Cannabinoids are produced by the Cannabis sativa L. (Cannabis) plant, by the human body and synthetically in laboratories. Cannabinoids produced by plants are phytocannabinoids, those produced by the body are endogenous cannabinoids or endocannabinoids and those formulated in a laboratory are synthetic cannabinoids. There are also several common plants that contain compounds which are cannabimimetic, literally mimicking the biological activity of the classical cannabinoids, despite not sharing their structure.
Cannabis has been an important tool in the herbalist’s arsenal and the medical pharmacopoeia for millennia, but it has only been in the past twenty-five years that science has provided a better understanding of its myriad benefits and cannabimimetics are of increasing importance within medicinal cannabinoid research. The discovery of cannabinoid receptors was followed by the discovery of endogenous cannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their regulatory metabolic and catabolic enzymes (fatty acid amide hydrolase [FAAH], monoacylglycerol lipase [MAGL]), known collectively as the endocannabinoid system (ECS).
The ECS performs major regulatory homoeostatic functions in the brain, skin, digestive tract, liver, cardiovascular system, genitourinary function and even bone. This network of cell receptors and corresponding molecules in humans and other animals is responsible for maintaining optimal balance affecting many different functions including regulation of sleep, appetite, immune function, mood and pain. The list of systems the ECS modulates increases with additional research discoveries.
Many of these also work on other important biological messaging systems such as the opioid, serotonergic and dopaminergic signalling systems. Various lifestyle factors including diet and aerobic activity affect the overall ECS function or ‘endocannabinoid tone’, a function of the density of cannabinoid receptors, their functional status (upregulated or downregulated) and relative abundance or dearth of endocannabinoids. The long-held belief that natural substances that affected cannabinoid receptor 1 (CB1) were limited to tetrahydrocannabinol (THC) and a few other phytocannabinoids has changed, as other plants can modulate the receptor and deserve examination. Advancing this knowledge will have important implications for human health and nutrition.
CB1, the neuromodulatory cannabinoid receptor, was discovered in 1988 as a result of decades of research on THC and has proven to have a major homoeostatic influence in the central nervous system (CNS), wherein it is the most abundant G-protein-coupled receptor (GPCR), far exceeding those for the neurotransmitters it modulates. A similar integral role is played in various other physiological systems throughout the body.
Cannabimimetics are a general class of compounds that have a specific action, namely, binding to CB1, not unlike Cannabis. The most well-known include Coneflower (Echinacea), Black Pepper (Piper nigrum) and Rosemary (Rosmarinus officinalis). Cannabimimetic compounds aren’t the same as those found in Cannabis, yet they have positive effects on the ECS. As understanding of the ECS has grown, so too has the number and type of different compounds that act on the receptors.
Around 200 terpenes have been identified in Cannabis with about 20,000 existing in nature, produced in secretory cells within the trichomes (microscopic resinous stalks that cover the flowers and leaves). This is where all cannabinoids like THC and cannabidiol (CBD) are created. Most Cannabis enthusiasts will have heard of the classic cannabinoids; THC, CBD, Cannabichromene (CBC) and Tetrahydrocannabivarin (THCv) which for many years were thought to be the only compounds that acted on cannabinoid receptors. The ‘classic’ cannabinoids all share the same chemical formula, C21H30O2.
Black Pepper (Piper nigrum)
Black Pepper contains the terpene, beta-caryophyllene (βCP), and is a cannabinoid receptor 2 (CB2) agonist (substance which initiates a physiological response when combined with a receptor) that also modulates the ECS via guineensine, which inhibits AEA uptake dose-dependently without significant effect on FAAH, MAGL, cannabinoid receptors, or fatty acid binding protein 5 (FABP5).
Black Truffles (Tuber melanosporum)
Much to the surprise of many, Italian researchers found Black Truffles create AEA, also known as the ‘bliss molecule’ (ananda is Sanskrit for bliss), the endogenous version of THC. This endocannabinoid is usually made by animals and binds to CB1. While Truffles don’t have cannabinoid receptors, they do produce AEA. So, the theory is the fungus creates the compound to attract animals that will eat them and spread their spores.
Carrot (Daucus carota)
A common foodstuff, the Carrot contains falcarinol (carotatoxin), a natural pesticide and fungicide, which molecularly binds to CB1, acting as an inverse agonist, blocking AEA in keratinocytes (epidermal cells which produce keratin) and producing contact dermatitis in the presence of histamine. The particular relevance of these findings remains to be determined and would include consideration of whether Carrots pose a particular allergy risk or, whether, despite their high glycaemic index, the CB1 antagonism may suggest their use as an appetite suppressant if carotatoxin is even absorbed via the gastrointestinal tract.
Chinese Rhododendron (Rhododendron anthopogonoides)
A 2011 study, New Cannabinoid-Like Chromane and Chromene Derivatives from Rhododendron anthopogonoides, stated; “Two new cannabinoid-like chromane and chromene derivatives named anthopogocyclolic acid and anthopogochromenic acid and five related compounds known as synthetic analogues of cannabinoids: cannabichromene (CBC) type, cannabicyclol (CBL) type and cannabicitran (CBT) type, have been isolated together with geranyl orsellinic acid from the Chinese medicinal plant Rhododendron anthopogonoides”.
Coneflower (Echinacea spp.)
Echinacea has been found to contain cannabimimetic N-acylethanolamines (NAE’s) and N-alkylamides (NAA’s). NAE’s are a class of fatty acid compounds heavily involved in biological signalling which have been found to occur in many plant species. NAE’s include N-arachidonoylethanolamine (AEA), N-palmitoylethanolamine (PEA), N-linoleoylethanolamide (LEA) and N-oleoylethanolamine (OEA). AEA is well known for being the biological compound which most closely resembles the activity of THC, as it directly agonises (promotes a receptor-mediated biological response) the principal cannabinoid receptors. It is now also known that AEA directly agonises a third cannabinoid receptor known as GPR119, which is also affected by N-oleoylethanolamine.
As well as directly acting on the principal and minor cannabinoid receptors, NAE’s are also known to exert a range of indirect effects. For example, LEA, PEA and OEA all inhibit levels of the FAAH enzyme that is responsible for degrading AEA itself, and thus can effectively increase levels of AEA in tissues over time. NAA’s are a similar but less well-researched class of cannabimimetic compounds that have been shown to exert selective effects on CB2 and have been shown to exert anti-inflammatory effects similar to AEA. The CB2 receptor is largely responsible for regulating the immune system, pain and inflammatory response. In Cannabis, THC is the primary stimulator of the CB2 receptor. THC’s affinity with this particular receptor is partly why it’s so effective in treating inflammation-related disorders.
With demonstrated CB2 agonistic activity, subsequent investigation elucidated activity as a partial and inverse agonist at CB1 which could suggest possible benefits on metabolic syndrome, also possible adverse event liabilities due to anxiety, depression and other sequelae (a condition which is the consequence of a previous disease or injury). It is very possible that this Native American herbal agent will see much wider clinical application in the future as it can do a little bit of everything from fighting the common cold to relieving symptoms of anxiety, fatigue, arthritis, migraines and other ailments.
Contrary to popular belief, there are no endocannabinoids in chocolate. Derived from Cacao (Theobroma cacao), notably, OAE and LEA have both been found in the Cacao plant which do produce FAAH inhibition.
Copaiba Balsam (Copaifera officinalis)
Along with Black Pepper, Lemon Balm (Melissa officinalis), Cloves (Syzgium aromaticum), Hops (Humulus lupulus) Rosemary, Caraway (Carum carvi), Oregano (Origanum vulgare), Basil (Ocimum basilicum), Lavender (Lavandula), Cinnamon (Cinnamomum spp.) and Cannabis, Copaiba Balsam contains a sesquiterpenoid called beta-caryophyllene (βCP). Terpenes are flavour and aroma molecules found in plants. Around a decade ago, it was observed dietary intake of βCP at as little as 4 mg/kg/day might render it an effective anti-inflammatory.
βCP has quite a bit of therapeutic potential and has long been known for its prominent anti-inflammatory properties on experimentally induced fibrosis comparable in potency to phenylbutazone, the non-steroidal anti-inflammatory drug (NSAID) of equine medicine. Other possible applications are legion, from pruritus in dermatitis, to fibrosis in the liver, heart and other organs. This potential is more likely considering the fact this particular phytocannabinoid is widespread in plant kingdom essential oils, with Copaiba spp. (up to 53.3%) the richest source, Black Pepper (up to 35%), Lemon Balm (up to 19.1%), Cloves (up to 12.4%) and Hops, closest botanical relative of Cannabis (up to 9.8%).
βCP, in contrast to NSAID’s, is protective of the gastric lining. When combined with cannabinoids like THC and CBD, the terpene may help heal stomach ulcers and aid addiction recovery. The terpene engages CB2’s, predominant in the immune system. Research has shown βCP also has anti-depressant and anti-anxiety effects. This terpene, found in Cannabis and its oxide (which forms on contact with air) is the compound detected by drug-sniffing dogs. βCP has been shown to act as a full agonist of CB₂ although it does not act on CB1.
Everlasting Daisy (Helichrysum umbraculigerum)
Researchers have found both cannabigerol (CBG)-like and cannabigerol acid (CBGa)-like compounds (cannabimimetics) in this South African daisy. CBG occurs early on in the Cannabis growth cycle and is a precursor to major cannabinoids like THC and CBD. CBG has shown potential as an antibiotic, anti-depressant and even chemotherapeutic agent. Helichrysum umbraculigerum has been traditionally smoked by indigenous South African peoples, a 2008 study reviewed traditional uses, biological activity and phytochemistry. Research from 1979 also suggested the CBG- and CBGa-like compounds were present in this South African flower, “The occurrence of the cannabigerol-like compounds in a composite is surprising. Probably, some of these compounds are formed by the combination of three different biogenetic pathways”. The entire genus merits additional research, as it harbours numerous unique phytochemicals, some of which suggest psychopharmacological effects.
Flax (Linum usitatissimum)
A 2012 study, Cannabinoid-like anti-inflammatory compounds from flax fiber, discussed a new terpenoid, a cannabinoid-like compound with a similarity to CBD. This was confirmed by mass spectra analysis. Further confirmation of the nature of the compound was based on biological activity assay. It was found the compound affects the expression of genes involved in inflammatory processes, fibroblasts (a cell in connective tissue which produces collagen and other fibres) and likely the CB2 receptor. The compound was found in all flax tissue, not just the fibres. The presented data suggest flax products can be a source of biologically active cannabinoid-like compounds able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties.
Frankincense (Boswellia carterii)
Frankincense displays properties in humans resembling those of Cannabis (the cannabinoid tetrad of analgesia, hypothermia, catalepsy, hypomotility), as well as anti-inflammatory, antioxidant and antiseptic effects. Subsequently, in a 2008 study, Incensole acetate, an incense component, elicits psycho-activity by activating TRPV3 channels in the brain, researchers stated, “We examined Boswellia extract for the presence of novel bioactive components and isolated incensole acetate (IA) as a major active constituent of Boswellia resin. IA showed an anti-inflammatory action as well as several CNS-associated activities … but has not been previously evaluated for its psycho-activity“. IA demonstrated potent agonism at TRPV3, producing feelings or warmth in skin and mind, anxiolytic and anti-depressant effects, as well as nuclear factor kappa B (NF-kB) inhibition with neuro-protective effects after brain trauma.
Hops (Humulus lupulus)
A very important terpene found in Cannabis and one that is also a major constituent of the essential oil of Hops is Myrcene. Although it is not thought that Myrcene directly acts on the cannabinoid receptors, it is now known its biological activity alters the neuro-active effect of THC. Myrcene is known to be present in high levels in Cannabis strains that exert what is commonly called a ‘couch-lock’ effect on the user. The sedative effects of Myrcene-containing plants such as Hops and Verbena (officinalis) have been known for millennia and it is now thought the sedative effect is due to Myrcene’s ability to agonise (activate) the opioid receptors and studies have shown the opioid antagonist naxalone blocks Myrcene’s effects, suggesting Myrcene is an agonist. Thus, although Myrcene isn’t typically classed as a cannabinoid in the currently existing scientific literature, it certainly is cannabimimetic. Myrcene is found in extremely high concentrations in Hop oil, almost 80% in some varieties and found in high levels in Mangoes (Mangifera), Lemongrass (Cymbopogon), Thyme (Thymus vulgare) and Verbena.
Japanese and New Zealand Liverwort (Radula spp.)
Another plant family with possible cannabimimetic action includes Japanese Liverwort (Radula perrottetii), yielding a THC structural analogue (very similar to THC), perrottetinene and the New Zealand Liverwort (Radula marginata), yielding perrottetinenic acid. Emerging research suggests these compounds engage CB1, like THC. Recent additional research confirms CB1 agonistic activity that, hopefully, will provide relevant context for the relative potency and possible therapeutic potential of this botanical agent.
Kava kava (Piper methysticum)
The ‘mystic pepper’, is a traditional beverage of South Pacific Island cultures, derived from the plant’s roots, which has grown in popularity for its anxiolytic (anti-anxiety), calming/sedative, pain relieving and euphoric effects. The active ingredients are lipid-soluble kavalactones. Dried rhizomes may be chewed or, alternatively, extracted in water, sometimes with the addition of ethanol or acetone. One kavalactone in particular, yangonin, has recently demonstrated significant CB1-binding activity. Whether a CB1 agonist or antagonist is under current investigation. Certainly, additional study of selectively bred chemovars of Kava with higher yangonin content is indicated, along with investigation of various extraction methods for greatest yield.
Maca (Lepidium meyenii)
Maca, a radish relative and foodstuff of the high Andes sometimes called ‘Peruvian ginseng’ for its use as an adaptogen, contains long-chain fatty acid N-benzylamides dubbed ‘macamides’, two of which showed reversible FAAH inhibition. It was conjectured the structure of these natural compounds would allow passage through the blood–brain barrier and that despite their low potency, regular consumption could produce alterations in amide signaling in the CNS, but this remains to be determined. The cannabimimetic action is not unlike CBD, which performs many functions in the body including blocking enzyme FAAH. Preventing the breakdown of endocannabinoids increases the amount of them in your system. This can cause a cascade of effects, including mood stabilisation. N-benzylamines improve endocannabinoid tone, boosting the system overall.
Oxeye (Heliopsis helianthoides)
A 2014 study identified endocannabinoid modulating NAA’s (N-alkylamides) in this common plant known as False Sunflowers. “The discovery of the interaction of plant-derived N-alkylamides (NAA’s) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous N-acylethanolamine signalling system have led to the re-evaluation of this group of compounds”.
Sage of the Diviners (Salvia divinorum)
A neuro-active divinatory plant from Mexico that is smoked or ingested, the cannabimimetic salvinorin A is a terpenoid, not an alkaloid, like mescaline or psilocybin. A dissociative hallucinogen, this agent previously tested negatively for neurotransmitter receptors. Interestingly, although salvinorin A, the primary active molecule in the plant was negative for CB1 activity, extracts of the whole leaves were positive. Salvinorin A does not interact with the classic cannabinoid receptors, but in fact interacts with a reputed ‘third cannabinoid receptor’ that apparently forms only in inflammatory conditions and acts as a kappa-opioid receptor.
The κ-opioid receptors are fundamental to pain regulation and are also the principal target of most hallucinatory compounds. Salvinorin A was identified as a specific κ-opioid agonist. Subsequent work demonstrated this substance had a low CB1 affinity and no effects on endocannabinoid degradation. Salvinorin A was shown to interact with CB1 / κ-opioid receptor dimers (macromolecular complex formed by two, usually non-covalently bound, macromolecules such as proteins or nucleic acids), possibly indicating the two systems might produce converging effects on the same pathway and indicating a complex relationship of Salvia to the ECS, deserving more elucidation. Salvinorin A is rare and appears to only be found in high quantities in Salvia divinorum itself. However, there are indications that other Sage species may contain traces of the compound itself, or closely related molecules.
Expanded and adapted from 6 Plants That Contain Healing Cannabinoids, Non-marijuana Plants That Contain Cannabinoids, Did You Know That Other Plants Produce Cannabinoids Too?, Weed and Cannabinoid as a Compound Part, Granny Storm Crows List, Beyond Cannabis: Plants and the Endocannabinoid System