In the last decade, over 560 substances between cannabinoids, terpenes and other non-cannabinoid constituents of the Cannabis plant have been isolated and identified (1). While most Cannabis literature focuses on the pharmacological effect of THC and CBD (Newsletter 4), these molecules only represent a small fraction of compounds produced by the plant. 

A large number of Cannabis compounds are known to interact with the human endocannabinoid system (ECS, Newsletter 6) when the plant is consumed. This interaction can happen either via direct binding of substances to cannabinoid receptors (mostly CB1 and CB2), such as in the case of THC, or via the indirect effect of other non-cannabinoid compounds on enzymes regulating signal transmission in the endocannabinoid system (2). Changes in the ECS have been observed to have major effects on neurotransmission in both the central and peripheral nervous system, ultimately affecting daily physiological processes such as sleep, appetite, mood, memory and immune response (1, 3,4). Therefore, there has been a recent spike in interest in compounds able to interact with the ECS. 

While naturally occuring endocannabinoids had been observed to be produced within the human body, it was believed until recently that only plants in the Cannabis genus could produce phytocannabinoids (plant-derived) and other phytochemicals affecting the endocannabinoid system (1,2). Instead, the ongoing search for different ECS-interacting compounds led to the discovery of numerous additional plants whose components have cannabimimetic (cannabis-like) properties, and are able to stimulate or modulate different aspects of the ECS (2). Cannabimimetic chemicals can in fact bind endocannabinoid receptors and be agonist (can “activate”) or antagonist (can “inhibit”) towards the receptor. Additionally, some cannabimimetic compounds can affect the ECS as enzyme inhibitors, and are able to play a role in the immune response to inflammatory and infectious diseases. Cannabimimetic chemicals include alkaloids, terpenes, terpenoids, polyphenols and derivatives of fatty acids found in common herbs, spices and other plant species (2,3,4). 

To date, there are more than 10,000 articles in literature covering phytocannabinoids and cannabimimetics (1). The study about terpenoids beyond the Cannabis plant has been earning ground in the research field due to the fact that cannabimimetic compounds can be utilized as tools for the improvement of therapeutic research in the medical field. 

While covering all cannabimimetic chemicals would be difficult, let’s have a look at some examples!

Effects on CB2 receptor

When looking at the 120 discovered cannabinoids, a large number of them are exclusive to Cannabis. However, some cannabinoids are widespread in many other plant groups (2). The Citrus genus (lemons and oranges) as well as many other plants from the Asteracee family (flowering plants) have been observed to produce cannabimimetic compounds and in some cases, cannabinoids that can interact with the CB2 receptor, the same receptor that CBD in Cannabis binds to (2,4,5).

Β-caryophyllene

The most striking example of a cannabinoid that is widespread in the plant kingdom is β-caryophyllene (figure 1), a main constituent of essential oils in over 30 different plant families including black pepper (Piper nigrum), lemon balm (Melissa officinalis), cloves (Syzygium aromaticum), and hops (Humulus lupulus), the closest botanical relative of cannabis (4, 5). For years, β-caryophyllene was known for its anti-inflammatory properties, but recent studies have shown that this chemical can also act as a full agonist (activator) of the CB2 receptor. A recent study reported that orally administered β-caryophyllene (<5 mg/kg body mass) produced strong anti-inflammatory and analgesic effects in mice with a CB2 receptor, but not in mice missing the CB2 receptor, which is a clear indication that β-caryophyllene may be a functional CB2 ligand which triggers an anti-inflammatory response (5). Due to this CB2 affinity, ongoing studies are now showing that β-caryophyllene is effective at reducing nerve pain. Therefore, the β-caryophyllene has the potential to become an attractive candidate for clinical trials targeting the CB2 receptor (5).  

Coneflowers

Some terpenoids and cannabinoid-like chemicals that are not majorly found in the Cannabis plant are instead highly expressed in other plants (3). The Echinacea (coneflower, seen in figure 2) genus has been observed to produce cannabimimetic chemicals (N-alkylamides, figure 3 shows the base structure) that are completely absent in Cannabis plants! These compounds are often found in the plant roots and flowers and have a strong affinity for CB2 receptors (2,4,5) . Echinacea plants have been used for years as a herbal remedy for common colds, but the reason for its anti-inflammatory properties were debated until the discovery of the ECS. Another study in-vitro (outside of living organisms) also showed how certain Echinacea alkylamides can inhibit reuptake of anandamide, one of the major endocannabinoids produced within the human body (2).

Effects on CB1 receptor

Some cannabimimetic compounds can bind the CB1 receptors, the same receptor that psychoactive THC binds to. Until recently it was believed that only Cannabis compounds such as 𝚫9 THC and 𝚫8 THC could bind this receptor (1). However, we now know about a few other examples in other plants:

Falcarinol

Falcarinol (figure 4), also known as carotoxin,  is a fatty alcohol found in carrots, parsley, celery, and ginseng (1). This compound is a natural fungicide, used by the plant to resist pests, but has been reported to also have anti-inflammatory and antitumor properties (1,3,4). Falcarinol has shown binding affinity to both CB1 and CB2 receptors. A study on mice showed that falcarinol concentrations can strongly bind CB1 receptors as an inverse agonist, meaning that it can still “activate” the receptor but result in an inverse response (1,5). A similar study on mice models has also shown an increase in gut-microbiota when falcarinol was consumed (1).

Curcumin

Curcumin (figure 5 shows the enol form) is the main component of the Curcuma spice. In addition to giving its name and color to this widespread spice, this bright yellow phenolic (complex organic chemical) was reported to be a potent therapeutic agent for a broad range of chronic disorders (1,2,4). The protective effects of curcumin firsts were only described by its antioxidant and anti-inflammatory properties. Further studies highlighted how curcumin is able to selectively bind to the human CB1 cannabinoid receptor (2,4). However, more recent studies have independently measured the binding affinities of curcumin for CB1 and CB2 receptors but only found affinity for the receptors at high concentrations, suggesting that curcumin concentration from dietary supplements are not enough to observe effects on the endocannabinoid system (4).

Effects on other ECS receptors, enzymes and other interactions

Other cannabimimetic compounds affect different parts of the ECS in addition to the CB1 and CB2 receptors.

Piperine and Gingerol

Piperine (figure 6) is an alkaloid present in black pepper (Piper nigrum). It has anti inflammatory, analgesic, antiulcer, and anticonvulsant activities, and is also shown to have a protective effect on the liver (1,3). Similarly, gingerol (figure 7), a main phytochemical present in ginger roots, was reported to have similar effects. Previous studies have shown that both chemicals are cannabimimetic and can bind the TRPV1 receptor, a minor receptor in ECS, and increase its activity (2). It is still unclear how this affects the rest of the signalling within the ECS but agonist chemicals such as piperine and gingerol, have been shown to cause conformational change in the receptor, progressively leading to desensitization of the receptor. This makes these two compounds functional antagonists of the TRPV1 receptor if applied chronically (2).

Frank-incense

Frankincense, Boswellia carterii, is an aromatic resin extracted from the Boswelia tree (shown in figure 8). When consumed, this resin displays properties in humans resembling those of CBD Cannabis (structure of frankincense shown in figure 9), as well as antiinflammatory, antioxidant, and antiseptic effects. Research on its active components demonstrated potent agonism of one substance, incensole acetate, on the TRPV3 receptor, producing feelings or warmth in skin and mind, anxiolytic and antidepressant effects in mice models (1).

What the future holds

Researching cannabimimetic compounds gives us a better understanding of the ECS, providing insights into its functioning, the role of each receptor, signalling pathways within the body and associated physiological processes. 

This knowledge helps us better comprehend the body’s regulatory mechanisms and how the ECS can be influenced for therapeutic purposes. For example, research has shown that paracetamol and dipyrone, two analgesics used worldwide, indirectly impact the CB1 receptor by influencing serotonin production and other pathways that are interconnected with the ECS (6,7). A 2018 study also showed that the ECS contributes not only to paracetamol’s analgesia against acute pain but also against inflammatory pain (7).

Similarly, cannabimimetic compounds have already shown therapeutic potential in various areas, but the exact effects of these chemicals for commercial drug production require further investigation. By studying these compounds, researchers aim to identify new treatments and develop drugs that target the ECS for specific medical conditions, for example to modulate pain management, inflammation reduction, anxiety, seizures and other pathologies affecting the central nervous system and the brain (5,6).

Lastly, investigating cannabimimetics helps in assessing the safety profile of these chemicals, such as potential side effects, and interactions with other medications. This knowledge is crucial for ensuring the responsible use of these compounds and minimizing potential risks. Studying cannabimimetics may lead to the development of novel drugs that target specific components of the ECS or modulate its activity in a controlled manner. This can potentially lead to more effective and targeted therapies with fewer side effects.