Tag: Bridging the Gap

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Beta-Caryophyllene: Terpene Powerhouse

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

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

A “Dietary Cannabinoid”

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

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

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

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

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

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

Alzheimer’s & Substance Abuse

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

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

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

Painkiller

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

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

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

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

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

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

Footnotes

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

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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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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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