Cannabis and Terpenes: What Do We Really Know?
Plants produce terpenes for interactions with other organisms, to help protect them against pathogens like mold, fungus and bacteria, and to attract pollinating insects or repel herbivores. Thousands of terpenes have been found across the plant kingdom, but some are concentrated in certain families such as Cannabaceae., which includes Cannabis sativa and Humulus lupulus (common hops). Terpenes found in both cannabis and hops, or more precisely, in their essential oils (EOs), are mainly mono- and sesquiterpenes: up to 99% of all terpenes found in the EO of hops and up to 98% in cannabis EO fall into this category. Cannabis and hops produce and accumulate a terpene-rich resin in glandular trichomes, which are most abundant on the surface of female inflorescences. Thus, the flowering parts have been utilized in remedies for millennia.
Today, it is increasingly common to test the terpene content of medical cannabis and, consequently, services that offer this testing are easy to find; presumably, it is good business too. The users of these services assume that the cannabis plant’s terpene profile contributes to the medical properties of the cannabis product. It is also noted that recreational users commonly describe different effects for different “strains” (let’s say “chemovars” from now on to be more accurate). In addition to cannabinoid content, it is now widely believed that the terpene content of a cannabis product plays a part in the effects reported by users. It is worth noting that a complete flowering cannabis plant contains terpenes in amounts of 2-4% of total dry weight; the question is whether that amount is enough to provoke medicinal effects, or the differences in effects between chemovars reported by recreational users. We also want to know what the effects could be for each individual terpene and, moreover, is there a synergistic function with cannabinoids; known as the “entourage effect” this theory was popularized by cannabis research veteran Ethan B Russo.
In this article we discuss what the scientific literature does, and doesn’t say, about some of the most common terpenes found in cannabis and hops. As author of a recent review paper on this subject published in the European Journal of Medicinal Chemistry I will highlight supporting studies throughout. You can view my full review paper and the associated references here.
Myrcene, one of the most abundant terpenes in cannabis, is worthy of specific attention. Recreational users report and sometimes assume that myrcene is responsible for the “couch lock”, an immobilizing effect of some cannabis chemovars. Scientific literature, however, does not support this assumption: only with doses as high as 200 mg/kg do we see an increased barbiturate-induced sleeping time and motor relaxation in mice. Interestingly though, it seems that recreational chemovars are commonly rich in this terpene. Whether this is just coincidence, i.e. founder effect, or because of unintentional selective breeding remains unclear, but the link between the couch lock effect and concentration of myrcene is certainly not proven. Myrcene possesses anti-inflammatory and pain-relieving properties, but again this would only be attainable with myrcene concentrations that are impossible to achieve by smoking cannabis.
Humulene is another suspect for the relaxing and sleep-inducing effects of cannabis and hops; this is because humulene-containing plants have traditionally been used for the treatment of insomnia, depression, nervousness, delirium, anxiety and digestive disorders. Although not yet recognized by modern science, humulene and its molecular derivatives may show anti-allergic, anti-inflammatory and anticancer potential with “reasonable” doses. A molecular relative, β-caryophyllene, is sometimes the predominant terpenoid in cannabis and interestingly, it is the only molecule outside of the cannabinoid family that has an affinity towards cannabinoid receptors. Surprisingly though, β-caryophyllene does not resemble any other ligands of cannabinoid receptors. Nevertheless, we can calculate that it could have anti-inflammatory effects on the central nervous system (CNS) with just a single dose of 200mg of cannabis inflorescence for the average person. This could point to beneficial effects in the treatment of MS disease, and suggests the potential for treating other neuroinflammatory diseases such as Parkinson’s - indeed there is an animal study that supports this idea.
Various in vitro and in vivo studies (see references in the original review paper) have shown that linalool has anti-tumor, anti-convulsant, anti-nociceptive, sedative, anti-depressant, anti-inflammatory, anti-oxidative, neuroprotective, hepatoprotective and anti-microbial properties. The CNS effects are likely to be mediated by neuropeptides, noradrenergic and glutamatergic systems along with the 5-HT1A receptor and altered blood flow in the brain. It is not yet established whether these effects could be achieved by cannabis consumption.
Limonene can promote wound healing and anabolism, it can also ameliorate stress, depression, inflammation, oxidative stress, spasms and viral infections. In addition, limonene shows a variety of anti-cancer and anti-tumor mechanisms: some of these effects may be due to its conversion to perillyl alcohol in the gastric system. Of note is that limonene is used in Brazil as a cancer drug, especially in the treatment of brain tumors. Finally, its derivatives can be powerful anti-convulsants via GABAergic action. Thus, as for many other terpenes, it is a target of drug design.
α-pinene and β-pinene
α-pinene, according to the studies referred to in the review, show anti-metastatic and anti-tumor activities – however, again this is only true in high doses and systemic intake. Moreover, it seems to be anti-inflammatory, anti-oxidant and an anti-allergic bronchodilator and can produce anxiolytic and hypnotic effects via the GABAergic system. Finally, it provides a molecular basis for the development of novel CB2 ligands. In contact with air, α-pinene is oxidized to pinocarveol and myrtenol amongst other molecules and is easily converted to other terpenes in industrial processes; conifers are a well-established source of α-pinene as they produce this terpene in abundance. β-pinene (at 100 mg/kg) showed antidepressant and sedative activities in mice with several experimental models. In addition, a study indicated that β-pinene (100 mg/kg) produces its antidepressant effect through the monoaminergic system. β-pinene reversed the anti-nociceptive effect of morphine in a degree equivalent to naloxone, indicating that it is a partial agonist of the µ-opioid receptors. β-pinene, when complexed with β-cyclodextrin, provoked an antihypertensive effect and vasorelaxation in rats. It showed synergistic interactions with a classical cancer drug against non-small-cell lung cancer cells. These results indicate that β-pinene, as with many other terpenes, can enhance the medicinal properties of other drugs. Moreover, it exhibits antiviral activity against herpes simplex and could be used to support the medicinal properties of other antiviral drugs. For other common terpenes see the review below.
Cannabis contains rare terpenes which can actually be responsible for some benefits at relatively low doses. These have not yet gained much attention in popularized science. These terpenes include nerolidol, ocimene, perillyl alcohol, terpinolones, fenchone, geraniol, borneol, α-bisabolol, and α-phellandrene among other less studied terpenes. As for many other terpenes, effective doses are unlikely achievable by the consumption of intoxicating chemovars.
The entourage effect
It is claimed that terpenes, together with tetrahydrocannabidiol (THC) or cannabidiol (CBD), evoke a so-called ‘entourage effect’, which means that the terpenes could have synergistic actions with these cannabinoids. Especially, myrcene is claimed to induce strong synergistic sedative/immobilizing action with THC. However, the study referenced in the review did not find any support for this or for the ‘entourage hypothesis’ in general. Thus, it may be possible that the yet-to-be-understood effects of some cannabinoids explain most of the different subjective effects reported by cannabis users. For example, CBD is known to antagonize psychotomimetic action of THC, among its properties in its own right. In addition, there are several other cannabinoids with distinct physiological effects. Cannabinoids; cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), Δ9- tetrahydrocannabivarin (Δ9-THCV), cannabivarin (CBV) and cannabidivarin (CBDV) among other less abundant cannabinoids have been shown to act – not only on the classical cannabinoid receptors, CB1 and CB2 – but also on other receptors like PPARγ, 5HT3A, A1A adenosine receptor, α2 adrenergic and on a variety of TRP channels and the non-classical cannabinoid receptors G protein-coupled receptors GPR55 and GPR18. Thus, it is not yet known whether different chemotypes of cannabis show their different effects through this complex interplay or by the support of terpenes or both. If terpenes do contribute to the sedative effects of cannabis, then limonene, terpinolene, nerolidol, bisabolol, isopulegol, borneol, linalool, linalyl acetate and ocimene may be the more probable candidates. Early studies, where animals or human subjects were exposed to inhalation of terpene odors, showed that terpineol, pinenes and linalool were able to alter activity, after all. However, these experiments should be repeated.
Interestingly, β-eudesmol was found to increase appetite and gastric emptying in rodents with supplementation of only 0.14 ppb in drinking water, which is comparable to the concentrations found in beer. This could – at least partly – explain why some recreational chemovars make consumer hungrier than others. Importantly, it might have several different molecular targets in the nervous system and effects could be cumulative or synergistic: for instance, unlike with the entourage hypothesis, a study found that some terpenes might have both synergistic and antagonistic effects on each other in the cholinergic system.
Terpenes and aromatherapy
Aromatherapy has been suggested to provide a potentially effective treatment for a range of psychiatric disorders by double-blind, controlled and randomized studies. Sedative, antidepressant, anxiolytic and analgesic effects are most commonly reported by subjects undergoing cannabis aromatherapy treatments. Similarly, studies in mice showed the inhalation of 27 mg linalool or 23 mg linalyl acetate decreased the motility of normal mice and reversed caffeine-induced over-agitation. Administration of only 0.05–0.1 ml/kg of essential oil (EO) of Eugenia caryophyllata (clove), comprised of 77% eugenol and 10% β-caryophyllene, suppressed tonic electroshock-induced convulsions and mortality in mice. In rats, 0.3 mg/kg of Tagetes minuta (Asteraceae) EO (containing mostly ocimene) displayed anxiolytic and antidepressant effects, while in chickens, administration of 0.04–0.45 mg/kg of the EO exhibited anxiogenic effects.
In summary, terpenes found in higher amounts in cannabis may not be solely responsible for the claimed medicinal properties of these compounds. Actually, we infer that popular web pages exaggerate the medicinal properties of the most abundant terpenes. Of course, we are aware of their strong medicinal properties, but those effects are not commonly attainable with consumption of cannabis products. Moreover, the popular entourage effect hypothesis is currently devoid of scientific proof. This does not necessarily mean it is untrue, merely that more trials are needed. On the other hand, some minor terpenes can have substantial effects in small amounts. It is also prudent to say that the potential of β-caryophyllene has been overlooked. In order to overcome the obstacle of low concentrations in consumable cannabis products, and obtain effective doses, one could purify terpenes by steam-distillation for example, this utilizes the fact that cannabis and hops are high-yielding plants in comparison to many other plants used for essential oil production. By selective breeding, which is easy with unisexual plants like cannabis, the content could be improved to meet the best medicinal effects. Although there have been numerous studies on terpenes, more studies are needed to elucidate the medicinal properties at low doses.
Reference: Tarmo Nuutinen (2018): “Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus”. European Journal of Medicinal Chemistry, 157:198-228