic Law, a not-for-profit that advocates for responsible legal reform of psilocybin prohibition in the Sunshine State.

Teaching Resilience

Dr. Weiner’s interest in ketamine began during a residency and training fellowship at the University of Miami. “Back then we used ketamine differently than we do now,” she says. “We’d give patients a benzodiazepine sedative beforehand to tone down the hallucinatory experiences common with ketamine.” But after learning of ketamine’s potential as treatment for anxiety, depression, and PTSD, she changed her approach to encompass a dual-pronged focus on pain and mental health.

“Eighty-five percent of chronic pain patients also suffer from depression,” says Dr. Weiner. “You can’t successfully treat pain without concurrently treating mental health.” From her perspective, it’s all interconnected: chronic pain adversely impacts how the brain functions, causing maladaptive changes in the central nervous system and weakening synaptic circuitry between brain regions — and these changes often lead to depression, according to a 2017 study published in the journal Neural Plasticity. Not only does it offer rapid relief from both depression and pain, ketamine also appears to refresh and reset neural circuitry.

But the benefits of a single ketamine treatment are often short-lived (seven days on average for depression), and the drug may be contraindicated for certain conditions. Some people can’t tolerate ketamine’s intense hallucinogenic effects. Another major drawback: MediCare and health insurance companies don’t cover ketamine treatments, so patients must pay out of pocket. For those who can’t afford it, there are DIY at-home ketamine kits with medicine procured from less-than-reliable online sources, which is problematic.

“When used mindfully, ketamine, through its dissociative effects, allows patients a time-out from their pain.”

Ketamine treatment needs to be monitored by an experienced practitioner, says Dr. Weiner. Most of her patients come into the clinic once or twice a week for at least a month to receive ketamine by intramuscular or intravenous infusion, along with therapy sessions and lifestyle counseling for a better long-term outcome. Treatment is tapered off over time, and the benefits are maintained with occasional ketamine “boosters,” an approach backed by research. The goal is to relieve pain while helping patients learn new strategies for how to live with it.

“When used mindfully,” says Dr. Weiner, “ketamine, through its dissociative effects, allows patients a time-out from their pain. Yes, it’s temporary, but being able to take a break from intense pain also gives them a chance to see it from a different perspective. It’s not who they are. It’s not their identity. Ketamine disrupts the static and unproductive patterns with which patients deal with their pain and encourages the development of better life strategies. What we’re really doing is teaching them resilience.”

A Remarkable Drug

Unlike Dr. Weiner’s other patients, Irv Rosenfeld has her blessing to treat himself orally with ketamine at his own home. The fact that she makes an exception in Irv’s case is a testament to her admiration and respect for Rosenfeld, who has been under Dr. Weiner’s pain management care for many years.

Every five days or so, when the pain in his bones gets really bad, Irv texts his wife Debbie before he drives home from work: I’m doing ketamine tonight. Debbie knows to stay close by yet out of his way. In order to “do ketamine,” Rosenfeld needs complete isolation and quiet. Once at his house in Fort Lauderdale, he will put on some classical music. Then he’ll place one-and-a-half sublingual tablets containing a total of 300 milligrams of ketamine between his cheek and gum, sit down in a comfortable armchair, and wait for the portal to open. His flight from pain is about to take off.

About an hour passes before Rosenfeld notices any effects. When they arrive, the feelings are both physical and emotional. He can see “the pain flow out and float far away,” he tells Project CBD. Under the influence of “forgetamine,” existential agony and exhaustion are replaced by euphoric hallucinations lasting several hours with his eyes closed.

Rosenfeld accepts that the relief he gets from ketamine won’t last beyond his solitary, three-to-four-hour sit-down sessions. But the knowledge that he can occasionally be whisked away from the Land of Pain is in and of itself transformative, nourishing his innate resilience and helping him tackle life’s daily challenges.

“It’s a remarkable drug,” he says with an obvious tone of gratitude. Just as pain has influenced the course of Rosenfeld’s life, so has his outspoken activism, his efforts to get the word out about the therapeutic benefits of cannabis before most people knew much about it. And now he’s also singing the praises of ketamine. Listening to him talk is uplifting, like getting a dose of medicine you really need.

Melinda Misuraca is a Project CBD contributing writer with a past life as an old-school cannabis farmer specializing in CBD-rich cultivars. Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

Sources

  • Bilkei-Gorzo A. The endocannabinoid system in normal and pathological brain ageing. Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3326-41. doi: 10.1098/rstb.2011.0388. PMID: 23108550; PMCID: PMC3481530.
  • Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depresson: new insights from stress and rapid-acting antidepressants. Nat Med [Internet]. 2016;22(3):238–49.
  • Ferreira RCM, Castor MGM, Piscitelli F, Di Marzo V, Duarte IDG, Romero TRL. The Involvement of the Endocannabinoid System in the Peripheral Antinociceptive Action of Ketamine. J Pain. 2018 May;19(5):487-495. doi: 10.1016/j.jpain.2017.12.002. Epub 2017 Dec 13. PMID: 29247851.
  • Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrão J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):198-202. doi: 10.1016/j.pnpbp.2010.11.002. Epub 2010 Nov 7. PMID: 21062637.
  • Khakpai F, Ebrahimi-Ghiri M, Alijanpour S, Zarrindast MR. Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system. Biomed Pharmacother. 2019 Apr;112:108717. doi: 10.1016/j.biopha.2019.108717. Epub 2019 Feb 28. PMID: 30970516.
  • Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS, Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013 Aug 15;74(4):250-6. doi: 10.1016/j.biopsych.2012.06.022. Epub 2012 Jul 27. PMID: 22840761; PMCID: PMC3725185.
  • Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol. 2014;54:119-39. doi: 10.1146/annurev-pharmtox-011613-135950. PMID: 24392693; PMCID: PMC4089991.
  • Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69 Suppl E1:4-7. PMID: 18494537.
  • Pacheco DDF, Romero TRL, Duarte IDG. Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors. Neurosci Lett. 2019 Apr 23;699:140-144. doi: 10.1016/j.neulet.2019.01.059. Epub 2019 Feb 1. PMID: 30716423.
  • Pourmand A, Mazer-Amirshahi M, Royall C, Alhawas R, Shesser R. Low dose ketamine use in the emergency department, a new direction in pain management. Am J Emerg Med. 2017 Jun;35(6):918-921. doi: 10.1016/j.ajem.2017.03.005. Epub 2017 Mar 2. PMID: 28285863.
  • Riccardi A, Guarino M, Serra S, Spampinato MD, Vanni S, Shiffer D, Voza A, Fabbri A, De Iaco F; Study and Research Center of the Italian Society of Emergency Medicine. Narrative Review: Low-Dose Ketamine for Pain Management. J Clin Med. 2023 May 2;12(9):3256. doi: 10.3390/jcm12093256. PMID: 37176696; PMCID: PMC10179418.
  • Sheng J, Liu S, Wang Y, Cui R, Zhang X. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural Plast. 2017;2017:9724371. doi: 10.1155/2017/9724371. Epub 2017 Jun 19. PMID: 28706741; PMCID: PMC5494581.
  • Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018 Apr;23(4):801-811. doi: 10.1038/mp.2017.255. Epub 2018 Mar 13. PMID: 29532791; PMCID: PMC5999402.

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Memo to Congress: Fix the Farm Bill

Congress

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 contributor, 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

Synthetic Compounds & Escalating Potencies

While the recreational hemp market started with delta-8 THC, we’re now seeing pseudo-hemp companies in an all-out race to synthesize new compounds that are significantly stronger than anything naturally occurring. In this respect, the so-called hemp market has much in common with the illicit opiate market. This trend has given rise to a new generation of designer drugs with astonishingly high potencies. For example, one of the most recent synthetic cannabinoids to come to market, “delta-9P,” is 35 times more potent than the natural THC found in cannabis.7

The argument that anything that can be synthesized from hemp-derived CBD is legal is flat-out wrong. Methamphetamines can be synthesized from over-the-counter cough medicine, but that doesn’t make meth legal. In a shocking sign of just how far hemp purveyors are willing to take this thinking, the CEO of the hemp company 3Chi recently asserted in a legal proceeding that if heroin could be synthesized from CBD, it would be exempt from the Controlled Substances Act.8

Safety Issues Associated with Synthetic Cannabinoids

This new generation of designer drugs is reminiscent of “Spice,” “K2,” and other synthetic cannabinoids that emerged in the illicit drug market in the early 2000s.9 We cannot assume that these novel compounds are safe based on the safety profile of natural cannabinoids. On the contrary, there is significant evidence that synthetic cannabinoids are dangerous.10 They have been linked to seizures,11 acute respiratory failure,12 heart attack,13 stroke,14 lung injury,15 kidney damage,16 psychosis,17 and even death.18

Many “Hemp” Cannabinoids Are Made in a Lab – Not from Hemp or CBD

Synthesizing new compounds from hemp-derived CBD requires an enormous amount of biomass. Thus, it’s reasonable to assume that, as the “hemp” product market is exploding, the agricultural market should also be booming. But the opposite is true. The amount of hemp under cultivation in the U.S. has shrunk by 48 percent since 2021.19 This is in part because most of the new compounds being sold as hemp simply cannot be synthesized from CBD.20 They are “man-made chemicals produced in underground labs, often in China, and then shipped to the United States in powder or crystal form.”21

Manufacturing Impurities & Byproducts

Equally important, in the stampede to market “legal cannabis,” so-called hemp companies are willfully ignoring safety issues related to the acid-catalyzed conversion of CBD into THC-like compounds. According to experts, the conversion process can produce numerous additional THC isomers with unknown pharmacological and safety effects.22 These non-natural THC-like isomers are difficult to measure and almost impossible to remove from the end product.23 Yet this conversion is occurring without regulatory oversight to ensure process standardization, product specification, and accurate third-party testing, all of which are mandated in state-licensed cannabis programs.

Marketing to Minors

Unlike state-regulated cannabis, this new wave of acutely intoxicating substances is easily accessible to minors. These products are sold online, in convenience stores, gas stations, smoke shops, and vending machines across the country. A recent study in the Journal of Cannabis Research revealed that around 85 percent of intoxicating hemp brands lack substantial age verification at checkout.24 Over 80 percent did not have child-resistant packaging.25 Additionally, these brands often use child-friendly marketing strategies, such as cartoons and mimicry of popular candies and snacks, practices prohibited in most regulated cannabis markets. Some actively advertise their “discreet” shipping with no adult signature required.26

Capt’n Chronic27 Delta-8 Oreos28 Jolly Rancher29 Skittles30
Examples of intoxicating hemp products that appeal to children.

Notably, since Congress passed the 2018 Farm Bill, there has been a significant increase in reported cannabinoid poisonings among children and teens, an uptick that parallels the proliferation of intoxicating “hemp” products.31 The Centers for Disease Control and Prevention (CDC) reports that cannabinoid-related emergency department visits among young people also increased during this period.32

Pathways

The hemp framework under consideration today must prioritize consumer safety, provide a stable agricultural market for hemp farmers, and respect states’ rights to regulate intoxicating cannabinoid products. To achieve this, two things need to happen. First, Congress needs to close the loopholes in the Farm Bill, which was never intended to open the floodgates for intoxicating, synthetic products. Second, appropriate regulatory pathways (under FDA authority) must be defined for three distinct classes of cannabinoid products:

  1. Non-intoxicating naturally derived cannabinoid products
  2. Intoxicating naturally derived cannabinoid products
  3. Synthetic designer drugs

Step 1: Fix the Farm Bill

Based on the realities of the CBD/hemp market described above, it is imperative that the definition of hemp in the Farm Bill be amended to:

  • Include THC-equivalent compounds within the THC threshold.
  • Clarify that the THC percentage threshold applies strictly to hemp biomass, not finished goods.
  • Explicitly exclude novel synthetic compounds from the hemp definition and subject them to FDA oversight.

Step 2: Regulatory Pathways

Considering the public health crisis posed by the proliferation of intoxicating synthetic drugs sold as hemp, we believe that Congress and the FDA must utilize existing pathways to regulate hemp-derived cannabinoid products under FDA and state authorities, as described below. Concurrently, Congress must work with the FDA to develop a much-needed regulatory framework for the unique cannabinoid marketplace.

  1. Non-Intoxicating Naturally Derived Cannabinoid Products
    This category includes non-intoxicating natural cannabinoids that can be extracted from hemp (or cannabis), such as CBD, CBDA, and CBG. These compounds should be authorized as food additives consistent with state law and regulated appropriately under federal and state authorities based on the product’s end use, i.e., topicals, ingestibles, and inhalables. To mitigate toxicological concerns, the FDA might consider including a warning about the importance of consulting with one’s doctor on potential CBD-drug interactions. (It is worth noting that CBD is not the first natural compound to be used as an ingredient in both prescription drugs and foods, cosmetics, and over-the-counter medications. Caffeine can also be found in pharmaceutical33 and non-pharmaceutical products.)
  2. Intoxicating Naturally Derived Cannabinoid Products
    This category includes traditional delta-9 THC and other naturally occurring and intoxicating cannabinoids. These compounds (including delta-8) are molecularly similar to THC and arguably are THC analogues, as defined in the Federal Analogue Act, 21 U.S.C. § 813. As such, they should be treated in a manner that aligns with state-regulated cannabis products. All intoxicating cannabinoid products – whether derived from cannabis or hemp (which are the same plant) – should fall under the jurisdiction of state cannabis programs and be subject to the same sales and marketing restrictions and safety standards.
  3. Synthetic Designer Drugs
    This category includes cannabinoids that are chemically synthesized from hemp or other materials. They are not found in the plant in commercially meaningful quantities (if at all). As these compounds are new and distinct from natural plant cannabinoids, they should be subject to FDA oversight and undergo toxicology studies. This category includes THCO, THCB, THCP, delta9P, THCX, THCH, THCjd, HHCO, HHCP, HXCP, and numerous other new compounds being brought to market at an alarming rate.

In summary, we urge Congress to immediately rectify the loopholes in the Farm Bill and employ established regulatory structures to enable the sale of non-intoxicating CBD products as health supplements – not as starter material for concocting unregulated THC analogues and synthetics.

Safety

The Problem with Percentages

As mentioned earlier, the 0.3 percent delta-9 THC threshold for hemp is currently being misapplied to manufactured products. This is especially troubling in the edible market, where other non-hemp ingredients are present. THC is a potent compound – a dose is typically measured in milligrams (thousandths of a gram), not grams.

As shown in the table below, applying the THC percentage threshold to the final product means that hemp-infused edibles and beverages could have 100 times the amount of THC allowed in most state-regulated cannabis products.

PRODUCT TYPE 2 GUMMIES 1 COOKIE 1 BROWNIE 1 BEVERAGE
UNIT WEIGHT 5.8g 16g 70g 340g
ALLOWABLE THC (0.3%) 17.4mg 48mg 210mg 1020mg

(Unsurprisingly, a recent study found that 26.5 percent of so-called hemp delta-9 products are illegally sourced from marijuana plants.)34

The Need for THC Caps in Hemp Products

Since using a percentage threshold is not a workable regulatory strategy, hemp products must have THC caps to ensure that routine use of these products does not cause intoxication. Moreover, we must bear in mind that how product makers define a serving size often differs from how consumers define it. (Ben & Jerry’s can claim that a single serving of ice cream is just over a half cup, but many of us are eating a lot more.) Thus, the federal standard must specify the maximum THC per serving and package. A typical sub-intoxicating dose of THC for most people is between 0.5 and 2.5mg, depending on the person’s THC tolerance.35 Accordingly, several states36 have adopted the standard of 0.5mg of THC per serving and 2.5mg per package for hemp products. Others, like Washington state, restrict products with any THC to the state cannabis market.

Does CBD Really Have a “THC-Sparing” Effect?

Some hemp marketers have misleadingly argued that CBD has a “THC-sparing” effect. The implication is that CBD neutralizes or counteracts the intoxicating effect of THC,37 and therefore, THC limits can be higher if the two compounds are combined. Not so, according to a recent study in Neuropsychopharmacology that assessed the psychotropic effects of co-administering 10 mg of THC with 0, 10, 20, and 30 mg of CBD. The conclusion: “CBD did not impact THC-induced cognitive impairment, psychotic-like experiences, or ratings of intoxication, anxiety, or drug liking at any dose. These findings do not support the hypothesis that CBD has THC-sparing effects when co-administered according to commonly used doses and routes of administration.”38,39 Other studies suggest that low doses of CBD can amplify THC’s intoxicating effects, while very high amounts (400 or more milligrams) may reduce the THC high somewhat but extend its duration.40 In other words, the quantity of CBD in a hemp product is irrelevant to the question of how much THC is appropriate.

What About THCA?

Another emerging category in the unregulated hemp market is “smokable hemp” or “THCA flower.” THCA hemp flower has high concentrations of THCA and less than 0.3 percent delta-9 THC. However, when THCA is heated – as when smoked – almost 90 percent41 of it converts to traditional THC. In other words, THCA flower is essentially old-fashioned weed that’s been rebranded. Its existence rests entirely on the spurious argument that the Farm Bill doesn’t explicitly mention THCA. Here is a comparison of “hemp THCA flower” and cannabis flower from Cannabis Law:42

“Hemp THCA Flower” Cannabis Flower
THCA 25% 24%
Delta-9 THC 0.18% 1.24%
Total THC when heated 22% 22%

There is no meaningful difference.

It should be self-evident that the total amount of THC in hemp products must account for all potentially intoxicating cannabinoids, including THCA. Indeed, in state cannabis markets, THCA is always included in the definition of THC and the calculation of total THC.

Federal-State Interaction

Mixed Messages & Enforcement Failures

The sale and proliferation of pseudo-hemp designer drugs and “THCA hemp flower” have gone virtually unchecked. Some states have banned these substances, but enforcement has generally been anemic and unsuccessful in the face of an onslaught of online, direct-to-consumer mail-order businesses.

Moreover, several states have been stymied by the conflicting messages from the federal government. The Federal Analogue Act states that any substance that “has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in Schedule I or II” must be treated like a Schedule I substance.43 That would imply that intoxicating THC analogues synthesized from hemp warrant the same restrictions as marijuana. But in May 2022, the Ninth Circuit Court of Appeals upended the Federal Analogue Act when it ruled that products containing delta-8 THC are lawful under the Farm Bill because they meet the statutory definition of industrial hemp – even though they can get consumers high.44

This contradictory and controversial decision has been cited in several lawsuits45 aimed at overturning state laws restricting the sales of intoxicating products that product-makers claim to be derived from hemp. A Kentucky court referenced the Ninth Circuit’s decision when it rejected an argument that delta-8 is a derivative of a derivative and is, therefore, synthetic and illegal under the Farm Bill. A Georgia state court46 and the Minnesota legislature47 recently enacted similar positions.

Conclusions & Recommendations

The 2018 Farm Bill was enacted to legalize wildly popular, non-intoxicating CBD products. Instead, it inadvertently opened a Pandora’s Box of high-potency edibles, sketchy vape products, and the cannabis equivalent of bathtub gin. These products are rife with contaminants and chemical byproducts,48 easily accessible and sold without age gates,49 testing standards, packaging and labeling requirements, marketing limitations, or even a proper understanding of their potential effects on consumers. Otherwise put: In 2018, Congress set out to legalize the equivalent of kombucha (CBD) and accidentally appeared to legalize moonshine instead – all the while maintaining the prohibition on traditional THC, the wine or beer equivalent in this analogy.

Four things are needed to rectify this situation:

  1. The Farm Bill needs to be amended to close the unintended loopholes. Specifically, Congress needs to clarify that (i) the 0.3 percent THC threshold applies only to hemp biomass, not finished goods; (ii) “THC” legally refers to all forms of tetrahydrocannabinol, including THCA, delta-8 THC, and other natural THC analogs; and (iii) novel synthetic compounds are excluded from the definition of hemp and subject to FDA oversight.
  2. Until cannabis is legalized at a federal level, and to avoid undermining states’ rights to regulate intoxicating cannabinoid products, Congress must apply a cap on the amount of THC and THC-equivalent compounds in hemp consumer products to ensure they are non-intoxicating.
  3. A pathway needs to be established to sell CBD and other natural non-intoxicating cannabinoids as food additives and nutritional supplements.
  4. There must be a concerted effort by the FDA and DEA to address the public health crisis spawned by the proliferation of unregulated designer drugs being sold under the guise of hemp.

Lastly, in the long term, Congress should lay the groundwork for a unified regulatory framework for intoxicating cannabinoids, irrespective of whether they’re source from cannabis or hemp.

Tiffany Devitt heads up regulatory affairs for CannaCraft and March and Ash and sits on the board of the California Cannabis Industry Association (CCIA). May not be reprinted without permission.

Footnotes

  1. https://www.instagram.com/p/CszDtayPScA/?utm_source=ig_web_copy_link&igshid=MzRlODBiNWFlZA==
  2. https://fukedup.com/
  3. https://hionnature.com/products/3000mg-knockout-gummy-bites-clusterf-cks
  4. https://www.marijuanaventure.com/edibles-regulations-vary/
  5. https://chapoextrax.com/product/very-berry-live-resin-3500mg-gummies/
  6. https://chapoextrax.com/
  7. https://hightimes.com/sponsored/what-is-delta-9p-everything-you-need-to-know/
  8. 3C, LLC d/b/a/ 3Chi and MIDWEST HEMP COUNCIL, Plaintiffs, v. ATTORNEY GENERAL TODD ROKITA, in his official capacity, and STATE OF INDIANA, Case No. 1:23-cv-01115-JRS-MKK, U.S. DISTRICT COURT SOUTHERN DISTRICT OF INDIANA INDIANAPOLIS DIVISION.
  9. https://nida.nih.gov/publications/drugfacts/synthetic-cannabinoids-k2spice
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999798/
  11. https://publications.aap.org/aapnews/news/14002/Study-Seizures-coma-more-common-with-synthetic
  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875316
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826922/
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863350/
  15. https://pubs.acs.org/doi/10.1021/acs.chemrestox.2c00170
  16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033635/
  17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939204/
  18. https://pubmed.ncbi.nlm.nih.gov/31389266/
  19. https://downloads.usda.library.cornell.edu/usda-esmis/files/gf06h2430/76538f824/w9506f61g/hempan23.pdf
  20. https://projectcbd.org/hemp/expert-gives-delta-8-thc-a-thumbs-down
  21. https://www2.texasattorneygeneral.gov/files/initiatives/synth/Synthetic_drug_factsheet_accessible.pdf
  22. https://cen.acs.org/biological-chemistry/natural-products/Delta-8-THC-craze-concerns/99/i31
  23. https://projectcbd.org/hemp/expert-gives-delta-8-thc-a-thumbs-down/
  24. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  25. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  26. https://shop.cookies.co/pages/shipping-policy
  27. https://deltadreamz.com/shop/ols/products/cap-n-chronic-1000mg
  28. https://www.kratomstoresohio.com/delta-8-products/
  29. https://dazeddragons.com/store/delta-8-jolly-rancher/
  30. https://www.cbdsupplymd.com/shop/skittles-wild-berry-delta-8-400mg-20-count/
  31. https://publications.aap.org/pediatrics/article/151/2/e2022057761/190427/Pediatric-Edible-Cannabis-Exposures-and-Acute
  32. https://www.cdc.gov/mmwr/volumes/72/wr/mm7228a1.htm?s_cid=mm7228a1_w
  33. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c018be7d-f7b8-45e2-97b8-8e7a71740657
  34. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  35. https://weedmaps.com/learn/products-and-how-to-consume/decide-how-much-to-take
  36. Including Maryland and Montana.
  37. https://sensiseeds.com/en/blog/can-cbd-counteract-the-effects-of-thc/
  38. https://doi.org/10.1038/s41386-022-01478-z
  39. https://pubmed.ncbi.nlm.nih.gov/36380220/
  40. https://pubmed.ncbi.nlm.nih.gov/30661105/
  41. https://www.conflabs.com/why-0-877/
  42. https://cannabusiness.law/thca-flower-the-next-big-thing-in-hempland
  43. https://www.law.cornell.edu/uscode/text/21/813
  44. See AK Futures, LLC v. Boyd Street Distro, LLC, 35 F4th 682 (9th. Cir. 2022)
  45. https://www.courthousenews.com/wp-content/uploads/2023/06/Indiana-hemp-AG-opinion-lawsuit.pdf
  46. https://cannabislaw.report/lawsuit-filed-in-georgia-argues-delta-8-and-delta-10-products-are-legal-under-state-law/
  47. https://mjbizdaily.com/wp-content/uploads/2022/05/HF3595.2.pdf
  48. https://pubmed.ncbi.nlm.nih.gov/36264171/
  49. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6

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Memo to Congress: Fix the Farm Bill

Congress

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

Synthetic Compounds & Escalating Potencies

While the recreational hemp market started with delta-8 THC, we’re now seeing pseudo-hemp companies in an all-out race to synthesize new compounds that are significantly stronger than anything naturally occurring. In this respect, the so-called hemp market has much in common with the illicit opiate market. This trend has given rise to a new generation of designer drugs with astonishingly high potencies. For example, one of the most recent synthetic cannabinoids to come to market, “delta-9P,” is 35 times more potent than the natural THC found in cannabis.7

The argument that anything that can be synthesized from hemp-derived CBD is legal is flat-out wrong. Methamphetamines can be synthesized from over-the-counter cough medicine, but that doesn’t make meth legal. In a shocking sign of just how far hemp purveyors are willing to take this thinking, the CEO of the hemp company 3Chi recently asserted in a legal proceeding that if heroin could be synthesized from CBD, it would be exempt from the Controlled Substances Act.8

Safety Issues Associated with Synthetic Cannabinoids

This new generation of designer drugs is reminiscent of “Spice,” “K2,” and other synthetic cannabinoids that emerged in the illicit drug market in the early 2000s.9 We cannot assume that these novel compounds are safe based on the safety profile of natural cannabinoids. On the contrary, there is significant evidence that synthetic cannabinoids are dangerous.10 They have been linked to seizures,11 acute respiratory failure,12 heart attack,13 stroke,14 lung injury,15 kidney damage,16 psychosis,17 and even death.18

Many “Hemp” Cannabinoids Are Made in a Lab – Not from Hemp or CBD

Synthesizing new compounds from hemp-derived CBD requires an enormous amount of biomass. Thus, it’s reasonable to assume that, as the “hemp” product market is exploding, the agricultural market should also be booming. But the opposite is true. The amount of hemp under cultivation in the U.S. has shrunk by 48 percent since 2021.19 This is in part because most of the new compounds being sold as hemp simply cannot be synthesized from CBD.20 They are “man-made chemicals produced in underground labs, often in China, and then shipped to the United States in powder or crystal form.”21

Manufacturing Impurities & Byproducts

Equally important, in the stampede to market “legal cannabis,” so-called hemp companies are willfully ignoring safety issues related to the acid-catalyzed conversion of CBD into THC-like compounds. According to experts, the conversion process can produce numerous additional THC isomers with unknown pharmacological and safety effects.22 These non-natural THC-like isomers are difficult to measure and almost impossible to remove from the end product.23 Yet this conversion is occurring without regulatory oversight to ensure process standardization, product specification, and accurate third-party testing, all of which are mandated in state-licensed cannabis programs.

Marketing to Minors

Unlike state-regulated cannabis, this new wave of acutely intoxicating substances is easily accessible to minors. These products are sold online, in convenience stores, gas stations, smoke shops, and vending machines across the country. A recent study in the Journal of Cannabis Research revealed that around 85 percent of intoxicating hemp brands lack substantial age verification at checkout.24 Over 80 percent did not have child-resistant packaging.25 Additionally, these brands often use child-friendly marketing strategies, such as cartoons and mimicry of popular candies and snacks, practices prohibited in most regulated cannabis markets. Some actively advertise their “discreet” shipping with no adult signature required.26

Capt’n Chronic27 Delta-8 Oreos28 Jolly Rancher29 Skittles30
Examples of intoxicating hemp products that appeal to children.

Notably, since Congress passed the 2018 Farm Bill, there has been a significant increase in reported cannabinoid poisonings among children and teens, an uptick that parallels the proliferation of intoxicating “hemp” products.31 The Centers for Disease Control and Prevention (CDC) reports that cannabinoid-related emergency department visits among young people also increased during this period.32

Pathways

The hemp framework under consideration today must prioritize consumer safety, provide a stable agricultural market for hemp farmers, and respect states’ rights to regulate intoxicating cannabinoid products. To achieve this, two things need to happen. First, Congress needs to close the loopholes in the Farm Bill, which was never intended to open the floodgates for intoxicating, synthetic products. Second, appropriate regulatory pathways (under FDA authority) must be defined for three distinct classes of cannabinoid products:

  1. Non-intoxicating naturally derived cannabinoid products
  2. Intoxicating naturally derived cannabinoid products
  3. Synthetic designer drugs

Step 1: Fix the Farm Bill

Based on the realities of the CBD/hemp market described above, it is imperative that the definition of hemp in the Farm Bill be amended to:

  • Include THC-equivalent compounds within the THC threshold.
  • Clarify that the THC percentage threshold applies strictly to hemp biomass, not finished goods.
  • Explicitly exclude novel synthetic compounds from the hemp definition and subject them to FDA oversight.

Step 2: Regulatory Pathways

Considering the public health crisis posed by the proliferation of intoxicating synthetic drugs sold as hemp, we believe that Congress and the FDA must utilize existing pathways to regulate hemp-derived cannabinoid products under FDA and state authorities, as described below. Concurrently, Congress must work with the FDA to develop a much-needed regulatory framework for the unique cannabinoid marketplace.

  1. Non-Intoxicating Naturally Derived Cannabinoid Products
    This category includes non-intoxicating natural cannabinoids that can be extracted from hemp (or cannabis), such as CBD, CBDA, and CBG. These compounds should be authorized as food additives consistent with state law and regulated appropriately under federal and state authorities based on the product’s end use, i.e., topicals, ingestibles, and inhalables. To mitigate toxicological concerns, the FDA might consider including a warning about the importance of consulting with one’s doctor on potential CBD-drug interactions. (It is worth noting that CBD is not the first natural compound to be used as an ingredient in both prescription drugs and foods, cosmetics, and over-the-counter medications. Caffeine can also be found in pharmaceutical33 and non-pharmaceutical products.)
  2. Intoxicating Naturally Derived Cannabinoid Products
    This category includes traditional delta-9 THC and other naturally occurring and intoxicating cannabinoids. These compounds (including delta-8) are molecularly similar to THC and arguably are THC analogues, as defined in the Federal Analogue Act, 21 U.S.C. § 813. As such, they should be treated in a manner that aligns with state-regulated cannabis products. All intoxicating cannabinoid products – whether derived from cannabis or hemp (which are the same plant) – should fall under the jurisdiction of state cannabis programs and be subject to the same sales and marketing restrictions and safety standards.
  3. Synthetic Designer Drugs
    This category includes cannabinoids that are chemically synthesized from hemp or other materials. They are not found in the plant in commercially meaningful quantities (if at all). As these compounds are new and distinct from natural plant cannabinoids, they should be subject to FDA oversight and undergo toxicology studies. This category includes THCO, THCB, THCP, delta9P, THCX, THCH, THCjd, HHCO, HHCP, HXCP, and numerous other new compounds being brought to market at an alarming rate.

In summary, we urge Congress to immediately rectify the loopholes in the Farm Bill and employ established regulatory structures to enable the sale of non-intoxicating CBD products as health supplements – not as starter material for concocting unregulated THC analogues and synthetics.

Safety

The Problem with Percentages

As mentioned earlier, the 0.3 percent delta-9 THC threshold for hemp is currently being misapplied to manufactured products. This is especially troubling in the edible market, where other non-hemp ingredients are present. THC is a potent compound – a dose is typically measured in milligrams (thousandths of a gram), not grams.

As shown in the table below, applying the THC percentage threshold to the final product means that hemp-infused edibles and beverages could have 100 times the amount of THC allowed in most state-regulated cannabis products.

PRODUCT TYPE 2 GUMMIES 1 COOKIE 1 BROWNIE 1 BEVERAGE
UNIT WEIGHT 5.8g 16g 70g 340g
ALLOWABLE THC (0.3%) 17.4mg 48mg 210mg 1020mg

(Unsurprisingly, a recent study found that 26.5 percent of so-called hemp delta-9 products are illegally sourced from marijuana plants.)34

The Need for THC Caps in Hemp Products

Since using a percentage threshold is not a workable regulatory strategy, hemp products must have THC caps to ensure that routine use of these products does not cause intoxication. Moreover, we must bear in mind that how product makers define a serving size often differs from how consumers define it. (Ben & Jerry’s can claim that a single serving of ice cream is just over a half cup, but many of us are eating a lot more.) Thus, the federal standard must specify the maximum THC per serving and package. A typical sub-intoxicating dose of THC for most people is between 0.5 and 2.5mg, depending on the person’s THC tolerance.35 Accordingly, several states36 have adopted the standard of 0.5mg of THC per serving and 2.5mg per package for hemp products. Others, like Washington state, restrict products with any THC to the state cannabis market.

Does CBD Really Have a “THC-Sparing” Effect?

Some hemp marketers have misleadingly argued that CBD has a “THC-sparing” effect. The implication is that CBD neutralizes or counteracts the intoxicating effect of THC,37 and therefore, THC limits can be higher if the two compounds are combined. Not so, according to a recent study in Neuropsychopharmacology that assessed the psychotropic effects of co-administering 10 mg of THC with 0, 10, 20, and 30 mg of CBD. The conclusion: “CBD did not impact THC-induced cognitive impairment, psychotic-like experiences, or ratings of intoxication, anxiety, or drug liking at any dose. These findings do not support the hypothesis that CBD has THC-sparing effects when co-administered according to commonly used doses and routes of administration.”38,39 Other studies suggest that low doses of CBD can amplify THC’s intoxicating effects, while very high amounts (400 or more milligrams) may reduce the THC high somewhat but extend its duration.40 In other words, the quantity of CBD in a hemp product is irrelevant to the question of how much THC is appropriate.

What About THCA?

Another emerging category in the unregulated hemp market is “smokable hemp” or “THCA flower.” THCA hemp flower has high concentrations of THCA and less than 0.3 percent delta-9 THC. However, when THCA is heated – as when smoked – almost 90 percent41 of it converts to traditional THC. In other words, THCA flower is essentially old-fashioned weed that’s been rebranded. Its existence rests entirely on the spurious argument that the Farm Bill doesn’t explicitly mention THCA. Here is a comparison of “hemp THCA flower” and cannabis flower from Cannabis Law:42

“Hemp THCA Flower” Cannabis Flower
THCA 25% 24%
Delta-9 THC 0.18% 1.24%
Total THC when heated 22% 22%

There is no meaningful difference.

It should be self-evident that the total amount of THC in hemp products must account for all potentially intoxicating cannabinoids, including THCA. Indeed, in state cannabis markets, THCA is always included in the definition of THC and the calculation of total THC.

Federal-State Interaction

Mixed Messages & Enforcement Failures

The sale and proliferation of pseudo-hemp designer drugs and “THCA hemp flower” have gone virtually unchecked. Some states have banned these substances, but enforcement has generally been anemic and unsuccessful in the face of an onslaught of online, direct-to-consumer mail-order businesses.

Moreover, several states have been stymied by the conflicting messages from the federal government. The Federal Analogue Act states that any substance that “has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in Schedule I or II” must be treated like a Schedule I substance.43 That would imply that intoxicating THC analogues synthesized from hemp warrant the same restrictions as marijuana. But in May 2022, the Ninth Circuit Court of Appeals upended the Federal Analogue Act when it ruled that products containing delta-8 THC are lawful under the Farm Bill because they meet the statutory definition of industrial hemp – even though they can get consumers high.44

This contradictory and controversial decision has been cited in several lawsuits45 aimed at overturning state laws restricting the sales of intoxicating products that product-makers claim to be derived from hemp. A Kentucky court referenced the Ninth Circuit’s decision when it rejected an argument that delta-8 is a derivative of a derivative and is, therefore, synthetic and illegal under the Farm Bill. A Georgia state court46 and the Minnesota legislature47 recently enacted similar positions.

Conclusions & Recommendations

The 2018 Farm Bill was enacted to legalize wildly popular, non-intoxicating CBD products. Instead, it inadvertently opened a Pandora’s Box of high-potency edibles, sketchy vape products, and the cannabis equivalent of bathtub gin. These products are rife with contaminants and chemical byproducts,48 easily accessible and sold without age gates,49 testing standards, packaging and labeling requirements, marketing limitations, or even a proper understanding of their potential effects on consumers. Otherwise put: In 2018, Congress set out to legalize the equivalent of kombucha (CBD) and accidentally appeared to legalize moonshine instead – all the while maintaining the prohibition on traditional THC, the wine or beer equivalent in this analogy.

Four things are needed to rectify this situation:

  1. The Farm Bill needs to be amended to close the unintended loopholes. Specifically, Congress needs to clarify that (i) the 0.3 percent THC threshold applies only to hemp biomass, not finished goods; (ii) “THC” legally refers to all forms of tetrahydrocannabinol, including THCA, delta-8 THC, and other natural THC analogs; and (iii) novel synthetic compounds are excluded from the definition of hemp and subject to FDA oversight.
  2. Until cannabis is legalized at a federal level, and to avoid undermining states’ rights to regulate intoxicating cannabinoid products, Congress must apply a cap on the amount of THC and THC-equivalent compounds in hemp consumer products to ensure they are non-intoxicating.
  3. A pathway needs to be established to sell CBD and other natural non-intoxicating cannabinoids as food additives and nutritional supplements.
  4. There must be a concerted effort by the FDA and DEA to address the public health crisis spawned by the proliferation of unregulated designer drugs being sold under the guise of hemp.

Lastly, in the long term, Congress should lay the groundwork for a unified regulatory framework for intoxicating cannabinoids, irrespective of whether they’re source from cannabis or hemp.

Tiffany Devitt heads up regulatory affairs for CannaCraft and March and Ash and sits on the board of the California Cannabis Industry Association (CCIA). May not be reprinted without permission.

Footnotes

  1. https://www.instagram.com/p/CszDtayPScA/?utm_source=ig_web_copy_link&igshid=MzRlODBiNWFlZA==
  2. https://fukedup.com/
  3. https://hionnature.com/products/3000mg-knockout-gummy-bites-clusterf-cks
  4. https://www.marijuanaventure.com/edibles-regulations-vary/
  5. https://chapoextrax.com/product/very-berry-live-resin-3500mg-gummies/
  6. https://chapoextrax.com/
  7. https://hightimes.com/sponsored/what-is-delta-9p-everything-you-need-to-know/
  8. 3C, LLC d/b/a/ 3Chi and MIDWEST HEMP COUNCIL, Plaintiffs, v. ATTORNEY GENERAL TODD ROKITA, in his official capacity, and STATE OF INDIANA, Case No. 1:23-cv-01115-JRS-MKK, U.S. DISTRICT COURT SOUTHERN DISTRICT OF INDIANA INDIANAPOLIS DIVISION.
  9. https://nida.nih.gov/publications/drugfacts/synthetic-cannabinoids-k2spice
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999798/
  11. https://publications.aap.org/aapnews/news/14002/Study-Seizures-coma-more-common-with-synthetic
  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875316
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826922/
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863350/
  15. https://pubs.acs.org/doi/10.1021/acs.chemrestox.2c00170
  16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033635/
  17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939204/
  18. https://pubmed.ncbi.nlm.nih.gov/31389266/
  19. https://downloads.usda.library.cornell.edu/usda-esmis/files/gf06h2430/76538f824/w9506f61g/hempan23.pdf
  20. https://projectcbd.org/hemp/expert-gives-delta-8-thc-a-thumbs-down
  21. https://www2.texasattorneygeneral.gov/files/initiatives/synth/Synthetic_drug_factsheet_accessible.pdf
  22. https://cen.acs.org/biological-chemistry/natural-products/Delta-8-THC-craze-concerns/99/i31
  23. https://projectcbd.org/hemp/expert-gives-delta-8-thc-a-thumbs-down/
  24. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  25. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  26. https://shop.cookies.co/pages/shipping-policy
  27. https://deltadreamz.com/shop/ols/products/cap-n-chronic-1000mg
  28. https://www.kratomstoresohio.com/delta-8-products/
  29. https://dazeddragons.com/store/delta-8-jolly-rancher/
  30. https://www.cbdsupplymd.com/shop/skittles-wild-berry-delta-8-400mg-20-count/
  31. https://publications.aap.org/pediatrics/article/151/2/e2022057761/190427/Pediatric-Edible-Cannabis-Exposures-and-Acute
  32. https://www.cdc.gov/mmwr/volumes/72/wr/mm7228a1.htm?s_cid=mm7228a1_w
  33. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c018be7d-f7b8-45e2-97b8-8e7a71740657
  34. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6
  35. https://weedmaps.com/learn/products-and-how-to-consume/decide-how-much-to-take
  36. Including Maryland and Montana.
  37. https://sensiseeds.com/en/blog/can-cbd-counteract-the-effects-of-thc/
  38. https://doi.org/10.1038/s41386-022-01478-z
  39. https://pubmed.ncbi.nlm.nih.gov/36380220/
  40. https://pubmed.ncbi.nlm.nih.gov/30661105/
  41. https://www.conflabs.com/why-0-877/
  42. https://cannabusiness.law/thca-flower-the-next-big-thing-in-hempland
  43. https://www.law.cornell.edu/uscode/text/21/813
  44. See AK Futures, LLC v. Boyd Street Distro, LLC, 35 F4th 682 (9th. Cir. 2022)
  45. https://www.courthousenews.com/wp-content/uploads/2023/06/Indiana-hemp-AG-opinion-lawsuit.pdf
  46. https://cannabislaw.report/lawsuit-filed-in-georgia-argues-delta-8-and-delta-10-products-are-legal-under-state-law/
  47. https://mjbizdaily.com/wp-content/uploads/2022/05/HF3595.2.pdf
  48. https://pubmed.ncbi.nlm.nih.gov/36264171/
  49. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00197-6

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ICRS 2023: Report from Toronto

Toronto skyline

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.

CBD for psychosis.Dutch scientists from Utrecht University reported that impaired functioning of the brain’s default mode network “likely contributes to psychosis vulnerability.” They found that a CBD treatment regimen of 600 mg daily for four weeks attenuated dysfunctional default mode connectivity in a study of 31 recent-onset psychosis patients.

THC better than CBD for obesity. Israeli scientists assessed the impact of chronically administered CBD and THC on obesity and related metabolic disorders. Given the appetite-arousing qualities of cannabis (“the munchies”), it seems paradoxical that the “prevalence of obesity and metabolic diseases are lower in cannabis users compared to non-users,” the Israelis noted. Experiments on mice yielded biphasic results: 10 mg/kg of purified THC stimulated weight gain and impaired glucose-tolerance in mice, but 30 mg/kg of THC had the opposite effect, leading to a reduction in weight gain and improved glucose-tolerance. While CBD treatment enhanced glucose-tolerance regardless of weight gain, THC showed greater promise as an anti-obesity compound, according to this study. The researchers concluded that “chronic oral consumption of sufficient concentrations of THC, but not CBD, ameliorates diet-induced obesity and . . . metabolic disorders.”

Sufficient concentrations of THC, but not CBD, reduces diet-induced obesity and metabolic disorders.

CBD-rich cultivars for anxiety. University of Colorado researcher L. Cinnamon Bidwell examined the effects of three cannabis chemovars with different THC:CBD ratios. Not surprisingly, the CBD-dominant chemovar with little THC was associated with significant reductions in anxiety and tension among cannabis users as compared to the THC-dominant and the mixed THC:CBD chemovars.

Cannabis and cortisol. Washington State University researchers probed the chronic and acute effects of cannabis use on human cortisol rhythms. “Stress relief is the most cited reason for habitual cannabis use,” they noted in their assessment of how cannabis consumption impacts levels of cortisol, a stress-related hormone. “We found a significant decrease in cortisol concentrations following acute cannabis use,” they concluded. “These findings corroborate cannabis users’ self-reported experience of decreased stress following cannabis use.”

CBG and CBC. Preliminary results from a “double-blind, placebo-controlled, crossover, field trial” underscored the anxiolytic, stress-relieving, and memory-enhancing potential of cannabigerol (CBG), which produced greater reductions in anxiety than placebo. Cannabicromene (CBC), another minor phytocannabinoid, was reported to exert effects through various pathways, including the CB2 cannabinoid receptor, ion channels TRPA1 and TRPA4, and the nuclear receptor PPAR-gamma.

Pain, Opioids & Addiction

Pain, opioids, and addiction comprised a major area of focus at ICRS 2023. Much of this research involved animal models and other preclinical experiments that shed light on the subtleties and inner workings of the endocannabinoid system. Medical scientists, for example, at Mount Sinai’s Department of Psychiatry and Neuroscience probed the neurobiological underpinnings of CBD’s ability to attenuate opioid relapse. Building on their previous work, which showed that CBD lessens cue-induced heroin-seeking in an animal model of relapse, the Mount Sinai lab identified “discrete biological pathways impacted by heroin” in the nucleus accumbens (NAc), the brain region that regulates motivation and reward: “Bioinformatic analysis revealed that CBD reversed a number of metabolic and cell signaling pathway alterations induced by heroin particularly in the NAc shell.”

Neuroscientists at Indiana University explored how allosteric modulation of the CB1 cannabinoid receptor affected opioid self-administration and relapse. Allosteric modulators can either enhance or weaken how a receptor signals. A negative allosteric modulator (NAM) — a synthetic research compound identified as GAT358 — reduced the reinforcing properties of morphine by altering the shape of the CB1 receptor and weakening its signal. This approach might “represent a viable therapeutic route to decrease opioid addictive behaviors and relapse,” the scientists surmised. The same lab reported that GAT358 suppressed “opioid-mediated unwanted side effects including tolerance and withdrawal” but did not block opioid analgesia.

The wide range of topics at ICRS 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, it should be noted, also acts as a negative allosteric modulator at the CB1 receptor, meaning that CBD doesn’t cause the CB1 receptor to signal (like THC does) but CBD influences how it signals. If the CB1 receptor is like a dimmer switch, then CBD turns it down a notch. It’s also possible for a positive allosteric modulator (PAM) to turn the dimmer switch up a notch and amplify CB1 signaling.

The Indiana University group led by Andrea G. Hohmann studied PAMs as well as NAMs, fine-tuning CB1 receptor signaling in both directions. They found that strengthening CB1 signaling via positive allosteric modulation “could suppress neuropathic pain without producing unwanted CNS side effects or tolerance.” Tweaking the CB1 receptor in such a manner avoided potential problems (intoxication, impairment) associated with direct activation of CB1 by THC or various synthetic cannabinoids. Mohammed Mustafa of Virginia Commonwealth University reported that positive allosteric modulation of the CB1 receptor also reduced somatic withdrawal signs of nicotine-dependent mice.

On the Shoulders of Giants

2023 saw the passing of two research pioneers who were giants in the field of cannabinoid science. Mary E. Abood, PhD, conducted groundbreaking studies on the structure and function of cannabinoid receptors. She also identified other receptor subtypes that bind to cannabinoids. A leading figure in the ICRS since its founding in the early 1990s, Abood was known for mentoring young women scientists. After her death on Feb. 19, 2023, the ICRS announced the creation of the “Mary E. Abood ICRS Women in Cannabinoid Research Fund” to support women trainees and investigators.

Mechoulam, 92, passed away three weeks after Abood died. For all his stunning achievements as a chemist, perhaps his greatest contribution was how he nurtured a robust noncompetitive spirit, an ethos of cooperation and collegiality that persists among scientists involved in cannabinoid research. This was evident at the dinner and awards ceremony at the end of conference — an ICRS tradition — as young scientists were acknowledged for their research accomplishments and recently elected ICRS officers were introduced. When ICRS president-elect Ziva Cooper, the director of UCLA’s Center for Cannabis and Cannabinoids, greeted the group, it felt like a generational hand-off had occurred, a passing-of-the-baton from the old guard to younger scientists who stand on the shoulders of giants.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

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Expert Gives Delta-8 THC Thumbs Down

Bad Chemistry

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.

Project CBD: What comes to mind when you see an ad for “Δ8-THC pre-rolls” given that the plant doesn’t actually produce the Δ8-THC in the joint?

Scialdone: Did they spray or dip the flower or whole joint with synthetic Δ8-THC? How much Δ8-THC was added to the pre-roll? Did the manufacturers use a solvent to treat the flower? If a solvent is used, does it dissolve the phytocannabinoids and terpenes? What’s the actual Δ8-THC purity of what’s being applied to the flower? How much cheaper is it to produce Δ8-THC-pre-rolls than real cannabis pre-rolls? How much money are Δ8-THC producers making?

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.

Project CBD: Δ8-THC has proven to be a gateway drug of sorts for a new generation of unregulated, synthetic designer compounds — Δ10-THC, Δ12-THC, THCP, THCO, THCX, etc. — that are widely available. At issue are potent, intoxicating cannabinoids other than cannabis-derived Δ9-THC. Are these compounds actually derived from hemp? Does their greater cannabinoid receptor binding affinity translate into increased risk?

Scialdone: Only Δ8, Δ9, and Δ10 THC can be synthesized from hemp-derived CBD. All the others are made by chemical conversion. Producing and selling psychoactive products outside the regulatory auspices of the FDA or a state-regulated cannabis program is not ethical. These hemp hustlers are in it for the money, making active pharmaceutical ingredients using process chemistry and producing formulated end-products like vape pens, gummies, and sodas in garages, airplane hangars, basements, and warehouses. These products are sold over the internet, at gas stations, and in smoke shops to anyone with a credit card. Of course, the market for Δ8-THC and other recreational synthetics is only made possible by the ridiculousness of cannabis prohibition. End cannabis prohibition, the market for these products will go away and these compounds will be relegated to research labs, where they belong, not the marketplace.

Project CBD: What do you anticipate regarding the next iteration of the Farm Bill in terms of the legality of Δ8-THC and other synthetic intoxicants?

Scialdone: Unfortunately, I believe that this is a red herring since the USDA’s regulatory authority over hemp ends at harvest. The FDA is supposed to regulate hemp-derived CBD products. The FDA recognizes the need for a different regulatory pathway to properly regulate cannabis/hemp. But the FDA has failed to adopt a regulatory strategy to address this issue. The next version of the Farm Bill should clearly and concisely differentiate high Δ9-THC cannabis from industrial hemp. In no uncertain terms, the Farm Bill must be amended to close the specious THCA-hemp flower loophole that’s enabling the unregulated sale of concentrated, intoxicating, and synthesized cannabinoids. If farmers and manufacturers want to sell psychoactive cannabinoids, they should get a state-issued license to grow and process cannabis.

© Copyright, Project CBD. May not be reprinted without permission.

Rec reading:

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Three Delicious Raw Cannabis Smoothie Recipes

smoothie

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.

Several studies have shown that THCA, a neuroprotectant, has immunomodulatory, anti-inflammatory, antiseizure, and antineoplastic activity, while CBDA is a potent antiemetic and anticonvulsant. Dr. Dustin Sulak, an integrative physician and medical cannabis expert based in Maine, observes that “CBDA is stronger and more potent than CBD, not just because it’s getting absorbed better but because it is acting more powerfully.”

Beyond the Bud

Each part of the cannabis plant contains its own distinctive chemistries, and these may interact synergistically, increasing the therapeutic potential of the whole plant beyond the benefits of a single compound or botanical constituent. That includes all the components of raw cannabis — not just the flowers:

  • Cannabis shade leaves. Although they generally possess little cannabinoid content, cannabis leaves contain other beneficial compounds, including alkaloids, flavonoids, resins, and terpenes. Plentiful and relatively easy to obtain, shade leaves are also high in chlorophyll, which has an array of useful properties that promote wound and skin healing and help to detoxify the body from heavy metals. Many so-called folk remedies involve the use of raw cannabis leaves to treat various conditions. A study in the African Journal of Traditional, Alternative and Complementary Medicine mentions an effective traditional treatment for tuberculosis using cannabis leaf macerated in warm water, as administered by Bapedi healers of Limpopo province, South Africa.
  • Cannabis roots. Cannabis roots contain no phytocannabinoids, but they produce triterpenoids such as friedelin, which has anti-inflammatory, antipyretic, anticarcinogenic, and antimicrobial effects. And epifriedelanol, another triterpenoid found in cannabis roots, has anticancer and cytoprotective properties that could be useful in treating aging-related diseases, according to a review by Ethan Russo and Jahan Marcu in Advanced Pharmacology.
  • Cannabis and hemp seeds. Raw cannabis and hemp seeds have a mild, nutty flavor and are among the world’s most nutritious foods. An article by Jace Calloway in Euphytica reports that these nutrient-packed seeds have potent anti-inflammatory properties. Hemp seeds are rich in essential fatty acids that are metabolized into building blocks of the endocannabinoid system. Add hemp hearts (hulled hemp seeds) to your smoothie or sprinkle some on salads and vegetable dishes. You can also sprout cannabis seeds just as you would wheatgrass or other greens and juice them. Cannabis sprout juice is especially high in beneficial compounds. Cut the sprouts when they are four-to-five inches tall and juice away.

Fresh From the Garden

Where can you get fresh cannabis? The most obvious answer is to grow your own (if you live in a US state that allows this) or ask a grower friend for some trimmings. While the plant is still in the ground you may want to preserve the flowering colas for a ripe final product. Trimming some of the smaller buds for juicing won’t interfere with this and can actually increase the size and potency of the colas, so consider trimming from the lower branches.

(Many thanks to Cora Genetics for generously donating fresh cannabis so Project CBD could develop several smoothie recipes.)

When juicing or adding fresh cannabis in smoothies, make sure to use organic, unsprayed, freshly picked and washed flowers and leaves. The best flowers for juicing have sticky, resin-rich trichomes that have ripened to a milky or cloudy color. Leaves should be deep green and healthy looking. Roots should be washed and scrubbed well. Seeds generally don’t need washing but should be unsprayed, clean, and sorted.

It’s best to use your raw cannabis plant material soon after picking. If you don’t use it right away, keep it in an airtight bag in the fridge for a week or two. You can also freeze raw cannabis for later use. Note that the leaves and flowers will turn a darker color, but the compounds will stay fresh for several months in a well-sealed container. Another option is to juice or puree fresh cannabis and freeze it in ice-cube trays; just pop a few into a beverage. Cannabis puree can also be added to pesto!

Straight Shots & Mocktails

You can drink straight “shots” of fresh cannabis juice or add the freshly pressed juice to a smoothie or other drink. Even a mocktail can be doctored up with a jigger of C-juice. If you want a smooth, pulp-free juice, use a cold-process juicer such as a Champion or another type that removes the fiber.

If you aren’t afraid of a little texture, add whole, raw flowers, leaves, or a piece of cannabis root to your smoothie and you’ll gain all the benefits plus a fiber boost. It won’t feel like you’re gulping down a mouthful of grass clippings if you use a good-quality, high-speed blender that can pulverize the plant fiber to a fine, smooth consistency. (Note: stick or immersion blenders generally don’t work for this purpose.)

If you haven’t consumed raw cannabis before, it’s best to start slow. It won’t make you feel intoxicated, but some people may be allergic or extra sensitive to raw cannabis. Discontinue using if you have an adverse reaction. And keep in mind, if you are preparing a recipe with cannabinoid acid-rich flowers and decide to heat it, you will end up decarboxylating the cannabinoids and the THCA will turn into THC, “the High Causer.”

There’s no better way to level up on your micronutrients than with a swig of cold, freshly pressed cannabis juice or a raw cannabis smoothie. Project CBD has developed three, dare I say, delicious cannabis smoothie recipes for you to try. Give them a go, and let us know what you think!

Recipe: Virgin Mary Jane

Perfect for a warm afternoon, this ice-cold, zesty, savory beverage is chock full of veggies and spices that jive perfectly with fresh cannabis. Dial up the veggies if you want a thicker, gazpacho-like texture, or add more chili if you like it extra spicy. For a delicious mocktail, add a splash of lime-flavored kombucha or non-alcoholic beer and you’ve got yourself a virgin Red Eye. With so much flavor, it’ll feel like you’re getting away with something. Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • I stalk of celery, including leaves, diced, plus two stalks for serving
  • 1 Roma tomato, seeded and diced
  • ½ bell pepper, seeded and diced
  • 2 sprigs cilantro, leaves and stem, roughly chopped, plus some extra sprigs for serving
  • 1 teaspoon prepared horseradish
  • 1/2 teaspoon diced shallot or red onion
  • 1-2 cloves garlic, peeled (optional)
  • ½ to 1 japapeño or serrano chili, seeded and diced (optional)
  • Dash Worcestershire sauce
  • 1/2 teaspoon celery salt or ground celery seed
  • Kosher salt to taste
  • Black pepper to taste
  • Hot sauce to taste (Tabasco or other)
  • 1 lime, juiced
  • 16 ounces of low-sodium tomato juice

Directions: Blend all ingredients in a blender, adjusting seasonings and adding more juice if needed. Serve over ice in tall glasses with a celery stalk and a sprig or two of cilantro.

Recipe: Berry Cannalicious

Dark-colored berries are packed with antioxidants and flavonoids, and studies have shown that regular intake of flavonoids reduces the rate of cognitive decline in older adults, making this the perfect anti-aging smoothie. A splash of cherry or pomegranate juice, or hibiscus tea, adds even more flavor, color, and nutrients. You can tailor this smoothie to your sweetness quotient and sprinkle in some medicinal mushroom powder for more brain boost. Drink this smoothie and you just might live forever. And it tastes amazing! Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • 1 ½ to 2 cups mixed frozen berries: blueberries, raspberries, blackberries, strawberries, and/or cherries
  • ¾ cup of dark cherry or pomegranate juice, or cold, unsweetened hibiscus tea (you can find dried hibiscus flowers at your local Mexican market)
  • Juice of one lemon
  • ¾ cup unsweetened almond, cashew, soy, rice or other plant-based milk
  • Honey, 2-3 pitted medjool dates, or stevia to taste
  • Optional: Two teaspoons of mixed dried medicinal mushroom powder

Directions: Blend all ingredients in a blender until smooth, adding more liquid as needed. Serve in tall glasses.

Recipe: Tropic of Canna

This creamy smoothie is a beautiful, bright green color, and full of the tropical fruit flavors of mango, papaya, and pineapple. Throw in some hemp seeds for a fatty acid boost, or strawberries and mint to your liking. Guaranteed to transport you to a tropical island with the best waves for mind/body surfing. Serves two.

Ingredients:

  • 1 packed cup or more of fresh cannabis, torn into rough pieces: flowers, leaves, or a mix
  • 2 cups mixed frozen mango, pineapple, papaya, and/or strawberry
  • 1-inch piece of fresh, raw ginger root, diced
  • 2 cups or more of coconut water, plant-based milk or water
  • 2-3 tablespoons raw hemp seeds, optional
  • Honey, 2-3 pitted medjool dates, or stevia to taste
  • Couple of mint leaves for flavor and/or garnish (optional)

Directions: Blend all ingredients until smooth, adding more liquid or fruit to get the desired consistency. Serve in tall glasses with optional mint garnish.

Melinda Misuraca is a Project CBD contributing writer with a past life as an old-school cannabis farmer specializing in CBD-rich cultivars. © Copyright, Project CBD. May not be reprinted without permission.

References

  • Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, Stott CG, Javid FA, Parker LA, Pertwee RG. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behavior in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013 Mar;168(6):1456-70.
  • B.S. Audu, P.C. Ofojekwu, A. Ujah, M.N.O. Ajima. Phytochemical, proximate composition, amino acid profile and characterization of Marijuana (Cannabis sativa L.) The Journal of Phytopharmacology. 2014 3(1): 35-43.
  • Callaway, J. Hempseed as a nutritional resource: An overview. Euphytica. 2004 140. 65-72.
  • Dawidowicz AL, Olszowy-Tomczyk M, Typek R. CBG, CBD, Δ9-THC, CBN, CBGA, CBDA and Δ9-THCA as antioxidant agents and their intervention abilities in antioxidant action. Fitoterapia. 2021 Jul;152:104915.
  • Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 2012 Jul;72(1):135-43.
  • Pellesi L, Licata M, Verri P, Vandelli D, Palazzoli F, Marchesi F, Cainazzo MM, Pini LA, Guerzoni S. Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study. Eur J Clin Pharmacol. 2018 Nov;74(11):1427-1436.
  • Russo EB, Marcu J. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Advanced Pharmacology. 2017 80:67-134.
  • Semenya SS, Maroyi A. Medicinal plants used for the treatment of tuberculosis by Bapedi traditional healers in three districts of the Limpopo Province, South Africa. Afr J Tradit Complement Altern Med. 2012 Dec 31;10(2):316-23.
  • Takeda S, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012 Nov 15;214(3):314-9.
  • Yang HH, Son JK, Jung B, Zheng M, Kim JR. Epifriedelanol from the root bark of Ulmus davidiana inhibits cellular senescence in human primary cells. Planta Med. 2011 Mar;77(5):441-9. https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/chlorophyll-metallo-chlorophyll-derivatives#supplements

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Gut Feeling

Gut microorganism

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.)

Even small doses of cannabis can soothe the stomach and stimulate the appetite.

Inflammatory bowel disease is an umbrella term for two chronic disorders of the gut: Crohn’s disease, characterized by inflammation of the lining of the digestive tract; and ulcerative colitis, which involves inflammation and sores along the lining of the large intestine (colon) and rectum. Symptoms of both include diarrhea, fatigue, abdominal pain, reduced appetite, and weight loss.

IBD in Puerto Rico

In 2016, the government of Puerto Rico legalized medicinal cannabis for a relatively short list of specific conditions, including Crohn’s disease. Only non-smokable preparations are permitted, and all unauthorized cannabis use and possession remains illegal. As of March 2022, approximately 120,000 patients were registered in the program.

The recent survey was conducted through a clinic at the University of Puerto Rico Center for Inflammatory Bowel Diseases with around 900 patients. Ultimately 162 adults (85 males) completed the 27-item questionnaire. Among these, 60 (37%) reported current or past cannabis use, of which 39 used it to treat abdominal pain, 25 to treat weight loss, and 10 to treat diarrhea, among other symptoms.

But the most telling findings involve these patients’ perceptions of cannabis use as a treatment for IBD. The vast majority of current and past users noted that cannabis was beneficial for their health (94%), that it offered an improvement in their quality of life (84%), and that they would recommend it to other patients (86%). The study was published in March 2023 in the International Journal of Environmental Research and Public Health.2

Fewer ER Visits in New York & Minnesota

When researchers with Stony Brook University Hospital, Northwestern University, and Albert Einstein College of Medicine surveyed IBD patients in New York and Minnesota about their cannabis use, both states only allowed medical use. This study was conducted at medical cannabis dispensaries and relied on self-reported IBD diagnoses. Generally speaking, the 236 eligible respondents reported mild-to-moderate IBD disease activity. Most used cannabis at least once a week, primarily through high-THC vape pens and cartridges.

Euphoria was by far the most common side effect reported.

Again, the most notable findings reveal just how helpful these patients found cannabis in managing inflammatory bowel disease. Respondents reported fewer IBD-related emergency-room visits (a common concern across the patient population) in the year after they began using cannabis. They also saw a reduced impact of symptoms on their daily life. Euphoria was by far the most common side effect (75.4%), with drowsiness, memory lapses, dry mouth, anxiety, and paranoia all reported in low-single-digit percentages. The results appeared in the Journal of Clinical Gastroenterology in October 2022.3

Rave Reviews

Scientific review papers are typically circumspect in tone, more inclined to highlight evidence gaps than to draw grand conclusions. But two recently published reviews are clear when it comes to the benefits of cannabis for inflammatory bowel disease patients.

“Cannabinoid usage in IBD treatment comes with promising results as reported in the majority of the selected studies,” reads a systemic review of the literature from 2012 to 2022 published in the journal Cureus. “The selected studies’ point of convergence is that they confirmed the promising role of cannabinoids in steering improvements in IBD treatment through some objective clinical rating scales such as weight gain, Harvey-Bradshaw Index, Mayo score, CDAI score, and general well-being.” The main caveats? Heterogeneous study designs and a dearth of high-quality evidence for ideal dosage and mode of administration.

The second new review, set to be published in July in Current Opinion in Gastroenterology,4 similarly concludes that “there is a considerable amount of patient-reported outcome data that is significant in supporting the use of cannabis to provide symptom relief and overall increase in quality of life in patients with IBD.”

The authors do make an important distinction between symptoms and underlying conditions, however, by noting that existing evidence addresses the former, not the latter: “There are no data that cannabis has any benefit in decreasing the inflammation/fibrosis that continues to affect patients with IBD.”

This doesn’t mean that cannabinoids have been proven ineffective in addressing the root cause of IBD, just that there’s no evidence yet establishing that they do. “The most important point is that gastroenterologists need to ask their patients about their [cannabinoid] use, including discussion of the benefits and risks of using them,” the authors conclude.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Leung, Janni et al. “Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada.” Psychopharmacology vol. 239,5 (2022): 1509-1519. doi:10.1007/s00213-021-06047-8
  2. Velez-Santiago, Alondra et al. “A Survey of Cannabis Use among Patients with Inflammatory Bowel Disease (IBD).” International journal of environmental research and public health vol. 20,6 5129. 15 Mar. 2023, doi:10.3390/ijerph20065129
  3. Greywoode, Ruby et al. “Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.” Journal of clinical gastroenterology, 10.1097/MCG.0000000000001782. 14 Oct. 2022, doi:10.1097/MCG.0000000000001782
  4. Saidman, Jakob et al. “Inflammatory bowel disease and cannabis: key counseling strategies.” Current opinion in gastroenterology vol. 39,4 (2023): 301-307. doi:10.1097/MOG.0000000000000946

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Dumpster Fire: What Went Wrong with CA Cannabis?

dumpster fire

Cannabis is supposed to be relaxing and fun. What’s not to like about giggles, munchies, and a brief break from the mundane? Unfortunately, the news from California’s Emerald Triangle is anything but upbeat these days.

Report after report portends doom with headlines like “the world’s largest legal weed market is going up in smoke” (The Economist), “California pot industry facing ‘extinction event‘” (SF Gate), and “Despair in Emerald Triangle as CA legal cannabis collapses” (CalMatters).

Is It Really That Bad?

Yeah, it is.

Legal sales have been on a downward slide for over two years with no signs of relief on the horizon. At its roots, the main cause appears to be the overwhelming dominance of the illicit market, which is estimated to be twice the size of the regulated market (Politico).

The result: Cascading business failures across the industry.

One in five cultivators have voluntarily surrendered their licenses this year. Others are letting their licensed fields go fallow, unable to fund this year’s harvest on the heels of last year’s losses.

Things are no better in other corners of the industry. A year ago, there was a stunningly diverse and innovative brand community. In May 2022, there were close to 1500 brands in the market, according to Headset. A year later, less than a thousand remain.

Supply Chain Woes

Further up the supply chain, distributors are also buckling under. A 2022 report estimated that licensed California cannabis distributors are sitting on over $600 million dollars in aging accounts receivable that retailers are unable or unwilling to pay. One of the industry’s largest distributors appears to be in a full “meltdown” as brands call on retailers to halt payment for fear that they won’t be paid if and when it goes under.

As for California’s cannabis retailers, numerous industry observers are warning that hundreds of dispensaries will be out of cash and credit by the end of the year. The probable closure of a significant percentage of California’s retailers will further destabilize the overall industry as cannabis farmers and manufacturers lose access to legal-market customers.

One in five cannabis cultivators in California have voluntarily surrendered their licenses this year.

And for all the talk of social equity and “righting the wrongs” of the war on drugs, all of this is taking place in an industry where there are no bankruptcy protections, where individuals carry personal liability for business taxes owed regardless of the corporate structure, and where businesses are barred by federal tax law from writing off normal business expenses.

In other words, behind the industry’s imminent demise are thousands of personal stories of financial ruin.

Fatal Flaws

When Proposition 64 passed in November 2016, it established 27 voter-mandated goals. Five of these goals were about getting rid of the illicit market and providing a reasonable pathway to licensure.

From Prop 64: “It is the intent of the People in enacting this Act… to take marijuana production and sales out of the hands of the illegal market… to tax the growth and sale of marijuana in a way that drives out the illicit market….”

The failure to achieve these voter-mandated goals is at the root of much of the industry’s anguish. So, what happened? With the benefit of hindsight, it’s clear that Proposition 64 had two fatal flaws: high taxes and local control.

Just how high are California’s cannabis taxes? For comparison, the State Excise tax on a bottle of wine is a palatable four cents. The state excise tax on an eighth ounce of cannabis is $4.90 or over 100 times greater. Added to that, California products are taxed throughout the supply chain. A single cannabis product can be hit with a local cannabis cultivation tax, a local manufacturing tax, a local distribution tax, and a local retail tax. Heck, we’re even hit with a “road tax” for merely transporting products into some jurisdictions.

These taxes compound throughout the supply chain (meaning our taxes are taxed), resulting in a cumulative burden that goes a long way towards explaining why illegal products are typically half the price of licensed products.

That’s hardly the way to “tax the growth and sale of marijuana in a way that drives out the illicit market….” as required by Prop. 64. In the absence of real tax reform, enforcement against illegal cannabis will continue to be a losing game of whack-a-mole.

Local Control Means No Control

The second fatal flaw is the notion of “local control.” Local control refers to California’s dual approval approach, which means that every cannabis facility must secure local authorization and a state license. In concept, that doesn’t sound so bad. But in practice, it means that over 60% of jurisdictions have banned cannabis retail.

By allowing municipalities to opt-out, California has in effect surrendered most of the state market to illicit operators and criminals. Otherwise put, “local control” means no control. In these (legal) cannabis deserts across the state, unregulated, untaxed, and untested cannabis is king.

Adding to these woes, the face of illegal cannabis has changed in important ways. Thirty years ago, much of California’s underground cannabis economy was represented by off-the-grid, mom-and-pop growers hidden in the backwoods of Humboldt and Mendocino County.

Today, rumors abound about well-capitalized cannabis licensees, like mega-cultivator Glass House Brands, playing both sides of the fence and using massive profits from the illegal sale of cannabis to undercut their competitors in the regulated market or to offset the losses of legal operations.

Over 60% of jurisdictions in California have banned cannabis retail.

The glut of unregulated, intoxicating “hemp” products poses additional challenges. In spite of state prohibitions, a growing number of companies are openly selling highly intoxicating synthetic, lab-made cannabinoids under the guise of hemp. Chapo Extrax, for example – which proudly proclaims itself “the newest drug cartel in town” – sells gummies online with 175mg of uber-potent synthetic THC per piece, making it many times stronger than anything sold in the regulated market (which caps THC at 10mg per serving). These products are undermining the integrity of California cannabis, as well as endangering consumers.

Towards a Solution

There is still an opportunity to make changes that will enable California to build the vibrant, regulated, tax-generating industry Californians asked for in passing Prop 64. But that will require immediate and important changes to ensure that adult consumers across the entire state have access to legal cannabis that’s competitively priced.

It means significantly reducing the state and local taxes and prioritizing sensible law enforcement strategies that keep up with the rapidly changing market. It also means overhauling the dysfunctional two-tiered structure that allows local authorities to ban legal cannabis while unregulated markets flourish.

Cannabis is one of California’s great heritage industries, along with wine, technology, and entertainment – industries we’ve nurtured and fostered with supportive legislation and regulation. By right, we should also have a robust cannabis market that’s poised to be a dominate force in the national and even global markets in a post-legalization world. To ensure that, we need to address the urgent issues at hand.

Tiffany Devitt heads up regulatory affairs for CannaCraft and March and Ash and sits on the board of the California Cannabis Industry Association (CCIA).

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Beta-Caryophyllene: Terpene Powerhouse

Project CBD recently reported on studies indicating that cannabis terpenes — the compounds that give the plant its robust and distinctive smell — activate the CB1 cannabinoid receptor. What’s more, in the presence of THC (also a CB1 agonist), terpenes appear to modulate cannabinoid activity in varied and interesting ways.1,2 Today we focus on spicy-peppery beta-caryophyllene (BCP), one of the most common cannabis terpenes, which acts on several targets that impact the endocannabinoid system, not just CB1.

BCP is also a component of black pepper, basil, oregano, cinnamon, hops, rosemary, cloves, and citrus, as well as many leafy greens. Approved by the United States Food and Drug Administration for use as a flavoring and fragrance agent in food, this powerhouse sesquiterpene has been the subject of considerable medical-science research. Recent papers explore the potential role of BCP in treating a wide range of conditions including non-alcoholic fatty liver disease, chronic pain, and substance abuse.

A “Dietary Cannabinoid”

Beta-caryophyllene, a weak CB1 agonist, is what scientists refer to as a “full agonist” at the CB2 cannabinoid receptor, which plays an important role in regulation of immune function and inflammation. Its presence in many foods and spices and its strong affinity for CB2 has earned BCP recognition as the first known “dietary cannabinoid.”

Multiple studies have shown that beta-caryophyllene also interacts with peroxisome proliferator-activated receptors (PPARs, pronounced pee-parrs) located on the surface of the cell’s nucleus. CBD also activates these receptors, which regulate metabolism and energy homeostasis.

Given the role of PPARs and the endocannabinoid system in modulating metabolic processes, a group of researchers based in Turin, Italy, wanted to see if BCP was effective in a cellular model of non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide with a global prevalence of more than 30%.3

Because of its presence in many foods and spices and its strong affinity for the CB2 receptor, beta-caryophyllene is known as a “dietary cannabinoid.”

Writing in the International Journal of Molecular Sciences in March 2023,4 the researchers note that not only did they observe improvements in diseased liver cells, but they also confirmed through the use of specific receptor antagonists that these changes were indeed mediated by CB2 and two PPAR receptor types: PPAR-alpha and PPAR-gamma.

(Interestingly, multiple large epidemiological studies5 — including one published in May 2023 in the journal PLoS One6 — have linked cannabis use with reduced risk of fatty liver disease. This new evidence out of Italy suggests that activation of CB2 and PPAR receptors may be at least partly responsible.)

Alzheimer’s & Substance Abuse

Other studies in recent years have added to our understanding of beta-caryophyllene’s myriad potential health benefits and multiple methods of action. In 2014, for example, Chinese researchers at Chongqing Medical University reported that BCP prevented cognitive impairment in a mouse model of Alzheimer’s. This positive cognitive outcome “was associated with reduced beta-amyloid burden in both the hippocampus and the cerebral cortex,” according to their paper in the journal Pharmacology,7 which identified CB2 receptor activation and the PPAR-gamma pathway as mediators of BCP’s neuroprotective effects.

More recently, a July 2022 paper in BioFactors8 by Iranian scientists reviewed the antioxidant and immunomodulatory effects of beta-caryophyllene, which was shown to reduce relevant proinflammatory cytokines while increasing anti-inflammatory cytokines. CB2 and PPAR-gamma, among other cellular pathways, were cited as key mechanisms of action.

And a December 2022 article in Current Neuropharmacology,9by researchers in Brazil, investigated BCP’s potential “as a new drug for the treatment of substance use disorders.” The authors reviewed previous preclinical studies using animal models of addiction to cocaine, nicotine, alcohol, and methamphetamine. “Remarkably,” they concluded, the terpene “prevented or reversed behavioral changes resulting from drug exposure,” with evidence again pointing to the involvement of both CB2 and PPAR-gamma.

Painkiller

Finally, a paper by scientists with an Indian company called Vidya Herbs, which produces a black-pepper-seed extract called Viphyllin, suggests that beta-caryophyllene can reduce pain in mice primarily via activation of CB2, PPAR-alpha, and a third pathway also shared with cannabidiol: the TRPV1 (pronounced trip-vee-one) ion channel.

Published in the Journal of Pain Research10 in February 2022, the study involved administration of both 90% pure beta-caryophyllene and the black-pepper extract Viphyllin, which contains at least 30% beta-caryophyllene alongside lesser quantities of limonene, beta-pinene, and sabinene (three terpenes that can also be found in various cannabis strains).

Medical scientists are studying beta-caryophyllene as a treatment for non-alcoholic fatty liver disease, chronic pain, and substance abuse.

When Viphyllin was given at about three times the dose of pure BCP, the two treatments proved to be similarly effective at reducing pain in all four behavioral models employed.

In three of these tests, the researchers also used blockers of CB1, CB2, TRPV1, and PPAR-alphato evaluate how Viphyllin worked on the molecular level. They found that CB2, PPAR-alpha, and TRPV1 were most responsible for conveying the black pepper extract’s analgesic effect, but that the common terpene target CB1 may have played a role, as well.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Younossi, Zobair M et al. “The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.” Hepatology (Baltimore, Md.) vol. 77,4 (2023): 1335-1347. doi:10.1097/HEP.0000000000000004
  4. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  5. Kim, Donghee et al. “Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.” PloS one vol. 12,10 e0186702. 19 Oct. 2017, doi:10.1371/journal.pone.0186702
  6. Du, Rui et al. “Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study.” PloS one vol. 18,5 e0284859. 18 May. 2023, doi:10.1371/journal.pone.0284859
  7. Cheng, Yujie et al. “β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology vol. 94,1-2 (2014): 1-12. doi:10.1159/000362689
  8. Baradaran Rahimi, Vafa, and Vahid Reza Askari. “A mechanistic review on immunomodulatory effects of selective type two cannabinoid receptor β-caryophyllene.” BioFactors (Oxford, England) vol. 48,4 (2022): 857-882. doi:10.1002/biof.1869
  9. Asth, Laila et al. “Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction.” Current neuropharmacology vol. 21,2 (2023): 213-218. doi:10.2174/1570159X20666220927115811
  10. Venkatakrishna, Karempudi et al. “ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels.” Journal of pain research vol. 15 355-366. 5 Feb. 2022, doi:10.2147/JPR.S351513

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Cannabis & the Bible

Biblical scholars have written about the role of cannabis as a sacrament in the ancient Near East and Middle East. Archeological evidence confirms the use of the plant in fumigation rituals in ancient Israel. Scriptural references indicate that cannabis was a key ingredient in the holy anointing oil employed in religious rites. But Yahweh, the Almighty Jealous God, frowned upon the idolatrous use of cannabis, the polytheistic drug of choice. The Old Testament chronicles the embrace of One God instead of many, a major shift that coincided with the displacement of cannabis as a ceremonial substance, as Chris Bennett reports in his latest book, Cannabis: Lost Sacrament of the Ancient World.

Humankind’s connection to cannabis reaches back tens of thousands of years. The role of cannabis in the ancient world was manifold: with its nutritious seeds, an important food; with its long, pliable strong stalks an important fiber; as well as an early medicine from its leaves and flowers; and then there are its psychoactive effects . . .

Due to its usefulness, cannabis has a very long history of human cultivation. How long, exactly, remains unknown. “No other plant has been with humans as long as hemp,” says ethnobotanist Christian Rätsch. “It is most certainly one of humanity’s oldest cultural objects. Wherever it was known, it was considered a functional, healing, inebriating, and aphrodisiac plant. Through the centuries, myths have arisen about this mysterious plant and its divine powers. Entire generations have revered it as sacred . . . . The power of hemp has been praised in hymns and prayers.”

The Great Leap Forward

There has been interesting scientific speculation that the psychoactive properties of cannabis played a role as a catalyst in the “Great Leap Forward,” a period of rapid advancement for prehistoric humanity, which started about 50,000 to 65,000 years ago. In their fascinating paper, “The Evolution of Cannabis and Coevolution with the Cannabinoid Receptor — A Hypothesis,” Dr. John M. McPartland and Geoffrey W. Guy explain how ingestion of this plant may have aided prehistoric humans. “In a hunter-gatherer society,” they write, “the ability of phytocannabinoids to improve smell, night vision, discern edge and enhance perception of color would improve evolutionary fitness of our species. Evolutionary fitness essentially mirrors reproductive success, and phytocannabinoids enhance the sensation of touch and the sense of rhythm, two sensual responses that may lead to increased replication rates.”

The authors postulate that plant compounds, which interact with the human body’s endocannabinoid system, “may exert sufficient selection pressure to maintain the gene for a receptor in an animal. If the plant ligand [plant-based cannabinoid] improves the fitness of the receptor by serving as a ‘proto-medicine’ or a performance-enhancing substance, the ligand-receptor association could be evolutionarily conserved.” In essence they are suggesting that there’s a coevolutionary relationship between “Man and Marijuana” — and that somehow as we have cultivated cannabis, it may have cultivated us, as well.

Somehow as we have cultivated cannabis, it may have cultivated us, as well.

McPartland and Guy reference others who propose that cannabis was the catalyst that facilitated the emergence of syntactic language in Neolithic humans: “Language, in turn, probably caused what anthropologists call ‘the great leap forward’ in human behavior, when humans suddenly crafted better tools out of new materials (e.g. fishhooks from bone, spear handles from wood, rope from hemp), developed art (e.g. painting, pottery, musical instruments), began using boats, and they evolved intricate social (and religious) organizations . . . . This recent burst of human evolution has been described as epigenetic (beyond our genes) — could it be due to the effect of plant ligands?”

In his study on the botanical history of cannabis and man’s relationship with the plant, Mark Merlin, Professor of Botany at University of Hawaii, referred to hemp as one of “the progenitors of civilization.” Merlin was not alone in suggesting that hemp “was one of the original cultivated plants.” In The Dragons of Eden: Speculations on the Evolution of Human Intelligence, the late Carl Sagan conjectured that early man may have begun the agricultural age by first planting hemp. Sagan, who was known to have a fondness for cannabis himself, cited the pygmies from southwest Africa to demonstrate his hypothesis. The pygmies had been basically hunters and gatherers until they began planting hemp, which they used for religious purposes. The pygmies themselves profess that at the beginning of time the gods gave them cannabis so they would be both “healthy and happy.”

Gift of the Gods

Professor Richard E. Schultes, of Harvard University, considered the father of modern ethnobotany, believed it was likely in the search for food that humanity first discovered cannabis and its protein-rich seeds. Today, hempseed products are touted as a modern “super food” due to their richness in essential fatty acids.

“Early man experimented with all plant materials that he could chew and could not have avoided discovering the properties of cannabis (marijuana), for in his quest for seeds and oil, he certainly ate the sticky tops of the plant,” Schultes has written. “Upon eating hemp, the euphoric, ecstatic, and hallucinatory aspects may have introduced man to the other-worldly plane from which emerged religious beliefs, perhaps even the concept of deity. The plant became accepted as a special gift of the gods, a sacred medium for communion with the spiritual world and as such it has remained in some cultures to the present.”

Archaeological evidence attests to this ancient relationship as well. A hemp rope dating back to 26,900 BC was found in Czechoslovakia; it’s the oldest evidence of hemp fiber. Hemp fiber imprints over 10,000 years old in pottery shards in Taiwan, and remnants of hemp cloth from 8,000 B.C. have been found at the site of the ancient settlement Catal Hüyük in Anatolia (modern day Turkey). Much older tools for breaking hemp stalk into fibers indicate humanity has been using cannabis for cloth “since 25,000 B.C. at least,” according to prehistoric textiles expert Elizabeth Wayland-Barber.

Cannabis was also among our first medicines. A recent study by Washington State University scientist Ed Hagen suggests that our prehistoric ancestors may have ingested cannabis as a means of killing of parasites, noting a similar practice among the primitive Aka of modern-day central Africa. We do know that references to cannabis medicine appear in the world’s oldest pharmacopeias, such as China’s Shennong Ben Cao Jing, in ancient Ayurvedic texts, in the medical papyrus of Egypt, in cuneiform medical recipes from Assyria, first on a list of medicinal plants in the Zoroastrian Zend Avesta, and elsewhere.

Holy Smokes!

Evidence of cannabis being burnt ritually is believed to date as far back as 3,500 BCE based on archaeological finds in the Ukraine and Romania. In Incense and Poison Ordeals in the Ancient Orient, Alan Godbey attributes the genesis of the concept of “divine plants” to “when the primeval savage discovered that the smoke of his cavern fire sometimes produced queer physiological effects. First reverencing these moods of his fire, he was not long in discovering that they were manifested only when certain weeds or sticks were included in his stock of fuel. After finding out which ones were responsible, he took to praying to these kind gods for more beautiful visions of the unseen world, or for more fervid inspiration.”

Various Biblical scholars have written about the role of cannabis as a sacrament in the ancient Near East and Middle East. The ancient Hebrews came into contact with many cultures — the Scythians, Persians, Egyptians, Assyrians, Babylonians, and Greeks — that consumed cannabis. And these cultures influenced the Hebrew’s use of the plant in fumigation rituals and as a key ingredient in the holy anointing oil applied as a topical to heal the sick and reward the righteous.

There’s compelling evidence that in ancient Israel cannabis was used in fumigation rituals and as an ingredient in the holy anointing oil.

Compelling evidence of the ritual use of cannabis in ancient Israel was reported in a 2020 archaeological study, “Cannabis and Frankincense at the Judahite Shrine of Arad,” by the Journal of the Institute of Archaeology of Tel Aviv University. The authors noted that two altars with burnt plant residues had been found in a shrine at an ancient Hebrew outpost in tel Arad. One of the altars tested for frankincense, a well-known Biblical herb, and the other altar tested positive for cannabis resin.

The research, expectedly, caused a storm of controversy, with Biblical historians, religious authorities, and other parties weighing in. An article in Haaretz, headlined “Holy Smoke | Ancient Israelites Used Cannabis as Temple Offering, Study Finds,” raised a key question: “If the ancient Israelites were joining in on the party, why doesn’t the Bible mention the use of cannabis as a substance used in rituals, just as it does numerous times for frankincense?”

The Disappearance of “Kaneh Bosm”

Actually, several scholars have drawn attention to indications of cannabis use in the Bible. Polish anthropologist and etymologist Sula Benet contends that the Hebrew terms kaneh and kaneh bosm refer to cannabis. Benet identified five specific references in the “Hebrew Bible” (aka the Old Testament) — Exodus 30:23, Song of Songs 4:14, Isaiah 43:24, Jeremiah 6:20, and Ezekiel 27:19 — that mention kaneh and kaneh bosm. However, when one reads these passages individually and compares them, a stark contrast emerges.

In Exodus 30:23, the reference is to an ingredient in the Holy Oil, which was used in the Holy of Holies, the inner chamber of the Temple in Jerusalem, whereas in Jeremiah 6:20, this same previously sacred substance is wholly rejected as an item of foreign influence and disdain. It appears that Yahweh, the Jealous God, frowned upon the idolatrous use of cannabis, the polytheistic drug of choice.

The identity of kaneh and kaneh bosm has long been a topic of speculation. Benet’s view was that when the Hebrew texts were translated into Greek for the Septuagint, a mistranslation took place, deeming it as the common marsh root “calamus.” This mistranslation followed into the Latin, and then English translations of the Hebrew Bible. It should be noted that other botanical mistranslations from the Hebrew to Greek in the Hebrew Bible have been exposed.

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This article is adapted from Cannabis: Lost Sacrament of the Ancient World by Chris Bennett (TrineDay, 2023). Bennett is the author of several books, including Liber 420 and Cannabis and the Soma Solution.

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