Scientists are now formally acknowledging something that Cannabis consumers have long taken for granted: aroma is associated with effect.
Plant cannabinoids —21-carbon molecules found only in Cannabis— are odorless. It’s the terpenoids —components of the plant’s “essential oils”— that create the fragrance. Terpenoids contain repeating units of a 5-carbon molecule called isoprene and are prevalent in smelly herbs such as mints and sage, citrus peel, some flowers, aromatic barks and woods.
The aroma of a given plant depends on which terpenoids predominate. They tend to be volatile molecules that readily evaporate, and they’re very potent —all it takes is a few reaching the nose to announce their presence.
Evidence that “phytocannabinoid-terpenoid interactions” enhance the therapeutic effects of cannabis was presented by Ethan Russo, MD, at a conference in Israel in 2010 and published in the August 2011 British Journal of Pharmacology. Russo, a neurologist and ethnobotanist, is senior medical adviser at GW Pharmaceuticals.
Both terpenoids and cannabinoids are secreted inside the Cannabis plant’s glandular trichomes, and they have a parent compound in common (geranyl pyrophosphate). More than 200 terpenoids have been identified in Cannabis. The most common and most studied include limonene, myrcene, alpha-pinene, linalool, beta-caryophyllene, caryophyllene oxide, nerolidol and phytol. Anecdotal evidence suggests that pinene is alerting, limonene “sunshine-y,” and myrcene sedating.
The fact that most terpenoid compounds are common components of the human diet and “generally recognized as safe” by the Food and Drug Administration has made research possible, and scientists employed by flavor and fragrances manufacturers have investigated their properties over the years. But the terpenoids “remain understudied” in terms of therapeutic potential, according to Russo.
His paper mustered all the evidence —proof in some cases, hints in others— that cannabinoids and terpenoids can work in concert to abate symptoms of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA, which kills more Americans nowadays than AIDS) and other illnesses.
Jeffrey Hergenrather, MD, president of the Society of Cannabis Clinicians, who heard Russo’s presentation in Israel, expects its publication to “generate great interest in terpenes among medical cannabis users as well as physicians.” The SCC recently began collecting data on patients’ responses to CBD-rich Cannabis. Future surveys will seek to document which other cannabinoids and which terpenoids are associated with which effects.
The “Entourage Effect”
The conference at which Russo presented his paper was held at Hebrew University, Jerusalem, where Raphael Mechoulam directs a lab, in honor of Mechoulam’s 80th birthday.
In 1999 Mechoulam co-authored a paper with Shimon Ben-Shabat suggesting that cannabinoids made in the body work by means of an “entourage effect.” They had found that the endocannabinoid 2-AG (2-arachidonoylglycerol), when administered with two related compounds, would bind more readily at the cannabinoid receptors and exert more pronounced behavioral effect on mice.
To pharmacologists who customarily designed experiments aimed at finding the active ingredient, this had heavy implications. Mechoulam spelled them out: “Biochemically active natural products, from either plant or animal origin, are in many instances accompanied by chemically related though biologically inactive constituents. Very seldom is the biological activity of the active constituent assayed together with inactive ‘entourage’ compounds. Investigations of the effect of the active component in the presence of its ‘entourage’ compounds may lead to results that differ from those observed with the active component only.”
In 2001 John McPartland and Russo published a paper in the Journal of Cannabis Therapeuticsapplying the “entourage” concept to the plant itself. “Good evidence shows that secondary compounds in cannabis may enhance the beneficial effects of THC... and reduce THC-induced anxiety, cholinergic deficits, and immunosuppresion,” they wrote. “Cannabis terpenoids and flavonoids may also increase cerebral blood flow, enhance cortical activity, kill respiratory pathogens, and provide anti-inflammatory activity.”
A decade later, Russo is substantiating the molecular-teamwork hypothesis and expanding on it. His BJP paper, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” contains 304 citations.
Although the paper takes the form of a review of the literature, Russo’s perspective is forward-looking and practical. The paper can be read as a strategic guide for breeding and/or blending Cannabis so as to maximize specific medical effects. Its structure is straightforward:
1. Russo cites studies documenting the beneficial effects of THC, CBD, CBC, THCV, CBDV, CBG and CBN (noting the adverse effects attributed to THC).
2. He cites studies documenting the beneficial effects of Limonene, α-Pinene, Myrcene, Linalool, β-Caryophyllene, Caryophyllene Oxide, Nerolidol, and Phytol.
3. He notes which cannabinoid effects would be augmented by which terpenoids, and which terpenoid effects would be augmented by which cannabinoids.
There is a huge body of information to convey, and Russo’s style is compressed —documented fact after documented fact after documented fact, with insights positioned fittingly. The slides he showed in Israel have been integrated into two full-page tables for the BJP paper, listing the relevant studies and the cannabinoid-terpenoid combinations likely to produce a desired effect. The paper is well worth reading. My summary and the disjointed highlights that follow cannot do justice to Russo’s carefully constructed thesis.
The Cannabinoids Formerly Known as Minor (CFKMs)
The extensive breeding program directed by GW Pharmaceuticals’ Etienne de Meijer has yielded plants rich in CBD, CBC, CBG, and THCV.
Cannabichromene (CBC) is produced early in the plant’s life cycle according to a paper published by de Meijer in 2009. Citing de Meijer’s co-worker David Potter, Russo notes that “An innovative technique employing cold water extraction of immature leaf matter from selectively bred cannabis chemotypes yields a high-CBC ‘enriched trichrome preparation.’”
Cannabigerolic acid (CBGA), the precursor of THC, CBD, and CBC in their acid forms, is usually found at low concentrations. “But recent breeding work has yielded cannabis chemotypes lacking in downstream enzymes that express 100% of their phytocannabinoid content as CBG,” according to Russo. (More details are provided on GW Pharmaceuticals’ very informative website.)
Tetrahydrocannabivarin (THCV) blocks the CB1 receptor at low doses, and activates it at high doses. GW Pharmaceuticals hopes that a THCV-rich extract will be an effective appetite suppressant and will counter the symptoms of metabolic syndrome.
THCV is present in cannabis chemotypes from southern Africa —from which plants that are “highly predominant” in THCV have been bred.
Whereas plant cannabinoids are found nowhere else in nature, terpenoids are produced by countless plant species. Some 20,000 terpenoids have been identified by chemists; they constitute the largest group of plant chemicals. More than 200 have been found in cannabis.
“Essential oil composition is much more genetically than environmentally determined,” Russo states. Every compound the plant produces has or had an evolutionary purpose. The bitter 15-carbon terpenoids in the fan leaves repel grazing animals, while the predominantly monoterpene mix in the flowers is unappealing to insects —and, thanks to its stickiness, can also entrap them.
Alpha-pinene is the most common terpenoid in the plant world; limonene is second. Named for their strong presence in pine needles and lemons, respectively, they are monoterpenes, also prevalent in cannabis.
Terpenoids may account for only 1% of the weight when cannabis is tested but 10% of the weight within the trichome.
Monoterpenes evaporate more readily than the di- and sesquiterpenes during drying, storage, and production of extracts, which results in a relatively higher proportion of caryophyllene.
How do terpenoids exert effects within the body? Citing the relevant studies, Russo explains that they are “lipophilic, interact with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled (odorant) receptors, second messenger systems and enzymes.”
The beneficial effects are wide-ranging and, in many cases, well established. Limonene, for example, has been shown to decrease anxiety in mice via the serotonin receptors. “Compelling confirmatory evidence in humans,” Russo writes, was provided by a Japanese study of severely depressed hospital patients whose moods improved when exposed to citrus fragrance. (Nine of 12 were able to get off antidepressants.)
Limonene, inhaled, is an immunostimulant. In lab experiments it has killed breast cancer cells and acne bacteria. It is a potential treatment for gastro-esophageal reflux.
Alpha-pinene —as anyone who has walked into piney woods and breathed deeply can sense— is a bronchodilator. It also has anti-bacterial and antibiotic properties. α-Pinene inhibits the enzyme that breaks down acetylcholine, a neurotransmitter involved in memory. “This feature could counteract short-term memory deficits induced by THC intoxication,” Russo notes.
Myrcene, another monoterpene common in cannabis, is also abundant in the flowers of humulus lupulus —hops— the only other member of the Cannabinacae family. In addition to its anti-inflammatory effect, Russo writes, “Myrcene is a recognized sedative as part of hops preparations, employed to aid sleep in Germany... Myrcene acted as a muscle relaxant in mice, and potentiated barbiturate sleep time at high doses.
“Together, these data would support the hypothesis that myrcene is a prominent sedative terpenoid in cannabis, and combined with THC, may produce the ‘couch-lock’ phenomenon of certain chemotypes that is alternatively decried or appreciated by recreational cannabis consumers.”
Linalool, which is abundant in lavender, affects serotonin neurotransmission and counters anxiety, according to a study cited by Russo. Linalool has sedative and anti-convulant properties, and is also “the likely suspect in the remarkable therapeutic capabilities of lavender essential oil to alleviate skin burns without scarring.”
Beta-caryophyllene, which is found in black pepper, Echinacea, and marigolds, “is frequently the predominant terpenoid in cannabis extracts, particularly if they have been processed under heat.” β-caryophyllene is anti-inflammatory and, unlike other anti-inflammatories, protective of the stomach lining.
In 2008 Swiss investigators led by Jurg Gertsch showed that β-caryophyllene activates the CB2 receptor —making it “the first proven phytocannabinoid beyond the cannabis genus,” Russo proclaims. “Given the lack of psychoactivity attributed to CB2 agonists, caryophyllene offers great promise as a therapeutic compound, whether systemically or in dermatological applications.”
Other terpenoids with therapeutic potential mentioned by Russo in his BJP paper are nerolidol (found in citrus, it may have sedative and anti-fungal effects); caryophyllene oxide (found in the herb lemon balm, it repels insects); and phytol (a breakdown product of chlorophyll with relaxant properties that may be the reason that green tea, despite its caffeine content, doesn’t jangle the nerves).
In their landmark 2001 paper in the Journal of Cannabinoid Therapeutics, Russo and lead author John McPartland touched on the beneficial effects of eucalypytol, pulegone, alpha-terpineol and other possibly efficacious terpenoids. These compounds were not discussed in Russo’s 2011 BJP paper.
Russo describes several mechanisms by which terpenoids and/or cannabinoids can act synergistically.
• They can work on separate targets. For example, if CBD were combined with limonene as an acne treatment, the cannabinoid could penetrate the skin and induce the cells that produce sebum to self-destruct, while the terpenoid could inhibit production of the key pathogen, Propionbacterium acnes. (Linalool and alpha-pinene also suppress P. acnes.)
• They can interact to overcome bacterial resistance. For example, CBD and CBG “powerfully inhibit MRSA,” according to one study cited by Russo, while in another study, an essential oil rich in pinene proved “as effective against MRSA and other antibiotic resistant bacterial strains as vancomycin.”
• They can have an antagonistic effect, as in the case of CBD countering THC’s ability to promote an accelerated heartbeat, the munchies, drowsiness, and anxiety.
Key role for CBD
CBD will play a key role in extracts designed for medical use. Although deemed “non-psychoactive,” CBD reduces anxiety by affecting the serotonin receptors. It also reduces cravings —for heroin, cocaine, food, nicotine and other addictive substances.
Russo describes a recent study that “demonstrated the fascinating result” that stroke patients who had suffered damage to a part of the brain called the insula “were able to quit tobacco smoking without relapse or urges.”
“In a provocative parallel,” he adds, functional MRIs of patients given CBD (600 mg p.o.) dramatically reduced activity observed within the left insula “suggesting the possibility that CBD could act as a pharmaceutical surrogate for insular damage in exerting an anti-addiction therapeutic benefit.”
Which terpenoid(s) would be complementary? Citing a study in which inhaledvapor from an essential oil of black pepper reduced craving for cigarettes, Russo writes: “the terpene profile of black pepper suggests possible candidates: myrcene via sedation, pinene via increased alertness, or especially caryophyllene via CB2 agonism.”
The Research Agenda
Cannabis designer extracts are likely to yield safe, effective new treatments for a wide range of conditions, and —in due course, it is hoped— to regulatory approval and sales. GW Pharmaceuticals has already bred cannabis chemotypes with very high fractions of myrcene and limonene, and we assume they’re working on plants high in pinene, linalool and other terpenoids with therapeutic potential. As Russo puts it in his BJP paper, “Selective cross-breeding of high-terpenoid- and high-phytocannabinoid-specific chemotypes has... become a rational target.”
Meanwhile back in California, research-minded doctors, cannabis cultivators, dispensary and lab owners, have been thinking along similar lines. (The idea that cannabis can be bred to maximize production of more than one compound is as obvious as the association between aroma and effect.) We don’t have the resources to do high throughput pharmacological screening or animal studies involving radioactive labeling, but we do have access to labs that can identify the compounds in a cannabis bud, and we have our own senses to evaluate effects.