TheAnswerPage.com blog post by Jeffrey S. Block, M.D.
Founder, Nurturing Nature® Group Consultants
UF/IFAS Master Gardener (Miami-Dade County)
UF/IFAS Industrial Hemp Pilot Project Advisory Committee
Cannabis sativa – One plant, Many crops
Despite its cultivation as a source of food, fiber and medicine, and its global status as the most frequently used illicit drug, plants in the genus Cannabis currently experience an inconclusive taxonomic organization and evolutionary history. Because of the challenges in determining geographical origin of modern plants and the possibility for reproduction across the genus, all plants in the genus are most accurately Cannabis sativa. What is botanically indistinguishable has many distinctions as a crop.
Hemp is a Cannabis crop typically grown for seed and fiber production that more recently has been incorporated into the industrial manufacture of several derived products, including biodegradable plastics, biofuel, clothing, textiles, insulation, paper, food, and food for animal consumption. Hemp has traditionally contained low amounts of THC, but more recently has been hybridized as a source of CBD, or cannabidiol.
Cannabis plants that contain higher amounts of the intoxicating psychoactive cannabinoid THC are used for medical purposes and as a recreational drug. A burgeoning Cannabis industry currently provides both marijuana for therapeutic Δ-9 Tetrahydrocannabinol (THC), and industrial hemp for Cannabidiol (CBD), though both cannabinoids can be present in traditional marijuana and hemp.
Subspecies and Cultivars
Cannabis dispensaries and product manufacturers still mistakenly label their products based on a perceived distinction between different subspecies types of cannabis plants: indica and sativa. The historical basis to the evolution of these subspecies is that Cannabis sativa indica developed in northern latitudes, while Cannabis sativa sativa came from equatorial regions. Yet, recent genomic analyses of cannabis plants reveal that modern plants should generally be regarded as hybrids of the two, with little chemical distinction in terms of their THC:CBD profiles. In addition to THC and CBD, different cultivars also express various combinations of terpenes, flavinoids, and other minor cannabinoids.
As the chemical composition of a cannabis plant has been determined to be most important to distinguish between plant types and crops, the United States Pharmacopeia (USP) has evaluated specifications necessary to define key cannabis quality attributes. (6) Three main chemotypes have been identified as useful for labeling based on the following three cannabinoid constituents: (1) tetrahydrocannabinol (THC)-dominant chemotype; (2) intermediate chemotype with both THC and cannabidiol (CBD); and (3) CBD-dominant chemotype. Cannabis plants in each of these chemotypes may be further subcategorized based on the content of other cannabinoids and/or terpene profiles.
A 2017 federally commissioned report from the National Academies of Sciences, Engineering and Medicine (NASEM) recognized several conditions that have substantial and/or conclusive evidence-based data to support cannabis’ efficacy. Their statements relied on data accrued starting in 2000; when the average dry-weight percentage of THC was <5%. Archeological evidence suggests that a balanced cannabinoid profile had co-evolved after 5,000 years of human cultivated use. Extreme cannabinoid profiles accelerated after 1970’s Controlled Substances Act prohibition of Cannabis and later in efforts for modern medical and recreational markets.
While industry and marijuana advocates enthusiastically champion the plant’s safety based on the NASEM report’s research based on THC <5%; but contemporary plants sold and consumed typically exceed 20% THC. In addition to the THC potency of modern cultivars, one terpene of particular interest is myrcene. While several terpenes may contribute to calming or relaxing effects on the Cannabis user, myrcene is recognized for hypnotic properties that can negatively impact memory. The dominant genetics associated with myrcene result in its persistence within most modern cultivars.
Indeed, the NASEM report’s findings were able to confirm marijuana’s efficacy for a few indications, but the conclusions were based on evaluating a lower potency marijuana that was available between 2000 and 2016. Because currently used stronger Cannabis hybrids have yet to be objectively studied, we know very little about the safety and efficacy of the more potent “modern” cultivars and derived concentrates. More on potency will be discussed in future blogs.
What we know is that Cannabis sativa remains one plant with many crops requiring chemical analysis to distinguish types not only for legal purposes, but also for an educated consumer’s safe and efficacious use.
Healthcare….What is HealTHCare without THC®
Manktelow, M. (2010) History of Taxonomy – Lecture from Dept. of Systematic Biology, Uppsala University.
Swanson, TE (2015), “Controlled Substances Chaos: The Department of Justice’s New Policy Position on Marijuana and What It Means for Industrial Hemp Farming in North Dakota” (PDF), North Dakota Law Review, 90 (3): 613.
“Erowid Cannabis Vault : Culture #2”. erowid.org. Retrieved 2008-06-20.
Sawler, et al. Plos One, 2015; 10(8): e0133292 The Genetic Structure of Marijuana and Hemp
El Sohley, M. et al “Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes”. J. Nat. Prod. 2020, 83, 1334-1351.
Are you able to answer your patients’ medical marijuana questions? Well, if your answer is ‘no,’ you are definitely not alone. As reviewed in a recent Forbes article, “a study of more than 400 health care professionals has revealed that most physicians lack knowledge of medicinal cannabis, with 65% saying that they have been asked about medical marijuana as a treatment for chronic pain but were unable to answer their patients’ questions” (1). Also, a recent systematic review of healthcare professionals’ “cannabis knowledge” reported “there was a unanimous lack of self-perceived knowledge surrounding all aspects of medicinal cannabis” (2). These findings do not surprise me at all. As the Editor-in-Chief of the medical education website called TheAnswerPage.com for nearly two decades, I have assessed multiple educational gaps in the healthcare community. During my tenure, I have found the medical marijuana educational gap to be one of the most significant educational gaps that impacts a very broad range of healthcare providers. In fact, from pediatricians to geriatricians, I cannot think of any medical practitioner that does not need to be well informed about the endocannabinoid system and cannabis-based therapeutics.
Since 2012, TheAnswerPage.com has addressed the immense need for unbiased evidence-based high quality education focused on the endocannabinoid system and medical marijuana. We provide free educational resources, including ‘The Answer of the Day,’ a daily question and answer email that reviews the medical marijuana articles published in the peer-reviewed medical journals. We also provide free downloadable resources: ‘The Endocannabinoid System and Medical Marijuana in 15 minutes!’ and ‘The Perioperative Considerations for the Patient Utilizing Cannabinoid-based Medicines and Products.’ In addition, TheAnswerPage.com offers multiple accredited continuing medical education (CME/CE) marijuana courses for doctors, nurses, nurse practitioners, pharmacists, psychologists, and dentists, so that they can guide their patients on the use of cannabinoid-based therapeutics and can best manage their healthcare. If patients do not receive well-informed guidance about medical marijuana, it is unlikely that they will be able to maximize the benefits of the medical marijuana and simultaneously minimize the risks and complications associated with this medicine. In addition, if clinicians are not well informed about the health effects of cannabinoid-based products, clinicians will not be able to optimally treat their patients.
In November 1996, California became the first state to legalize the use of medical marijuana, and now 25 years later, more than 70% of the US population resides in a state or territory with medical marijuana laws in place, and there are nearly 5.5 million medical marijuana patients nationwide. Considering the remarkable growth of the medical marijuana patient population, one would expect that the availability of unbiased peer-reviewed medical marijuana educational offerings would increase to meet the needs of the healthcare community. Unfortunately, this did not occur. Thus, an educational gap developed, creating a less than ideal situation for medical marijuana patients. So, why did this educational gap develop? Medical marijuana, unlike every other legal medication in the US, has been legalized by the vote of the public and the work of policymakers. In most cases, state medical marijuana legislation was passed without input from individual medical professionals or the medical community. As a result, state medical marijuana rules and regulations have focused on the demands of the public without putting significant emphasis on the scientific data or the ability of the medical community to support and care for medical marijuana patients. For example, most, if not all, states have legalized the use of medical marijuana to treat specific health conditions for which there is no or only poor quality clinical evidence of efficacy and safety. Furthermore, the laws do not consider the level of “cannabis knowledge” of the healthcare provider community; a few states do have a mandated continuing medical education requirement for the clinicians recommending medical marijuana and for the pharmacists who work in the medical marijuana system, but no state medical marijuana laws require ALL healthcare providers (including doctors, nurses, pharmacists, psychologists, dentists, etc..) to take a medical marijuana course that reviews the endocannabinoid system and the therapeutic use of marijuana. Consequently, most clinicians are not familiar with the modes of administration and the pharmacodynamics/ pharmacokinetics of each mode, drug interactions, the different medical marijuana products (pills, flower, tinctures, topicals, etc..), the components of the cannabis plant (phytocannabinoids, terpenes, and flavonoids) and the health effects of cannabinoid-based therapy in the various patient populations.
According to state laws, in order to purchase medical marijuana products, a patient must first obtain a recommendation (not a prescription) for medical marijuana from a clinician and enroll in the state medical marijuana program. Most often the recommending clinician is not the patient’s primary care provider, oncologist, neurologist, pain specialist, psychiatrist or gastroenterologist. It is a provider that the patient sees once or maybe twice, and there’s no mandatory follow up with the recommending clinician. After purchasing the medical marijuana, patients often decide to initiate therapy without informing their physicians or enlisting help from their physicians due to fear of being stigmatized and/or due to a lack of trust in their physician’s knowledge and ability to incorporate marijuana into their medical treatment (3). The inability of most clinicians to safely and effectively treat medical marijuana patients is well documented in the medical literature. As recently as December 2021, the medical literature reports a common theme – ‘healthcare provider education on the endocannabinoid system and medical marijuana therapeutics is greatly needed’:
“Numerous studies in countries such as Canada, which have a national mandate for cannabis availability, as well as the USA, have shown that our providers, be they attending physicians, physicians in training, advanced practice nurses, pharmacists, or physician assistants, are ill prepared to counsel and utilize cannabis products in our patient populations” (4).
“As more states loosen their legislation surrounding marijuana use, health-care providers are increasingly expected to advise patients regarding its potential health benefits and safe use. Despite the growing public interest, medical teaching and training at the medical school and post-graduate levels are widely lacking” (5).
“Medical Marijuana (MM) use is increasing, requiring healthcare professionals, such as dentists, to increase their working knowledge of MM. Previous studies have indicated that MM education is lacking in current healthcare education…Practical Implications: The findings of this survey suggest more MM education and research is needed — statements with which the majority participants of this study have explicitly and strongly agreed” (6).
“However, most physicians experience a lack of knowledge of beneficial effects, adverse effects and of how to advise patients” (7).
So, who provides the necessary medical guidance to patients who qualify for medical marijuana? Who monitors their health and the long-term effects of the marijuana therapy? Many patients manage their own medical marijuana therapy and base their medical marijuana usage on internet websites, which may or may not be providing evidence-based information or safe guidance, and many medical marijuana patients follow the advice of family members and friends, who might not have any clinical training. Other patients rely on directions from budtenders (the dispensary workers who sell the marijuana products to patients). Some patients put faith in anecdotal reports or the encouraging results of observational studies, but anecdotal reports and observational studies are not double blind randomized controlled clinical trials and do not prove that a treatment is or is not effective. Results of an observational study merely suggest an association between a therapeutic agent or an event and an outcome. Other patients do read through the scientific literature, but might not know how to interpret the results of studies, and they may apply findings from preclinical studies to their medical care.
Unfortunately, in some instances, the actions of misguided medical marijuana patients further compromise their health. For example, according to a recent study published in Cancer, 49% of the surveyed breast cancer patients who use medical marijuana believed that the marijuana could treat the cancer, and there have been multiple reports of patients actually substituting FDA-approved chemotherapeutic agents with marijuana products (8). Although there is clinical evidence that some cannabinoids ameliorate chemotherapy-induced nausea and vomiting, and may improve the sleep and decrease the pain of cancer patients, medical marijuana has not been found to cure cancer in humans, at this point in time. Another example of how the actions of misguided patients may further compromise their own healthcare involves the use of cannabinoids to treat inflammatory bowel disease. Some ulcerative colitis and Crohn’s disease patients use marijuana to relieve pain/discomfort and decrease GI motility/diarrhea. And, for some, that marijuana therapy may work to relieve symptoms, but endoscopic examinations have not shown that cannabinoids decrease the progression of disease. Unfortunately, some patients may be falsely reassured that their condition is in remission and believe that it is safe to postpone a colonoscopy. Furthermore, if the healthcare provider is unaware of the patient’s marijuana therapy and/or is not knowledgeable about medical marijuana’s effects on inflammatory bowel diseases, the healthcare provider may be under the impression that the prescribed therapy is effective.
Practical Implications: Regardless of your field of medical practice or whether or not you recommend medical marijuana, there’s a high likelihood that some of your patients use cannabinoid-based products, including CBD. Thus, you should be well-informed of the health effects of cannabinoid-based products; it’s the only way that you will be able to openly and effectively communicate with your patients about the cannabinoid therapeutics they are utilizing (or considering) and about the recommended therapies they may choose to replace with cannabinoids. A patient’s healthcare management plan needs to be the result of a well-informed shared decision making process.
- Herrington AJ. Study Shows Most Physicians Lack Knowledge Of Medical Cannabis. Forbes. Nov 24 2021. https://www.forbes.com/sites/ajherrington/2021/11/24/study-shows-most-physicians-lack–knowledge-of-medical-cannabis/?sh=3a79787b94e6
- Gardiner KM, Singleton JA, Sheridan J, Kyle GJ, Nissen LM. Health professional beliefs, knowledge, and concerns surrounding medicinal cannabis – A systematic review. PLoS One. 2019;14(5):e0216556. Published 2019 May 6. doi:10.1371/journal.pone.0216556
- Holman A, Boehnke K. Tackling the taboo: a sensible prescription for appropriate cannabis use in fibromyalgia. Pain Management. No 2021. Issn 1758-1869.
- Zimberg S. Medical Marijuana: An Overview for Obstetricians/Gynecologists. Journal of Clinical Gynecology and Obstetrics, North Amer, 0 Nov 2021. Available at: https://www.jcgo.org/index.php/jcgo/article/view/757/479 Accessed 05 Dec. 2021.
- Le-Short C., Narouze S.N. (2021) The Demand for Medical Cannabis Education. In: Narouze S.N. (eds) Cannabinoids and Pain. Springer, Cham. https://doi.org/10.1007/978-3-030-69186-8_3
- Szyliowicz D. Survey of Medical Marijuana Knowledge and Attitudes In a Dental School. University of the Pacific Publication 2021. https://scholarlycommons.pacific.edu/faculty-showcase/fall-2021/events/21/ -Accessed December 5, 2021
- Rønne ST, Rosenbæk F, Pedersen LB, et al. Physicians’ experiences, attitudes, and beliefs towards medical cannabis: a systematic literature review. BMC Fam Pract. 2021;22(1):212. Published 2021 Oct 21. doi:10.1186/s12875-021-01559-w
- M Weiss et al. A Coala-T-Cannabis Survey Study of Breast Cancer Patients’ Use of Cannabis Before, During and After Treatment. Cancer Oct 2021. https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.33906
About the Author
Meredith Fisher-Corn, MD is a board-certified physician specializing in anesthesiology, perioperative and pain medicine. She received a Bachelor of Science in biomedical engineering from Duke University School of Engineering and a Medical Degree from the Mount Sinai School of Medicine. Following an anesthesiology residency and fellowship at Brigham and Women’s Hospital, Harvard Medical School, she was an attending anesthesiologist at Women and Infants Hospital, Brown University Medical School.
Since 2009, Dr. Fisher-Corn has served as Editor-in-Chief of TheAnswerPage.com
In 2016, Meredith Fisher-Corn, MD was named “Medical Professional of the Year” by the Americans for Safe Access in Washington DC.
Meredith Fisher-Corn, MD, along with Stephen B. Corn, MD, are the 2017 recipients of the International Association for Cannabinoid Medicine “Special Award for Major Contributions to the Reintroduction of Cannabis as Medicine.”
TheAnswerPage is a medical education resource that has been providing the highest quality accredited education to the healthcare community for over two decades. Awarded in the US and internationally, TheAnswerPage is now a recognized leader for providing comprehensive education on the endocannabinoid system and medical cannabis, pain medicine, and opioid prescribing practices.
TheAnswerPage creates tailored medical cannabis educational programs for Departments of Public Health, state medical societies, hospitals, and medical schools.
TheAnswerPage is the only education company where the Founding Editor-in-Chief and Editor-in-Chief trained and served together with distinction at Harvard Medical School and their affiliated teaching hospitals, and have both been the recipients of numerous awards including the “Medical Professional of the Year Award” presented by the Americans for Safe Access (ASA) and the “Special Award for Medical Cannabis Education” bestowed by the International Association of Cannabinoid Medicine (IACM).
TheAnswerPage.com blog post by Professor Raphael Mechoulam, PhD
Faculty of Medicine, The Hebrew University of Jerusalem, Member, Israel Academy of Science
Until recently, addiction was assumed to be mainly a psychological state. Now it is believed that it represents a central nervous system disease. George Koob, an eminent researcher in the addiction field, states in his book on addiction (1), “The view that drug addiction and alcoholism are the pathology that result from an allostatic mechanism that usurps the circuits established for established natural rewards provides an approach to identifying the neurobiological factors that produce the vulnerability to addiction and relapse“.
Assuming that the animal body recognizes addiction as an undesirable state (aka disease), it was plausible to assume that the animal body may try to establish ways to lower the effects of such a disease. Indeed, we are aware that some individuals do not get addicted using addictive drugs, while others do get addicted. The reason for these differences is not known yet.
On the above basis we – a joint group from the US, Canada, Italy and my lab – looked for a natural anti addiction defense mechanism. We started our research based on an observation made by Naqvi et al (2), who reported that cigarette smokers suffering from traumatic brain injury, which included insula cortex damage, abruptly ceased their nicotine addiction. This observation, along with more recent data (3,4) showing that the insula may control processes that moderate or inhibit addictive behavior, suggested the existence of a neurochemical, sensitive to brain injury, that might counteract nicotine reward and dependence.
After several years of research, we found that mouse insula after trauma produces a molecule, oleoyl glycine (OlGl) that has powerful anti-nicotine addiction properties (5). Oleoyl glycine is the amide of oleic acid with the amino acid glycine. We found that OlGl in mice blocks the establishment of nicotine place preference (CPP) – a test for addiction formation – and reduces withdrawal responses in nicotine-dependent mice. In morphine dependent rats OlGl reduced withdrawal responses, but did not affect morphine CPP, demonstrating selectivity (6,7).
We also found a tentative mechanism of the anti-nicotine addiction effect. OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) in vitro and a PPAR-α antagonist restored nicotine CPP in OlGly-treated mice (5). We also found that OlGl has protective effects in a mouse model of mild traumatic brain injury (8).
We assumed that OlGl, being an amide, may be easily degraded by amidases in the body. Hence we synthesized a derivative, oleoyl alanine, in which the amide bond is somewhat protected. Indeed, it was noted that oleoyl alanine (OlAla) is a more stable and effective treatment for opiate withdrawal than oleoyl glycine (9). Indeed, OlAla maintained its effectiveness in reducing opioid withdrawal responses in rats experiencing both acute opioid withdrawal (9) and chronic opioid withdrawal. However, neither OlGl nor N-OlAla modify tolerance to nociception, hyperthermia, and suppression of activity produced by morphine (10).
On the basis of the above recent discoveries ,we assume that exogenous administration of oleoyl glycine, or compounds with similar characteristics, like oleoyl alanine, will be beneficial for the modification or the prevention of the nicotine addictive state, as well as, nicotine and opiate withdrawal.
- F.Koob, M.A.Arends, M.Le Moal. Drugs, Addiction and the Brain. Academic Press, Elsevier, Amsterdam 2014.
- Naqvi NH, Rudrauf, D., Damasio, H., Bechara, A., 2007. Damage to the insula disrupts addiction to cigarette smoking. Science 315, 531–534.
- Naqvi NH, Gaznick N, Tranel D, Bechara A (2014): The insula: a critical neural substrate for craving and drug seeking under conflict and risk. Ann N Y Acad Sci. 1316: 53–70.
- Abdolahi A, Williams GC, Benesch CG, Wang HZ, Spitzer EM, Scott BE, et al. (2015): Damage to the insula leads to decreased nicotine withdrawal during abstinence. Addiction. 110: 1994–2003.
- Donvito, F.Piscitelli, P.Muldoon, A.Jackson, R.Vitale, E.D’Aniello, C.Giordano, B.Ignatowska-Jankowska, M. Mustafa, F.Guida, G.Petrie, L.Parker, R.Smoum, L.J. Sim-Selley, S.Maione, A.H.Lichtman, M.I.Damaj,V.Di Marzo, R. Mechoulam. N-Oleoyl glycine reduces nicotine reward and withdrawal in mice. Neuropharmacol. 148: 320-331 (2019). 6
- N. Petrie, K. L.Wills, F. Piscitelli, R. Smoum, C. L. Limebeer, E. M. Rock, S. M. Ayoub, A. E. Humphrey, M. Sheppard-Perkins, A. H. Lichtman, R. Mechoulam, V. Di Marzo, L. A Parker. Oleoyl glycine: interference with the aversive effects of acute naloxone precipitated MWD, but not morphine reward, in male Sprague–Dawley rats. Psychopharmacology (Berl). 236, 2623-2633 (2019).
- M. Rock, S.M. Ayoub, C.L. Limebeer, A. Gene, K.L. Wills, M.V. DeVuono, R. Smoum, V. Di Marzo, A.H. Lichtman, R. Mechoulam, L.A. Parker. Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine. Psychopharmacology (Berl). 237, 375-384 (2020).
- Piscitelli, F. Guida, L. Luongo, F. Iannotti, S. Boccella, R. Verde, A. Lauritano, R. Imperatore, R. Smoum, L. Cristino, A. Lichtman, L. Parker, R. Mechoulam, S. Maione, V. Di Marzo. Protective effects of N-oleoylglycine in a mouse model of mild traumatic brain injury. ACS Chem. Neurosci. 11, 1117-1128 (2020).
- M. Ayoub, R. Smoum, M. Farag, H. Atwal, S. A. Collins, E. M. Rock, C. L. Limebeer, F Piscitelli, F. A. Iannotti, A. H. Lichtman, F. Leri, V. Di Marzo, R. Mechoulam, L. A. Parker. Oleoyl alanine (HU595): A stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats. Psychopharmacology, 237, 2753-2765 (2020).
- M. Rock, C. L. Limebeer, M. T. Sullivan, M. V. DeVuono, A. H Lichtman, V. Di Marzo, R. Mechoulam, L. A. Parker. N-Oleoylglycine and N-oleoylalanine do not modify tolerance to nociception, hyperthermia, and suppression of activity produced by morphine. Frontiers Synaptic Neurosci. 13, 620145 (2021).
TheAnswerPage.com blog post by Professor Raphael Mechoulam, PhD
Faculty of Medicine, The Hebrew University of Jerusalem, Member, Israel Academy of Science
Incense burning was a central ceremony in the religious and cultural life of many – probably most or even all – ancient tribes and nations in the Middle East. In ancient Egypt incense burning signified a manifestation of the presence of the gods and a gratification to them. The ancient Greeks used incense burning as an offering to God, an oblation. In ancient Judea it was a central ceremony in the Temple. In Christendom its use in worship has continued since the 4th or 5th century C.E. However, it may have had also non- religious use. The famous Greek historian Herodotus (ca 450 B.C.) writes that “Whenever a man of Babylon has intercourse with his wife, he sits before an offering of incense, and the woman sits opposite him…” Was it an early Viagra?
A major ingredient in Middle Eastern incense is the resin of the Boswellia plant (known as frankincense, olibanum). In the ancient world Boswellia resin was considered a highly precious commodity, carried in caravans from sub-Sahara regions, where it is still a major export product. The Roman authority on scientific matters, Pliny the Elder (1st century C.E.), writes that only 3000 families of the Sabei tribe beheld the sacred trees, which produced the resin and while pruning the trees or gathering the resin, men were not to be ‘polluted’ by sexual intercourse or contact with a corpse.
The psychoactivity of Boswellia was recognized in ancient times. The Greek physician Dioscorides (1st century C.E.), whose book on medicinal plants was the leading text in pharmacology for many centuries, writes that it causes madness. In the Jewish Talmud (300-600 C.E.) Boswellia resin is mentioned as a potion (in wine) given to prisoners condemned to death to ‘benumb the senses’ or so that “he (the condemned) will not worry”. Indeed, some scholars suggest that the drink offered to Jesus on his way to Golgotha was wine with frankincense. In Abysinia Boswellia resin is still used as an antianxiety drug.
The use of Boswellia for its psychoactive properties extends beyond the Near East and Europe. In Ayurveda, an Indian medical tradition, it is reported to have a ‘strong action on the nervous system’. Surprisingly, in spite of the information stemming from the ancient texts, and present use in local traditions, the constituents of Boswellia had not so far been investigated for their psychoactivity. Apparently most present-day worshippers assume that incense burning has only a symbolic meaning.
We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. The assays employed were standard tests, used by many academic groups and industrial firms, for evaluation of drugs for these activities
To investigate the action of incensole acetate on different brain regions we studied its effect on c-Fos formation in mice brains 60 min after administration of the drug. c-Fos is a protein formed during changes in brain function. We found that, indeed, incensole acetate significantly changed c-Fos levels in brain areas known to be involved in the expression of emotions and in nerve circuits that are engaged by drugs that affect anxiety.
What is the mechanism in the body which causes these effects? We noted that incensole acetate does not bind to, and therefore does not affect, a large number of known receptors, through which mammalian biological systems cause changes in body functions. However, we found that it activates a receptor (known as ion channel TRPV3) which is implicated in the perception of warmth in the skin. It seems reasonable to assume that this effect may contribute to the spiritual exaltation associated with religious ceremonies, particularly on the conductors of the ceremonies, who presumably inhale large amounts of smoke. The ion channel TRPV3 is also found in the brain, but its functions there are unknown. Again, it seems reasonable to assume that, in view of our results, TRPV3 channels in the brain play a role in emotional regulation, possibly in anxiety and depression. Strong support to these assumptions was our observation that the effects of incensole acetate were not noted in mice in which (by genetic manipulation) the TRPV3 channels had been eliminated.
However, until the effects of incensole acetate have been confirmed in humans, we should remain cautious as to its effects.
We believe that our work on the biochemical and pharmacological effects of incensole acetate may be of importance in 3 directions:
- It provides a biological basis for deeply rooted cultural and religious traditions.
- The effects observed with a novel-type drug may open an alternative route to therapeutic agents in anxiety and depression, two major disorders found in large number of people. Although drugs are available for both conditions not all patients are well treated and novel drugs in both conditions are badly needed.
- The observation that the TRPV3 receptor in the brain is involved in emotional regulation may lead to novel neurochemical insights. Research over decades on plants eliciting psychoactive effects, such as Cannabis sativa (yielding marijuana), Papaver species (the source of morphine) and Nicotiana tabacum (the tobacco plant) has provided important insights into neurochemical processes and diseases of the central nervous system (CNS).
- A.Moussaieff, E.Lev, Z.Amar, E.Fride, D.Steinberg, R.Gallily, R. Mechoulam. The Jerusalem balsam: from the Franciscan Monastery in the Old City of Jerusalem to Martindale 33. Ethnopharmacology, 101, 16-26 (2005).
- Moussaieff, E. Shohami, Y. Kashman, E. Fride, M. Lienhard Schmitz, F. Renner, B. L. Fiebich, E. Munoz, Y. Ben-Neriah, R. Mechoulam. Incensole acetate, isolated from Boswellia resin, inhibits nuclear factor NFĸB activation. Mol Pharmacol. 72, 1657-1664 (2007).
- Moussaieff, N.A. Shein, J.Tsenter, S. Grigoriadis, C. Simeonidou, A.G.Alexandrovich, V. Trembovler, Y. Ben-Neriah, M.L. Schmitz, B.L. Fiebich, E. Munoz, R. Mechoulam, E. Shohami. Incensole acetate: a novel neuroprotective agent isolated from Boswellia carterii. J Cereb Blood Flow Metab. 28, 1341-1352 (2008).
- A.Moussaieff , N. Rimmerman, T. Bregman, A. Straiker, C. C. Felder, S. Shoham, Y. Kashman, S. M. Huang, H. Lee, E. Shohami, K.Mackie, M. J. Caterina, J. M.Walker, E. Fride and R. Mechoulam. Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. FASEB J. 22, 3024-3034 (2008).
- Moussaieff, R. Mechoulam. Boswellia resin: from religious ceremonies to medical uses: a review of in vitro, in vivo and clinical trials. J. Pharmacy & Pharmacol. 61, 1281-1293 (2009).
TheAnswerPage.com blog post by Jeffrey S. Block, M.D.
Founder and President – Nurturing Nature®
Plants and Animals Have Co-Evolved
Comparing botanical medicines with plant substances
As our ancestors evolved in prehistoric times, healers were depended upon as horticultural botanists. If they did not understand how to keep plants alive, healers would have lost their formulary and most certainly would have failed at their craft. From the earliest of primitive nomadic tribes to the advancing agricultural civilizations that followed, knowledge of botanical skills (botany) has proved central to mankind’s successful evolution.
Civilizations’ earliest “physician” healers included Imhotep (2667-2648 BC) in Egypt and Hippocrates (460-370 BC) in Greece, as well as Acharya Charaka (100? BC – 200? CE) in India and Zhang Zhongling (150-219CE) in China. They all understood and shared certain knowledge about the importance of plants to sustain health. Accordingly, these historical figures are widely regarded as Fathers of Modern Medicine by their respective cultures in that they each recorded their botanical findings to herald the historical beginnings of evidence-based healthcare.
Illustration by Jeannette Aquino (2020)
The endogenous cannabinoid system carries the plant’s name because study of cannabis effects led to the system’s discovery, however, this bodily regulatory system is in fact older than the plant. All animals, vertebrates and even invertebrates, have an endocannabinoid system (ECS, the oldest identified being the sea squirt, a creature that developed nearly 600 million years ago. By comparison, cannabis developed as a distinct botanical genus no earlier than 34 million years ago during the Oligocene epoch, and its closest genetic relative, hops, does not appear as a species in the fossil record until only around six million years ago. The appearance of a botanical compound that interacts with a much older animal receptor system may support a teleological or ethnobotanical contention that there is a coevolutionary relationship in which plants have developed highly sophisticated chemistries to cooperatively appeal to creatures unwittingly assisting with those plants’ reproduction and dissemination, as well as to repel insect and animal herbivore threats. An understanding of the plant’s survival rationale also helps to explain why its offensively bitter-tasting defensive chemical alkaloids often are taken along with a proverbial ‘spoonful of sugar’ when used as medicines to make their ingestion more palatable.
Cannabinoid Biochemistry and Physiology
Common Ancestral Links Between Flora and Fauna
Evolutionary natural selection provides indirect evidence of mankind’s effective use of botanical substances. Whether for nutrition or remedies, plant source chemicals are essential to sustain life and have been exploited by animals since the beginning of time. Human life’s evolution along with plant life has revealed common ancestral chemicals recognized to be essential to our health and survival. One has only to look at essential “life-blood” molecules of hemoglobin next to those of chlorophyll to appreciate that their remarkably similar chemistries connect an ancient botanical past to the complexities of our evolved modern human physiology.
Other than their respective 2+ cations (magnesium in chlorophyll and iron in hemoglobin), these life Kingdom defining molecules share remarkably similar biochemistries
Molecular similarities attest to the core of biochemical evolutionary links between plants and animals. This becomes apparent when comparing the critical energy molecules of plants and animals. Light energy processing is possible through chlorophyll that allows photosynthesis, while animals’ hemoglobin molecule is responsible for O2 exchange to derive energy. The mere substitution of magnesium (a 2+ cation) at the core of chlorophyll with iron (another 2+ cation), dramatically changes that molecule into serving as hemoglobin. This similarity of molecular structure is most remarkable when one considers the resulting essential consequence of each molecule’s unique bioactive purpose.
Human Agriculture Spreads Cannabis Around the Globe
During the Pleistocene Ice Age
Adaptable human beings and cannabis plants survived in “refugia”
Unlike most plants that use several methods of distribution such as wind, insect cross-pollination, or seed dispersal by animals, human agriculture is credited for Cannabis’ worldwide transport from Asia after the last ice age.
There is accumulating genomic evidence that native and natural traditional landrace Cannabis varieties evolved their ancestral balance of synergistic phytocannabinoids and essential oils to successfully co-evolve with humans and eventually find their way around the world.
Bekka Valley (Lebanon) – Cultivated “landrace” cannabis plants
evolved with humans into a balanced ration of THC = CBD.
Evolution’s threat to survival is indeed nature’s ultimate knock-out experiment! Contrasting with most plant and animal species that met with extinction during the last ice-age, mankind’s long-term survival along with the Cannabis plant has persisted since prehistoric times.
Co-evolutionary stressors imposed by ethnobotanical challenges may intuitively be regarded as indirect evidence of human-plant therapeutic tolerances that have withstood the critical test of time. Teleological discussions reason that if used by human beings for over 10,000 years, these traditional Cannabis varietals likely interplayed favorably with human genes well-enough to meet the survival needs of adaptive physiology.
Human agriculture was the vector for Cannabis’ current global distribution.
For all the importance of plant-human interactions in identifying endogenous mechanisms and targets for healthcare, future therapeutic applications will have less to do with the plant’s chemicals, and more to do with other pharmacological ways to manipulate the endocannabinoid receptors’ functions. This integrating system appears to be the body’s key regulatory mechanism, particularly in the brain, where it is known to affect memory, pain perception, and mood, among other things.
TheAnswerPage.com blog post by Professor Esther Shohami, PhD
Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Israel
Traumatic brain injury (TBI), resulting from sport, battlefield, falls, motor vehicle accidents and domestic violence injuries, affects millions of people worldwide each year and is a leading cause of death and disability among all age groups (1). TBI patients suffer from long-lasting persistent and serious deficits which include cognitive, motor and sensory dysfunction, anxiety, depression, post-traumatic stress disorder and an increased risk of developing neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease. Despite its being a major public health issue, there is no FDA-approved treatment for TBI.
Research developments on cannabinoids (CBs) have indicated the possibility to separate some of their proposed therapeutic effects from the undesirable psychoactivity. Moreover, CBs were found to activate specific CB1 receptors in the brain which are associated with “on demand” synthesis (2,3,4). Further studies have identified the endocannabinoid (eCB) system consisting of ligands, such as 2-arachidonoyl glycerol (2-AG; 5) and eCB-like ligands, such as arachidonoyl serine (AraS; 6). Taken together, these observations raised the question of whether CBs, either plant-derived or eCB, might exert neuroprotective properties in animal models of TBI. The information derived from these studies can then be translated into the clinic, which is in great need of novel therapeutics for TBI patients.
Our pioneering study in the field (7) revealed that, 4 hours after TBI, there is a tenfold increase in 2-AG in the injured hemisphere. To examine whether these high levels are toxic or beneficial, mice were treated with synthetic 2-AG one hour after injury. A greater recovery of the neurobehavioral function was observed, along with attenuation of the harmful consequences of the injury, namely, edema, infarct volume, blood-brain barrier permeability, neuronal cell loss, and neuroinflammation (8,9). Moreover, improved recovery of the neurobehavioral function was even noted up to 3 months after treatment of TBI mice with 2-AG. To further explore the role of the eCB system as a self-neuroprotective mechanism after TBI, the eCB-like molecule, AraS, was administered to TBI mice, resulting in reduced disability, smaller edema and infarct volumes and activation of pro-survival signaling (10-12). Palmitoyl serine is another endogenous neuroprotective eCB-like entity which was also shown to exert neuroprotective properties after TBI (13). A recent study showed that post-TBI inhibition of monoacylglycerol lipase (MAGL), the major degradation enzyme of 2-AG, which leads to the accumulation of 2-AG, is efficacious in attenuating TBI-induced neuronal dysfunction at site of injury (14). Collectively, these observations support the notion that the eCB is indeed a “self-protective” mechanism which is set in motion after TBI.
The CB2 receptor is expressed in low levels in the CNS, where it appears more in microglia rather than in neurons. Recently, synthetic agonists of this receptor were tested in a TBI mouse model and were found to result in improved motor and cognitive function, along with reduced pathologies such as edema, lesion volume, cell loss, inflammation and BBB disruption (15).
Cannabidiol (CBD), one of the major nonpsychoactive cannabinoids produced by Cannabis sativa, has a broad pharmacological profile, including anti-inflammatory and anti-oxidant properties. It was shown to exert neuroprotection in different brain pathologies and recently we investigated its effects on functional recovery, pathological outcomes and BBB integrity after TBI. The diverse pathology of TBI was found to be well addressed by the multi-target CBD in a mouse TBI model with a signiﬁcant improvement of motor and cognitive functions, survival of tissue, protection of axons from degeneration, and preservation of BBB integrity (16).
Collectively, the results suggest CB2 agonists as well as CBD, which are devoid of psychoactivity, as very promising candidates for future TBI therapy.
- Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Report to Congress on traumatic brain injury in the United States: Epidemiology and rehabilitationpdf icon. Atlanta (GA): Centers for Disease Control and Prevention; 2015.
- Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., and Bonner, T.I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.
- Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–84
- Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S.C., Cascio, M.G., Gutie´rrez, S.O., van der Stelt, M., Lo´pez-Rodriguez, M.L., Casanova, E., Schu¨tz, G., Zieglga¨nsberger, W., Di Marzo, V., Behl, C., and Lutz, B. (2003). CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88.
- Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR et al. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50: 83–90.
- Milman G, Maor Y, Abu-Lafi S, Horowitz M, Gallily R, Batkai S et al. (2006). N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Proc Natl Acad Sci U S A 103: 2428–2433.
- Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanus, L., Breuer, A., Mechoulam, R., and Shohami, E. (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–31.
- Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, et al. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis 2006;22:257–64.
- Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E. CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J Cereb Blood Flow Metab 2005;25:477–84.
- Shohami E, Cohen-Yeshurun A, Magid L, Algali M, Mechoulam R. Endocannabinoids and traumatic brain injury. Br J Pharmacol 2011;163:1402–10. – 531.
- Cohen-Yeshurun A, Trembovler V, Alexandrovich A, Ryberg E, Greasley PJ, Mechoulam R, et al. N-Arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J Cereb Blood Flow Metab 2011;31:1768–77.
- Cohen-Yeshurun A, Willner D, Trembovler V, Alexandrovich A, Mechoulam R, Shohami E, et al. N-Arachidonoyl-L-serine (AraS) possesses proneurogenic properties in vitro and in vivo after traumatic brain injury. J Cereb Blood Flow Metab 2013;33: 1242–50.
- Mann A, Smoum R, Trembovler V, Alexandrovich A, Breuer A, Mechoulam R, et al. Palmitoyl serine: an endogenous neuroprotective endocannabinoid-like entity after traumatic brain injury. J Neuroimmune Pharmacol 2015;10:356–63.
- Elizabeth A Fucich, Zachary F Stielper, Heather L Cancienne, Scott Edwards, Nicholas W Gilpin, Patricia E Molina, Jason W Middleton. Endocannabinoid degradation inhibitors ameliorate neuronal and synaptic alterations following traumatic brain injury. J Neurophysiol 2020 123 :707-717
- Magid, L., Heymann, S., Elgali, M., Avram, L., Cohen, Y., Liraz-Zaltsman, S., Mechoulam, R., Shohami, E. The role fo CB2 receptor in the recovery of mice after traumaitc brain injury. J. Neurotrauma, 36:1836-1846, 2019.
- Liraz-Zaltsman S., Shemesh C., Sachsse R., Friedman- Levi , Last D., Sharabi S., Mardor Y., Mechoulam R., Shohami E. The Effects of Cannabidiol on the Recovery of Mice after Traumatic Brain Injury. Abs. presented at the ICRS meeting, Jerusalem, Israel, 2021