Category: Minor Cannabinoids

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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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Which Terpenes Enhance the Cannabis High?

Ten years ago, most cannabis consumers couldn’t tell a terpene from a cannabinoid. But today things are different. Cannabis flower is categorized according to terpene profile. Product manufacturers add terp blends back into edibles and concentrates. Limonene is practically a household name.

And for good reason. Sure, terpenes impart desirable flavors and aromas. They appear to be good for the body, as well.1 Now it turns out that some terpenes also may contribute to the cannabis high.

A 2021 study2 by University of Arizona scientists concluded that certain terpenes are “cannabimimetic” (in a mouse model of cannabis intoxication) and can selectively enhance cannabinoid activity.

And this month comes a brand-new paper in the journal Biochemical Pharmacology3 by Israeli researchers who report that three cannabis terpenes — at concentrations similar to those found in actual cannabis plants — significantly boost THC signaling at the CB1 receptor.

CB1 Activation

Using an in vitro cellular model, the Israeli team compared CB1 receptor activation by 16 different cannabis terpenes to that of THC alone and to THC-terpene blends with a botanically relevant ratio of 10:1.

When tested individually, all 16 terpenes activated CB1, at about 10% to 50% of activation of THC alone. This is notable in and of itself, though not a huge surprise. While their chemical structures differ quite a bit, terpenes and cannabinoids share key features; both belong to a larger group of plant compounds called terpenoids. In fact, cannabinoids are technically classified as “terpeno-phenolic” substances.

Varying Responses

Next, the researchers tested terpenes and THC together. What they found runs the gamut. In the cases of beta-pinene and geraniol, the mixtures actually produced a smaller effect than the sum of the individual parts, as if these terpenes negated some of THC’s activity.

For eight of the THC-terpene blends, including some of the most common cannabis terpenes — alpha-pinene, beta-caryophyllene, bisabolol, eucalyptol, humulene, myrcene, nerolidol, and terpinolene — CB1 activation equaled that of THC alone. The presence of the terpene seemed to make no difference.

A 2021 study reports that some terpenes are “cannabimimetic” and can enhance cannabinoid activity.

But with three other terpene-THC blends — linalool, ocimene, and terpineol — the researchers observed an additive effect, meaning that CB1 activity equaled the sum observed with THC and the terpene separately. In other words, if the terpene was a 3 and THC was a 7, the blend was a 10.

Finally, three of the terpenes — limonene, borneol, and sabinene — produced a synergistic effect in combination with THC. In these cases, the whole was greater than the sum of its parts: an 11 or 12 rather than the expected 10.

THC-Terpene Synergies

The researchers consider this latter point their most significant finding. It represents the first demonstration of THC-terpene synergism in an in vitro controlled setting, and lends the paper its title: “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.”

Is this evidence of the fabled cannabis entourage effect? Strictly speaking, no, according to the paper’s authors. They note that the term “entourage effect,” as originally coined in a 1998 article in the European Journal of Pharmacology,4 refers to cases where compounds that don’t directly bind to CB1 or CB2 nonetheless boost the activity of the endocannabinoid system.

Since terpenes do activate CB1, this doesn’t fit with the original concept of the entourage effect. “Given that cannabis terpenes demonstrate direct agonism at CB1 receptor,” the authors contend, “THC-terpene effects are beyond the classical definition of entourage.”

Therapeutic Applications?

Semantics aside, the paper’s fundamental findings around THC-terpene interactions, at ratios similar to those in the cannabis plant and at very low terpene concentrations, could have significant implications for both future research and real-world cannabis use.

The simple fact that different terpenes can modify THC activity in different ways seems worthy of attention on its own, but the authors put particular emphasis on their discovery of a synergistic effect for limonene, borneol, and sabinene. While limonene is among the most common cannabis terpenes, borneol is less so, and sabinene is rarer still. As a result, they suggest that these terpenes could be intentionally added to cannabis extracts to maximize effectiveness of their THC content.

Terpenes could be added to cannabis extracts to maximize the effectiveness of their THC content.

“The use of selected terpenes may enable reducing the THC dose in some treatments, and as a result, potentially minimizing the THC-related adverse effects,” they conclude. “This would also help in adjusting the treatment to more sensitive populations such as children and elderly.”

The authors continue, “Enrichment with selected terpenes may allow for composition adjustment to personal needs and to changes during chronic use, such as for daytime versus for sleep.”

Of course, these statements are speculative and not necessarily supported by clinical research. They also smack a bit of marketing-speak, which is not surprising given that four of the authors are employees of the Bazelet Group, a medical cannabis manufacturer in Israel that boasts of using a “breakthrough technology” to “formulate specific desired [cannabinoid-terpene formulations] to supply enhanced therapeutic effect in various medical conditions.”

As always in cannabis science and medicine, the real world is far more complex than the lab, and preclinical findings don’t always translate into lived experience. But at the very least, the study provides further evidence of interactions between terpenes, cannabinoids, and the endocannabinoid system — something Project CBD will explore further in a subsequent article on beta-caryophyllene, the “super terpene.”

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. Cox-Georgian, Destinney et al. “Therapeutic and Medicinal Uses of Terpenes.” Medicinal Plants: From Farm to Pharmacy 333–359. 12 Nov. 2019, doi:10.1007/978-3-030-31269-5_15
  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. 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
  4. Ben-Shabat, S et al. “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.” European journal of pharmacology vol. 353,1 (1998): 23-31. doi:10.1016/s0014-2999(98)00392-6

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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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Getting to Know Cannabigerol with Bonni Goldstein, MD

This transcript is adapted from CannMed’s weekly podcast, hosted by Ben Amirault, who recently interviewed Bonni Goldstein, MD, one of the country’s most respected and experienced medical cannabis physicians. Dr. Goldstein has treated thousands of patients with medical cannabis. She is the medical director of Canna-Centers Wellness & Education and the clinical advisor to Cannformatics. She is also the author of Cannabis is Medicine: How Medical Cannabis and CBD are Healing Everything from Anxiety to Chronic Pain. Dr. Goldstein will be leading the Medical Practicum at CannMed 2023 (May 15-17), where she will also be speaking about CBG and other minor cannabinoids during the main session.

Ben Amirault, CannMed: I wanted to discuss one of the so-called minor compounds that you’ll be covering during your talk at CannMed this month. You have said that cannabigerol, or CBG, is one of your favorite cannabinoids. Why?

Dr. Goldstein: It appears that CBG does a lot of things that THC does and a lot of things that CBD does — but maybe even a little bit better. It’s kind of a bridge between THC and CBD. CBG is not intoxicating or impairing. It seems to be effective at lower doses compared to CBD. And it does appear to address some of the main issues that people turn to cannabis for — inflammation, pain, anxiety, sleep problems, depression, and cancer. So, like it checks all the boxes, especially for people who don’t want to get high and who don’t have the ability to pay for very high doses of CBD.

CannMed: It’s interesting that you say CBG is a bridge between THC and CBD. Is that because CBG is a precursor for the other plant cannabinoids?

Dr. Goldstein: CBG’s parent compound, cannabigerolic acid (CBGA), is kind of known as the mother of all the cannabinoids in that it’s the compound that’s found in immature cannabis flower. And then, based on the genetics of the plant and the enzymes that it’s exposed to, CBGA changes into CBDA and/or THCA, which turn into CBD and THCA when heated. CBGA hasn’t really been studied very much. I would say it is highly understudied. But I suspect that we will eventually find out that CBGA has some very interesting anti-inflammatory and anti-cancer properties. We don’t know really know yet. But at least CBG is being studied. I constantly look at the scientific literature, and just this year there’s a study published from Israel on how CBG may be helpful for multiple sclerosis. And there’s another study that looked at CBG’s mechanism of action in terms of how it works for pain and inflammation. So, there’s a lot of interest in CBG, which is really exciting.

CannMed: For what conditions do you think CBG has the most promise? What are you most interested in?

Dr. Goldstein: I think CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression. Ethan Russo, along with other researchers, recently did a survey of CBG users. About 70 percent of people said CBG was superior to their conventional medication. It was highly rated for anxiety, pain, depression, and sleep problems. I don’t know that it’s a direct sleep agent, but when you are having less anxiety and less pain you likely will fall asleep a little bit easier and maybe sleep better. It’s noteworthy that much of this anecdotal data is supported by findings from preclinical research.

CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression.

CannMed: In the survey you mentioned, was that CBG being taken by itself or in combination with other cannabinoids?

Dr. Goldstein: In the survey, I think they tried to sort that out, and it was people taking plant CBG that they buy in the hemp market because most CBG products that are on the market do not contain a significant amount of THC. They are coming from hemp plants, so they are readily available on the hemp market. I’ve seen it as flower, I’ve seen it as topical, which has anti-bacterial and anti-psoriatic effects. Psoriasis is a well-known condition where people get not only joint pain but they also get these thick red patches and scales on their skin. It can be a very difficult condition. And CBG has been found to have anti-psoriatic properties. It acts on the skin cells themselves and inhibits the build-up of those scaly patches. I think this just goes to show that the applications of cannabinoids are truly wide-ranging. People often ask: How is it possible that these compounds can do so many things? Well, they have multiple targets in the brain and body and that’s what makes them so amazing. Remember, the pharmaceutical model is “this medicine addresses this specific target.” Whereas cannabinoids are what we call promiscuous – they go to a lot of targets.

CannMed: How does CBG differ in its targets from other plant cannabinoids? Does it work on the same receptors with similar mechanisms of action?

Dr. Goldstein: There’s overlap with some of the actions of THC and CBD, for example. But then there are also some opposite reactions. CBD and CBG have opposite reactions at a specific serotonin receptor — 5HT1A — where CBD binds to it and CBG blocks it. They both act at that receptor, but in different ways. CBG also overlaps with CBD by binding to what we call PPAR receptors [on the surface of the cell’s nucleus]. And both of these plant cannabinoids interact with TRP [ion] channels to help with inflammation and pain.

CBG is the only cannabinoid that has been found to work at the alpha-adrenergic receptor, which mediates pain perception and inflammation. There are pharmaceuticals for ADHD or behavioral issues, for example, which target this receptor. CBG is always a compound I consider when treating children who have either behavior or other types of difficulties. I have used it in some of my patients with autism. Some families report their child is calmer, has better focus, even speech is improving in some of the children with autism who are non-verbal. But other parents report that CBG makes their child way too hyper. That may be a dosing issue. Why not try it? We know that it’s safe. And it’s under medical supervision. We start with very low doses so that we can control what’s going on and of course there’s a lot of oversight. The parents are watching, I’m watching. We’re just trying to make sure that we do no harm. Thus far, I’d say about 60 percent of kids that try CBG seem to get some benefit from it.

CannMed: I’m glad you brought up ADHD. Full disclosure: my son has been diagnosed with ADHD. I was surprised to learn that CBG might be helpful for that.

Dr. Goldstein: We don’t have clinical trials to say, yes this is definitively beneficial or detrimental for children. But we may be on the cusp of having those trials, which would be very exciting. In my practice, which is in California, I am allowed to work with parents to try different cannabinoids to see what might help. We do it very methodically. As I discuss in my book, we have a saying, ‘Rule it in or rule it out’. We start low dose, and we titrate up. We focus on one compound to see if there are benefits. And remember, too, that sometimes when we’re seeing a benefit it may be because the child is also on CBD — and maybe that combination is working well. If you add a compound and see enhanced benefits, you don’t know if it’s working because of that particular compound or the combination of the two if they’re already on something else. There’s a lot of trial and error involved, and it takes time to sort it out. I always tell families when I first meet them that we’re going to be working together for quite some time. It’s not like we just pick something and it immediately works great. We might get lucky. That happens, but that’s not the usual case.

CannMed: Another thing that stood out to me was this idea of CBG enhancing the body’s function. I was wondering if you could speak a bit to that.

Dr. Goldstein: A number of endocannabinoids, including CBD and CBG, delay the breakdown of our endocannabinoids. Remember, our endocannabinoids are our inner cannabis-like compounds, which our body releases on demand in response to a trigger, usually something that is stressing us, whether it be an illness or a traumatic insult or an infection of some sort. Your body cranks out these endocannabinoids to help maintain balance among all the various messages that our cells are constantly sending and receiving. The endocannabinoid system is a physiological regulator, and it’s helping you stay in balance. We can enhance our own natural endocannabinoid system with plant cannabinoids, which delay the breakdown of endogenous cannabinoids so that they last longer. It’s kind of like the way some anti-depressants work by increasing how long serotonin is hanging around.

We can enhance our own natural endocannabinoid system with plant cannabinoids.

CannMed: Now correct me if I’m wrong, but physical exercise is another way to spur your body into creating endocannabinoids?

Dr. Goldstein: Yes.

CannMed: Would supplementing with CBD or CBG be an effective way to keep anandamide in the system and get more benefits from our natural cannabinoids?

Dr. Goldstein: Theoretically you could look at it that way. I don’t know that there’s a direct correlation, as in take a dose and now you have extra anandamide. But I do think the literature supports this whole idea of cannabinoids being anti-inflammatory, antioxidant, neuroprotective — and one dose is not going to do the trick. It’s helpful to think in terms of a wellness regimen that includes cannabinoids, of course, in addition to other healthy things that you should be doing to enhance your endocannabinoid system – healthy diet, exercise, good sleep, really trying to control your stress.

CannMed: Could you speak to how CBG might enhance the effects of other cannabinoids or situations where you think the combination is useful?

Dr. Goldstein: There’s a 2019 animal study that showed the combination of CBD and CBG decreased neuroinflammation. They were looking specifically at neurodegenerative disorders with dementia, what we call Lou Gehrig’s Disease or ALS. And it showed in this preclinical study that CBD and CBG worked together and gave better results for protecting against neuroinflammation. This ties into the concept of the entourage effect, whereby combinations of cannabinoids and terpenes appear to enhance the benefits, the positive results. Another recent study showed that CBG in addition to THC and/or CBD has anti-cancer effects in test tube experiment looking at certain brain tumor cells. When some of my cancer patients come to me with advanced cancer, very poor prognosis — and I’ve been doing this now for a number of years — I add CBG into the mix. To me there is no harm in doing so. It doesn’t cause the impairment that anti-cancer doses of THC can sometimes cause.

CannMed: What other scenarios or situations do you encounter where you think CBG is either the right tool or might be a good companion if you have already started a cannabis regimen and you’re not getting the right results?

Dr. Goldstein: I think that if you’re trying to treat anxiety, pain, inflammation, and you are not getting great results with either THC and/or CBD, which, of course, are the two most common cannabinoids being used right now, then certainly the addition of CBG is worth a try. Remember too, that when you combine cannabinoids sometimes you can get away with a lower dose of either or both, while getting an enhanced effect from that entourage. Because there are studies that show sub-therapeutic doses of cannabinoids — meaning doses not expected to do anything clinically — when combined will work better. For a lot of people high, high doses are just not financially feasible. And sometimes that combination of small amounts of two compounds actually is more effective. As for what I would recommend CBG for — anxiety, pain, psoriasis, I use it in my patients with autism, I use it in my patients with cancer. Because it’s safe, and if somebody’s struggling and conventional medicine is not helping them or it is only helping to a point, I don’t see any reason, especially under medical supervision, not to try CBG and other cannabinoids when there’s compelling preclinical research that begs for clinical trials.

CBG is always a compound I consider when treating children who have behavior or other types of difficulties.

CannMed: It seems like CBG is very well tolerated by patients, but are there adverse reactions that you’ve run into?

Dr. Goldstein: I haven’t really seen a lot of adverse reactions, except for a few specific ones related to the population of children that I take care of. In some kids with autism, it’s just too overstimulating. It makes behavior go off the charts. So, I warn the families about this before we get started. It may be a dosage thing. Dosing is very, very important. Lower doses may be overstimulating. If that’s the case, we might try higher doses. But that’s specifically related to a certain population. I have not observed or heard of too many side effects from adults taking CBG. Some patients say that CBG is somewhat alerting, meaning it feels a little up. So, you would not want to take CBG right before bedtime. You figure out how you respond to it, and then don’t use it at night if that’s the effect you get. On the other hand, some people say it helps with sleep. Maybe it’s helping with sleep because it’s calming and decreases anxiety. When a doctor hands you an antidepressant or an opioid, nobody knows how you’re going to respond if you’ve not taken that before. It’s the same thing with CBG. There is always a chance when you take a new medication that you may be the person who doesn’t respond very well. Or you might be the person who gets a great result.

CannMed: CBG is still one of the lesser-known cannabinoids. How easy is it to access CBG products?

Dr. Goldstein: In the video that I put up on YouTube, there’s a slide that shows some of the CBG products. You can get it as flower if you want to vaporize it. You can get it as a topical, as I’ve mentioned. Mostly I’ve seen it in tincture form, which means an extract in a bottle where you have a little eyedropper or syringe and you measure out your dose and squirt it under the tongue. I don’t endorse any company, but certainly a quick Google search will lead you to where you can find CBG. And of course, always, always before you purchase anything, you want to make sure you get a Certificate of Analysis (CoA) so you see what is supposed to be in that bottle before you buy it. And if a CoA isn’t available or not readily transparent, move on to the next product.

CannMed: We actually did a podcast with a laboratory professional who was talking about how some manufacturers will even falsify their CoA’s. She had some good tips for being able to spot the real ones and the less scrupulous ones. So, Bonni, before I let you go, I want to thank you so much for talking about CBG with us. I look forward to hearing your talk on some of the other cannabinoids at CannMed 2023, where you’re also going to be leading our Medical Practicum, along with Dustin Sulak, Kevin Spelman, and Eloise Thiessen. Could you give us a sneak quick preview of what people can expect at the Practicum and why you believe it’s important to have events like this to educate clinicians and laypersons about cannabis medicine.

Dr. Goldstein: It’s important because for health care professionals there is no full board training program, no residency or internship that focuses on cannabis therapeutics. The feedback we’ve gotten is it’s very helpful to hear directly from clinicians who are actually practicing this type of specialty and who are exploring the nuances of cannabis medicine. The practicum is a full day of education. We start off with endocannabinoid system physiology, the physiology of the cannabinoids and other constituents of the plant. Dr Kevin Spelman, who’s a brilliant botanist and herbalist with many years of experience, is one of the teachers. His lectures are amazing. Especially coming from my world as an MD, an allopathic world, it was a big change for me to understand botanical medicine. Having him on board really helps bridge that gap for those of us who are coming from the allopathic field. During the practicum, we also go through clinical applications for cannabis, special considerations for geriatric patients, chronic pain treatment. I’ll be talking about pediatrics, my area of specialty. And then there will be practical panels where we’ll be giving case reports and advice on how to help your patients pick the right medicine. It’s really a full day with lots of information for anyone who wants to advance their knowledge. I really enjoy it. It’s great to be around like-minded people, and it’s great to hear about other people’s experiences. I always learn something from my colleagues at CannMed, from people in the audience, and from the other speakers.

For more information on Dr. Goldstein, visit her YouTube channel Bonni Goldstein MD. She occasionally posts on Instagram, and she is also on LinkedIn. To hear the full CannMed podcast with Dr. Bonni Goldstein, go here.

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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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