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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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Finding Rare Cannabinoids in Non-Cannabis Plants

Special glands protruding from cannabis flowers express a series of unique molecules. Cannabinoids, as they are known, exist in cannabis. But it turns out that identical molecules are present in non-cannabis plants, as well. Researchers from Israel’s Weizmann Institute recently reported that they found cannabigerolic acid (CBGA) and other rare cannabinoids in Helichrysum umbraculigerum, a perennial shrub informally known as the woolly umbrella.1

A South African Botanical

Ferdinand Bohlmann and Evelyn Hoffman first discussed the chemical irregularity of Helichrysum. In a 1979 paper published in Phytochemistry2, they analyzed the South African species H. umbraculigerum, native to the eastern part of the country, where it was used in traditional medicine and fumigation rituals.

Bohlmann and Hoffman asserted that the plant’s tops — both leaves and flowers — produce cannabis-specific compounds. But a follow-up study conducted by Italian researchers in 2017 failed to find CBG or its acidic precursor in H. umbraculigerum flowers. They did, however, identify an analog of CBG known as Heli-CBG (also present in some fiber hemp varietals), which binds to the CB2 cannabinoid receptor.3,4

In a May 2023 article in Nature Plants, Weissman Institute scientists confirmed that woolly umbrella produces CBGA in trichomes on its leaves, but hardly any CBGA was present on its flowers. That’s different from cannabis, where CBGA and other cannabinoids are concentrated in trichomes on flower tops.1

Trichomes found on cannabis inflorescence (flowers) have a special cellular build, according to a 2022 study by University of British Columbia researchers in Current Biology. The gland’s bulbous head holds large porous cells that let acidic cannabinoids (CBGA, CBDA, THCA, etc.) move through the trichome.5 The Weizmann Institute team reported that H. umbraculigerum produces a similar cannabinoid transport network on its leaves.1

Sourcing Rare Cannabinoids in Non-Cannabis Shrubs

How did the Israeli scientists figure this out? They fed woolly umbrella precursor compounds responsible for making cannabinoids in cannabis. When given two precursors (hexanoic acid and phenylalanine), the shrub produced more cannabinoids compared to plants fed regular nutrients. This means that the same biosynthetic pathway exists in both cannabis flowers and woolly umbrella leaves.

The woolly umbrella shrub naturally produces on its leaves over 4% cannabigerolic acid alongside other rare cannabinoids. The shrub also contains water-soluble cannabinoids, which are not found in cannabis.

The woolly umbrella shrub produces CBGA in trichomes on its leaves, but not on its flowers.

Essentially, two different plant species have developed the same machinery to produce CBGA. Yet, woolly umbrella is evolutionarily distinct from cannabis. And unlike the shrub, cannabis makes two unique enzymes that flip CBGA into either THCA and/or CBDA.

Exploring a New Phytocannabinoid Toolkit

Thus, there are two toolboxes for cannabinoid phyto-synthesis in the phylogenetic tree. Terpenes and a few flavonoids accompany lipophilic cannabis flowers, whereas a complex array of flavones and water-soluble cannabinoids develop in H. umbraculigerum. By understanding their similarities and differences, we can better assess the therapeutic potential of each plant.

Cannabinoid compounds found in woolly umbrella dissolve more easily in water and can target specific areas of the body, such as the deeper bowel. But greater bioavailability, an argument for water-soluble cannabinoids, is not necessarily equivalent to greater potency. That which is absorbed quickly and easily also leaves the body and loses efficacy faster. And cannabinoid receptors have more affinity for fat-loving compounds compared to water-soluble agonists.6,7

Travis Cesarone is a freelance writer and communicator focusing on medical cannabis sciences. © Copyright, Project CBD. May not be reprinted without permission.

References

  1. Berman, P., de Haro, L.A., Jozwiak, A. et al. Parallel evolution of cannabinoid biosynthesis. Nat. Plants (2023).
  2. Cannabigerol-ähnliche verbindungen aus Helichrysum umbraculigerum. Phytochemistry. 1979;18(8):1371-1374.
  3. Pollastro, F., De Petrocellis, L., Schiano-Moriello, A., Chianese, G., Heyman, H., Appendino, G., & Taglialatela-Scafati, O. (2017). Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum. Fitoterapia, 123, 13–17.
  4. Pollastro F, Taglialatela-Scafati O, Allarà M, Muñoz E, Di Marzo V, De Petrocellis L, Appendino G. Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 2011 Sep 23;74(9):2019-22. doi: 10.1021/np200500p. Epub 2011 Sep 8. PMID: 21902175.
  5. Livingston, S. J., Rensing, K. H., Page, J. E., & Samuels, A. L. (2022). A polarized supercell produces specialized metabolites in cannabis trichomes. Current biology : CB, 32(18), 4040–4047.e4. https://doi.org/10.1016/j.cub.2022.07.014
  6. Li, X., Chang, H., Bouma, J. et al. Structural basis of selective cannabinoid CB2 receptor activation. Nat Commun 14, 1447 (2023).
  7. Stadel, R., Ahn, K. H., & Kendall, D. A. (2011). The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. Journal of neurochemistry, 117(1), 1–18. https://doi.org/10.1111/j.1471-4159.2011.07186.x

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Psychedelic Research Potpourri

Recently I was chatting with a friend who is casually interested in psychedelic science. He told me he hadn’t read as much coverage of psychedelics in popular magazines and other mainstream outlets lately, and asked whether research has slowed. My response? Not at all.

According to Pubmed, the online repository of the National Library of Medicine, last year saw far more papers published on psychedelics than ever before — about 33% more than in 2021, which itself was a 19% increase over 2020. And this year is well on pace to surpass 2022.

Every day another email arrives in my inbox with word about the latest papers, many of which address the promise of psychedelic-assisted therapy for depression, addiction, PTSD, and other mental health disorders.

But dig deep into the scientific literature and you’ll find plenty of outliers and oddities that have nothing to do with therapy per se, covering fascinating subjects like psychedelics for headaches or color-blindness; “entity” encounters; and the still-mysterious question of what, exactly, these compounds do to the brain.

Mood-Elevating Microdosing

Whether microdosing psychedelics can help people in meaningful ways independent of the placebo effect continues to be a subject of debate. A March 2023 paper in the journal Biological Psychiatry1 adds to the discourse by reporting that in a placebo-controlled study of 40 healthy male volunteers, microdosing LSD improved self-reported ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days relative to non-dose days. However, microdosing was not sufficient to promote enduring changes to overall mood or cognition. Nor was it entirely harmless. Seven of the 40 participants reported treatment-related anxiety, and four dropped out as a result.

Psychedelics for Vegetative Patients

On the other end of the psychedelic spectrum are high doses that completely alter one’s perception of self and reality. If the psychedelic state represents a truly different, “higher” level of consciousness — as implied by the entropic brain theory first posited by Robin Carhart-Harris, David Nutt, and others in an influential 2014 paper2 — could psychedelics then be used to treat disorders of consciousness? More specifically, could they be administered as medicine to a minimally conscious or vegetative patient? And if so, what ethical challenges would be involved in such a treatment? These are some of the thought-provoking questions raised in an April 2023 article in Neuroscience of Consciousness.3

Methods of Action

Two other recent papers further investigate the neurobiology (the biological mechanisms through which nervous systems mediate behavior) and pharmacokinetics (the movement of drugs within the body) of various psychedelics.

On the former front, an article in the journal NeuroImage4 explores how three very different compounds eliciting psychedelic and psychedelic-like effects — nitrous oxide, ketamine, and LSD — induce common brain network changes. Although they act on different receptors (nitrous oxide and ketamine on the NMDA glutamate receptor; LSD on the 5-HT2A serotonin receptor), all three compounds produce consistent changes in specific brain regions involved in sensory integration and consciousness. They also similarly reduce within-network connectivity and increase between-network connectivity in the brain, the authors report.

DMT user survey: “Profound and highly intense experiences occurred.”

Another new paper, published in the European Journal of Drug Metabolism and Pharmacokinetics,5 refines our understanding of the body’s metabolism of N,N-dimethyltryptamine (DMT), a powerful psychedelic being explored as a potential treatment for depression. When DMT is taken alone, its effects are extremely short-lived, typically lasting no longer than about 15 minutes. When ingested as part of the psychedelic brew ayahuasca, which also includes compounds that impede the breakdown of DMT, its effects persist for many hours.

The new study relies on a series of experiments in healthy adults receiving intravenous DMT. According to the authors it is the first to determine, in detail, the full pharmacokinetic profile of DMT following a slow IV infusion in humans. “These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of major depressive disorder,” they conclude.

Real-World Trip Reports

Two additional studies published in March 2023 survey psychedelic drug users about their experiences with DMT, LSD, and psilocybin.

In Frontiers in Psychology6 comes a thematic and content analysis of the DMT experience developed from in-depth, semi-structured interviews with 36 “screened, healthy, and experienced” DMT users immediately following the trip. The study authors’ insights into how the compound alters “one’s personal and self-referential experiences of the body, senses, psychology, and emotions” are too complex to summarize here. Put it this way: “invariably, profound and highly intense experiences occurred.” The paper also covers convergences with alien-abduction, shamanic, and near-death experiences.

Finally, in the Journal of Psychopharmacology,7 we find survey results from thousands of users of LSD (n=1,996) and psilocybin mushrooms (n=1,368) compiled through the UK-based Global Drug Survey between November 2019 and February 2020. Positive changes were reported across all 17 outcomes evaluated (especially relative to insight and mood), the authors report. Variables most strongly associated with positive outcomes include psilocybin use (versus LSD), seeking advice before use, and seeking to treat post-traumatic stress disorder.

Negative effects were reported by nearly a quarter of respondents. They were most closely associated with LSD use (versus psilocybin) and younger age. Meanwhile, more intense psychedelic experiences were associated with both more positive and more negative outcomes, suggesting that higher doses can be riskier as well as more rewarding.

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

Footnotes

  1. Murphy, Robin J et al. “Acute mood-elevating properties of microdosed LSD in healthy volunteers: a home-administered randomised controlled trial.” Biological psychiatry, S0006-3223(23)01164-2. 28 Mar. 2023, doi:10.1016/j.biopsych.2023.03.013
  2. Carhart-Harris, Robin L et al. “The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs.” Frontiers in human neuroscience vol. 8 20. 3 Feb. 2014, doi:10.3389/fnhum.2014.00020
  3. Rankaduwa, Sidath, and Adrian M Owen. “Psychedelics, entropic brain theory, and the taxonomy of conscious states: a summary of debates and perspectives.” Neuroscience of consciousness vol. 2023,1 niad001. 4 Apr. 2023, doi:10.1093/nc/niad001
  4. Dai, Rui et al. “Classical and non-classical psychedelic drugs induce common network changes in human cortex.” NeuroImage vol. 273 (2023): 120097. doi:10.1016/j.neuroimage.2023.120097
  5. Good, Meghan et al. “Pharmacokinetics of N,N-dimethyltryptamine in Humans.” European journal of drug metabolism and pharmacokinetics, 1–17. 22 Apr. 2023, doi:10.1007/s13318-023-00822-y
  6. Michael, Pascal et al. “An encounter with the self: A thematic and content analysis of the DMT experience from a naturalistic field study.” Frontiers in psychology vol. 14 1083356. 27 Mar. 2023, doi:10.3389/fpsyg.2023.1083356
  7. Kopra, Emma I et al. “Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: Findings from the Global Drug Survey 2020.” Journal of psychopharmacology (Oxford, England), 2698811231158245. 6 Mar. 2023, doi:10.1177/02698811231158245

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Cannabichromene, a Minor Cannabinoid with Major Upside

In 2013, Noriko Shinjyo, Ph.D., a Research Associate at Chiba University in Japan, coauthored a study with Italian scientist Vincenzo Di Marzo on cannabichromene (CBC), a phytocannabinoid that exerts profound effects on the nervous system.1

Published in Neurochemistry International, their paper probed how CBC influences the fate of adult neural stem progenitor cells, which are described as “an essential component of brain function in health as well as in pathology.” As stem cells mature, they change and differentiate into new neurons and other cells. CBC was shown to have a positive effect on neural stem progenitor cells during their maturation phase, according to in vitro research.

Recently a different group of scientists has followed up on this decade-old discovery by delineating seven mechanisms through which CBC is able to protect and regenerate the nervous system. They reported their findings in Life, a Swiss scientific journal, noting that CBC, a “neurogenesis enhancer,” enables stem cells “to sustain their viability and differentiation.”2

What Are Neural Stem Cells?

Scientists have identified specific areas of the brain — the hippocampus and the lateral ventricles — where neural stem cells are created. These cells undergo a maturation process, known as differentiation, which is an important stage for young cells located in the spinal cord, brainstem, and brain regions programmed for muscle control. Young stem cells evolve into new neurons, but they can also form cells that comprise the protective sheath surrounding nerves.

Some neural stem cells differentiate into astroglial cells, also known as astrocytes. These abundant star-shaped cells populate the grey and white matter of the brain, where they regulate cerebral blood flow and the transmission of electrical impulses. They also play a crucial role in maintaining the blood-brain barrier and repairing the brain and spinal cord following an infection or a traumatic injury.

CBC is a “neurogenesis enhancer” that enables stem cells “to sustain their viability and differentiation.”

But a subpopulation of these mature cells remains dormant. That’s fortunate, given that active astrocytes can stunt the brain’s natural ability to regenerate after an injury. This means that a regulated maturation of neural stem cells, located in the brain and spinal cord, helps to protect and regenerate the nervous system. And this process is augmented by CBC, a cannabis compound, which regulates the production of new neurons, while also reducing the formation of active mature cells that may impede regeneration after a brain injury.

Can CBC Regenerate Embryonic Cells?

In 2023, a team of six Italian scientists published new details that explain how CBC protects and regenerates damaged neurons and nervous system components. They used a special type of spinal cord cell derived from an embryonic mouse, combined with neuroblastoma cells, to make their discovery. The team assessed changes in the genetic landscape of the cells after exposing them to CBC and a control media.

By further refining their analysis, the team elucidated newly discovered mechanisms behind cannabichromene. The plant cannabinoid helps to facilitate proper dopamine neuron and glutamate receptor maturation. And while various cannabinoids regulate the formation of the nerve’s protective sheath, their neuronal regeneration depends on other functions of CBC.

A Balancing Act with Choline

It seems that one newly found mechanism of CBC might work synergistically with tetrahydrocannabinol (THC), while also counteracting the effects of alpha-pinene, a terpene found in various cannabis chemovars and other botanicals.3

Alpha-pinene appears to act directly against CBC at a specific neurotransmitter that sends signals from muscle to neuron. That transmitter is in the choline family, which is protected by pinene but is broken down more rapidly under CBC exposure. Choline is important for cognition, brain development, neural stem cell maturation, muscle movement, and other basic functions.

THC downregulates the choline transmitter, while CBC boosts a gene that codes for a special choline-destroying enzyme; thus, both CBC and THC are implicated in the reduction of choline, and this can protect the nervous system and regenerate neurons. Alpha-pinene, on the other hand, keeps cognition taut by protecting choline. It’s a balancing act. The use of CBC, the scientists conclude, “could represent an important addition to the regeneration of the nervous system, but further experiments need to clarify and optimize how CBC could be effectively used for this purpose.”

Travis Cesarone is a freelance writer and communicator focusing on medical cannabis sciences. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Shinjyo, N., & Di Marzo, V. (2013). The effect of cannabichromene on adult neural stem/progenitor cells. Neurochemistry international, 63(5), 432–437. https://doi.org/10.1016/j.neuint.2013.08.002
  2. Valeri A, Chiricosta L, D’Angiolini S, Pollastro F, Salamone S, Mazzon E. Cannabichromene Induces Neuronal Differentiation in NSC-34 Cells: Insights from Transcriptomic Analysis. Life (Basel). 2023 Mar 9;13(3):742. doi: 10.3390/life13030742. PMID: 36983897; PMCID: PMC10051538.
  3. Russo, E. B., & Marcu, J. (2017). Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Advances in pharmacology (San Diego, Calif.), 80, 67–134. https://doi.org/10.1016/bs.apha.2017.03.004

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CBD Enhances Glucose Metabolism via Nuclear Receptors

Cannabinoid receptors CB1 and CB2 are the definitive and best-known targets of endogenous and plant-derived cannabinoids, but they’re far from the only ones.

Several phytocannabinoids, including cannabidiol (CBD), for example, and the two primary endocannabinoids — anandamide and 2-AG — have been shown to interact with peroxisome proliferator-activated receptors, or PPARs1 (pronounced pee-parrs), which are found on the surface of the cell’s nucleus. This may help to explain how CBD, which has little affinity for either CB1 or CB2, can do so much.

Get to Know the PPARs

PPARs are a group of nuclear receptors that play important roles in regulating metabolism, inflammation, and gene expression. Triggered by hormones, endocannabinoids, and other fatty acid derivatives, and various nutritional compounds,2 PPARs are expressed in different parts of the body:

  • PPAR-a(PPAR-alpha) is found in the liver, kidney, heart, and skeletal muscle, as well as adipose (fat) tissue and the intestinal tract;
  • PPAR-b(PPAR-delta) is expressed in adipose tissue, skeletal muscle, heart, and liver; and
  • PPAR-y (PPAR-gamma), which comes in two forms, is expressed in almost all tissues of the body including the colon, the cardiovascular system, and immune cells.

The first evidence of an endocannabinoid interacting with PPARs came in 2002, when a research team in Tennessee showed that a metabolite of 2-AG activated PPAR-a.3 Since then many more breakthroughs have been made, and peroxisome proliferator-activated receptors are now viewed as an extension of the classic endocannabinoid system (ECS).

PPARs are now viewed as an extension of the classic endocannabinoid system.

Two recent papers reiterate the point that to really understand cannabinoids (especially CBD) and the ECS, it’s essential to get to know the PPARs.

CBD, Psychosis & Glucose Metabolism

A March 2023 study in the journal Frontiers in Psychiatry4 suggests that CBD may act through a PPAR receptor to enhance cerebral glucose metabolism, alterations of which are associated with a host of metabolic and cognitive disorders.5

The paper describes the case of a 19-year-old man in Germany who presented at the Cologne Early Recognition and Intervention Center with “a marked cognitive decline within [six] months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief, limited intermittent psychotic symptoms, particularly delusions and hallucinations.”

Prior to this, the man had no psychiatric history, the authors note. He had never taken anti-psychotic drugs nor received psychological treatment. And besides an uncle with bipolar disorder, he had no family history of other psychiatric or neurological diseases.

The man’s doctors — two of the paper’s four authors — knew that over the last decade-plus, CBD has begun to be recognized through animal and human studies as a novel therapeutic compound for psychosis that acts via indirect effects on the ECS.6,7 They wanted to try it.

“Due to its excellent tolerability and promising efficacy … and its innovative new mechanisms of action, we decided to offer a respective treatment with cannabidiol to [the] patient,” they write.

The prescription was 600 mg of pure CBD orally per day for 30 days. And it worked. The authors report a substantial clinical improvement in attention, visual processing, visuomotor speed, working memory, and other parameters beginning by day seven, with no adverse events or side effects. That’s quite notable in and of itself — but it’s their investigation of potential mechanisms of action that really contributes to the conversation.

Mechanisms of Action

Using brain scans and blood draws, the researchers observed that this reduction in clinical symptoms was accompanied by enhancement of cerebral glucose utilization — a critical metabolic process whose impairment is implicated in Alzheimer’s Disease, schizophrenia, diabetes, obesity, and more.8

They suggest that the underlying mechanism linking CBD intake, cerebral glucose utilization, and improved psychiatric symptoms may be none other than PPAR-y, one of the three known PPAR receptors. PPAR-y plays an essential role in regulating glucose homeostasis and neuroinflammation, and is directly activated by both CBD and the endocannabinoid anandamide (AEA). (AEA’s molecular fatty-acid cousins, PEA and OEA, activate PPAR-a.)

The activation of PPAR-γ by CBD may be one of the mechanisms relevant to the promising antipsychotic effects of cannabidiol.

The proposed link between CBD, cerebral glucose metabolism, psychiatric symptoms, and PPAR-y makes sense, even if it has yet to be proven definitively. Previous research has linked CBD’s efficacy in treating psychosis to its ability to boost AEA,9 which binds with PPAR-y. PPARs in general are recognized as a potential target for treating psychiatric disorders.10 And a 2022 study showed that CBD treatment improved both glucose metabolism and memory in a rat model of Alzheimer’s Disease.11

“The direct or indirect activation of PPAR-γ by cannabidiol may represent one of the various possible mechanisms relevant to the promising antipsychotic effects of cannabidiol,” the authors conclude. Yes, more research is needed — but what matters most to the patient is that it helps.

Cannabidiol Goes Nuclear

A review article in the journal Phytomedicine12 also published in March 2023 provides a broader look at the clinical implications of CBD’s affinity for PPAR-y. Appearing under the catchy title “Cannabidiol goes nuclear: The role of PPARy,” the paper summarizes existing research into the many ways in which interactions between the two influence human health.

Based on an examination of 78 previous articles, the Iran-based authors determined that CBD’s effects on a long list of conditions (Alzheimer’s disease and memory loss, Parkinson’s disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular disease, immune conditions, cancer, and obesity) are mediated at least in part by PPAR-y.

The ubiquitous receptor manages this not only through glucose homeostasis, the authors write, but also by changing the expression of various genes implicated in insulin release, lipid metabolism, inflammation, and immunity. And they note that many effects of CBD can be prevented by synthetic PPAR-y antagonists, which are utilized as research tools.

Ultimately, the review underscores that PPAR-y is a key target for CBD — and argues quite convincingly that “[the receptor’s] activation by CBD should be considered in all future studies.”

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

Footnotes

  1. O’Sullivan, Saoirse Elizabeth. “An update on PPAR activation by cannabinoids.” British journal of pharmacology vol. 173,12 (2016): 1899-910. doi:10.1111/bph.13497
  2. 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
  3. Karkhanis, Anil et al. “15-Lipoxygenase Metabolism of 2-Arachidonylglycerol: Generation of a Peroxisome Proliferator-Activated Receptor α Agonist.” Journal of medicinal chemistry vol. 57,11 (2014): 4830-4840.
  4. Koethe, Dagmar et al. “Cannabidiol enhances cerebral glucose utilization and ameliorates psychopathology and cognition: A case report in a clinically high-risk mental state.” Frontiers in psychiatry vol. 14 1088459. 3 Mar. 2023, doi:10.3389/fpsyt.2023.1088459
  5. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  6. Rohleder, Cathrin et al. “Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.” Frontiers in pharmacology vol. 7 422. 8 Nov. 2016, doi:10.3389/fphar.2016.00422
  7. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  8. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  9. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  10. Matrisciano, Francesco, and Graziano Pinna. “The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.” Advances in experimental medicine and biology vol. 1411 (2023): 513-535. doi:10.1007/978-981-19-7376-5_22
  11. de Paula Faria, Daniele et al. “Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study.” International journal of molecular sciences vol. 23,3 1076. 19 Jan. 2022, doi:10.3390/ijms23031076
  12. Khosropoor, Sara et al. “Cannabidiol goes nuclear: The role of PPARγ.” Phytomedicine: international journal of phytotherapy and phytopharmacology vol. 114 (2023): 154771. doi:10.1016/j.phymed.2023.154771

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Mechoulam on the Future of Cannabinoid Research

I was fortunate to cross paths with Raphael Mechoulam, “the father of cannabis research,” at several science conferences over the years. The most memorable occasion was the 22nd annual meeting of the International Cannabinoid Research Society (ICRS) in Freiburg, Germany, in July 2012. Mechoulam delivered a plenary speech at the symposium, addressing the future of cannabinoid research and key areas of study that should be pursued.

It was exactly fifty years earlier, in 1962, when Mechoulam launched his scientific investigation into the chemistry of cannabis. In 1963, he and Yuval Shvo first reported the molecular structure of cannabidiol (CBD). And the following year Mechoulam coauthored a paper that elucidated the molecular structure of tetrahydrocannabinol (THC). Although he didn’t know it at the time, Mechoulam had lit a slow burning fuse that would detonate a revolution in medical science.

As a young scientist, Mechoulam set out to understand how cannabis works; he ended up unlocking a treasure trove of information about how we work. Known affectionately as “Raphi” to many of the scientists he mentored, Mechoulam tirelessly promoted cooperation between researchers around the world to advance the study of the body’s “endocannabinoid system,” which produces chemicals similar to THC, CBD, and other plant cannabinoids, and mediates their effects.

In 1992, Mechoulam’s research group at Hebrew University in Jerusalem discovered an endogenous THC-like compound that activates receptors in the mammalian brain. He named it “anandamide,” the bliss molecule. And in 1995, Mechoulam and his team identified a second endocannabinoid compound, 2-arachidonoyglycerol or 2-AG for short. Anandamide and 2-AG are part of an internal lipid neurotransmitter system that regulates a wide range of physiological processes, including appetite, mood, pain perception, and immune function.

“Planning Research for the Next Half Century”

“It’s time to plan ahead for the next half a century,” Mechoulam, age 81, told the Freiburg ICRS attendees, who had gathered to honor his 50 years as a pioneer cannabis scientist. Mechoulam cited three specific areas that should be research priorities: CBD, the CB2 cannabinoid receptor, and a cluster of endogenous fatty acid compounds in the brain that he referred to as FAAA’s.

Mechoulam set out to understand how cannabis works. He ended up unlocking a treasure trove of information about how we work.

Keep in mind that this was in 2012, when CBD was virtually unknown to the general public. But it was already a hot topic among ICRS scientists who were probing the compound’s anti-inflammatory, antioxidant, anticonvulsant, anti-tumoral, neuroprotective, and analgesic properties. The preclinical science was truly jaw-dropping, and Mechoulam envisioned a wide array of therapeutic applications for CBD and its derivatives. But clinical studies of plant cannabinoids were lagging because of strict drug laws in the United States and elsewhere.

THC directly activates both cannabinoid receptor subtypes — CB1 and CB2. However, when THC binds to CB2, it does not trigger the psychoactive high that cannabis is known for because CB2 receptors are not concentrated in the brain. THC binding to CB1, the abundant central nervous system receptor, causes the intoxicating effect. Consequently, researchers set their sights on healing without the high by experimenting with drugs that stimulate the CB2 receptor — while bypassing CB1 in the brain.

CB2 receptors are present throughout the immune system, the peripheral nervous system, metabolic tissue, skin cells, and in many internal organs. Aberrant CB2 signaling is implicated in a raft of autoimmune, neurodegenerative, metabolic, and psychiatric disorders. This makes modulating CB2 an attractive target for drug development and therapeutic intervention.

A Cluster of FAAA’s

Mechoulam was particularly excited about the third area of research — the FAAA’s — which comprise a cluster of fatty acid compounds in the brain. Little is known about “the chemistry of the human personality” or the innate biochemical variations that that may account for individual differences in temperament, he explained, adding: “Accumulation of such knowledge is essential for a future biochemical basis of psychology.”

If specific chemical differences “are the cause, or one of the causes, of the differences in personalities,” then it’s essential “to look for a large ‘catalog’ of compounds, which cause central nervous system effects,” Mechoulam asserted. “The variability of such a cluster of compounds – their levels, their ratios and presumably their effects, not only as individual compounds, but also as a group” (a type of entourage effect) could result in “an infinite number of individual differences.”

Little is known about the chemistry of the human personality or the innate biochemical variations that that may account for individual differences in temperament.

Mechoulam drew attention to the importance of several dozen endocannabinoid-like lipids and other FAAA’s, which include various fatty acid amides of amino acids (and their derivatives, such as ethanol amides) or fatty acid esters with glycerol and related compounds. A partial list of these compounds had been identified and analyzed by Heather Bradshaw’s group at the University of Indiana. Some of these compounds were “evaluated for their biological effects,” Mechoulam noted. “Amongst them are anandamide, 2-AG, NADA, palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), stearoyl ethanolamide, and a few others,” whose individual effects vary considerably, but “the joint effects of groups of these components . . . have not been evaluated.”

Mechoulam and his colleagues looked closely at “oleoyl serine,” which is anti-osteoporotic, but is also found in the brain. “Arachidonoyl serine,” another endogenous lipid compound of interest, “lowers damage caused by closed head injury.” And he observed that “oleoyl glycine” and PEA concentrations are enhanced after damage in a specific brain region. These studies gave rise to the concept of the “endocannabinoidome” — an expanded endocannabinoid system that encompasses a plethora of fatty acid neurotransmitters in addition to anandamide and 2-AG.

“It is tempting to assume,” Mechoulam concluded, “that the huge possible variability of the levels and ratios of substances in such a cluster of compounds may allow an infinite number of individual differences, the raw substance which of course is sculpted by experience. If this intellectual speculation is shown to have some factual basis it may lead to major advances in molecular psychology.”

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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