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How Cannabis Works

The chemical structure of tetrahyrdocannabinol (THC) was determined in 1964 by Raphael Mechoulam and Yechiel Gaoni. For more than three decades thereafter, its blatant psychoactivity induced scientists to define THC as the active ingredient in the plant.

Experienced marijuana smokers who tried the drug Marinol (pure, synthetic THC) when it became prescribable in the mid-1980s, reported that the effects were noticeably dissimilar. But it wasn’t until the late 1990s that the research establishment acknowledged that another compound, cannabidiol (CBD), was exerting significant effects, too.

In 1999 a British start-up, G.W. Pharmaceuticals, began clinical trials of a plant extract containing equal amounts of THC and CBD. Multiple Sclerosis patients found the combination more effective in reducing pain and spasticity than a THC extract, and less psychoactive. The THC-CBD combo, “Sativex,” has now been approved for use by MS patients in England, Canada, New Zealand, and a growing list of European countries.

Several of the so-called “minor cannabinoids” ?notably tetrahydrocannabavarin (THCV), cannabigerol (CBG) and cannabichromene (CBC)? also show therapeutic promise, and plants with high levels of each have been grown out in G.W.’s glasshouses for research purposes.

Now scientists are formally acknowledging something else 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. The cannabinoid content of a trichome might be 10 times heavier than the terpenoid content.

Evidence that “phytocannabinoid-terpenoid interactions” enhance the therapeutic effects of cannabis was presented by Ethan Russo, MD, at a conference in Israel last fall and is about to be published in the British Journal of Pharmacology. Russo, a neurologist and ethnobotanist,, is senior medical adviser at G.W. Pharmaceuticals.

Terpenoids and cannabinoids are both secreted inside the Cannabis plant’s glandular trichomes and they have a parent compound in common (geranyl pyrophosphate). More than 100 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 alpha-pinene is alerting, limonene is “sunshine-y,” and beta-myrcene is sedating.

 As the names suggest, pinene is abundant in pine needles and limonene in lemons. Myrcene is found in hops (Humulus), the only other member of the Cannabicae plant family.

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 flavors 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, mere hints in others?  that cannabinoid-terpenoid synergy is involved when Cannabis abates the symptoms of various conditions. He listed “pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus).”

For example, as an indication that some terpenoids may, like CBD, be “antidotes to the intoxicating effects of THC,” Russo noted that traditional responses to Cannabis overdose include limonene-rich citrus and pinene-rich black pepper.

Jeffrey Hergenrather, MD, president of the Society of Cannabis Clinicians, who attended Russo’s talk 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 terpenoids are having 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), tested by itself, did not bind very strongly to the cannabinoid receptors or exert pronounced behavioral effect on mice. But when administered with two related compounds, it did both.

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 Therapeutics applying 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 forthcoming BJP paper, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” contains 304 citations.

A really good scientific review paper is built like a stone wall by an artistic mason. Documented fact upon documented fact upon documented fact, with insights positioned fittingly. Russo, citing Robert Clarke (2010), suggests that “distinctions between available cannabis ‘strains’ are most likely related to relative terpenoid contents and ratios.” Citing David Potter (2009), he notes that “the mechanical stickiness of the trichomes [is] capable of trapping insects with all six leg.”  Citing Jirovetz et al, “Linalool is the likely suspect in the remarkable therapeutic capabilities of lavender essential oil to alleviate skin burns without scarring.”

Citing investigators too numerous to list here, Russo reports the effects attributed to various terpenoids:

Limonene (also found in lemon): Potent immunostimulant via inhalation. Anxiolytic. Apoptosis of breast cancer cells. Active agent against acne bacteria. Dermatophytes. Gastro-esophaeal reflux.

Alpha-pinene (found in pine needles): Bronchodilatory in humans. Acetylcholinesterase inhibitor, aiding memory.

Beta-myrcene (found in hops): Blocks inflammation via PGE-2. Analgesic, antagonized by naloxone. Sedating, muscle relaxant, hypnotic. Blocks hepatic carcinogenesis by aflatoxin.

Linalool (found in lavender): Anti-anxiety. Sedative on inhalation in mice. Local anesthetic. Anagesic via adenosine A2A. Anticonvulsant/anti-glutamate.

Beta-Caryophyllene (found in pepper, Echinacea): Potent anti-leishmanial. Gastric cytoprotective. Anti-malarial. Selective CB2 antagonist. Treatment of pruritis? Treatment of addiction? Decreases platelet aggregation.

Caryophyllene Oxide (found in lemon balm): Anti-fungal. Insecticidal.

Nerolidol (found in orange): Sedative. Skin penetrant. Potent antimalarial. Anti-leishmanial activity. Breakdown product of chlorophyll.

Phytol (found in green tea): Prevents Vitamin-A teratogenesis. Increases GABA.

Cannabinoids Formerly Known as Minor

Although this article has focused on the terpenoids, Russo’s talk in Israel gave equal time to CBD, THC-V, CBC, and CBG (the parent compound of the others). Evidently the extensive breeding program directed by G.W.’s Etienne de Meijer has yielded plants rich in each of these cannabinoids, and probably others. At the 2011 meeting of the International Cannabinoid Research Society, held in Chicago in July, several talks and posters described promising results with G.W. extracts whose exact contents were not revealed by the investigators.

Intrepid California cultivators are trying to follow G.W.’s lead. Labs have already begun testing for the cannabinoids that may not be “minor” after all, and for terpenoids.

Projectcbd.org will help collect and report on patients’ responses to the newly identified active ingredients. Maybe we should have called it BeyondTHC.com? The “entourage effect” applies to politics, too. The drug policy reform movement, like all single-issue movements, is the political equivalent of Marinol… More on all this in O’Shaughnessy’s, due out next month. To order or place an ad (enabling us to pay the printer), contact the managing editor (me), fred@plebesite.com.

Fred Gardner has been an editor of Scientific American and public information officer for the District Attorney of San Francisco.

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Fred Gardner is the managing editor of O’Shaughnessy’s. He can be reached at fred@plebesite.com

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