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Terpenoid Synergy Date: 11-30-2011 HC# 081145-437

Re: Synergy between Specific Cannabinoids and Terpenoids Suggests Potential for Broader Therapeutic Applications of Selective Cannabis Chemotypes



Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. August 2011;163(7):1344-1364. Tetrahydrocannabinol (THC) has been the focus of cannabis (Cannabis sativa) research since it was identified and synthesized in 1964. The discovery of the human endogenous cannabinoid or "endocannabinoid" system (ECS) has sparked research into other phytocannabinoids: cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and over 100 more. CBD is already used therapeutically, and many applications seem promising for other cannabinoids and whole-plant extracts from specialty chemotypes that express cannabinoids in the desired proportions. Russo summarizes current research findings on cannabinoid activity, emphasizing those effects of particular interest for potential synergy. Phytocannabinoids are synthesized in secretory cells of glandular trichomes most concentrated in unfertilized female cannabis flowers. Other compounds are also synthesized from the same precursor, geranyl pyrophosphate. These are terpenoids, components of essential oils (EOs) and the largest group of plant chemicals with 15-20,000 fully characterized. Over 200 terpenoids occur in cannabis. The terpenoids, not cannabinoids, create the plant's characteristic aroma. Representing about 1% of most cannabis assays, they may be 10% of trichome content. In most recreational cannabis (marijuana), bred to express THC to the virtual exclusion of other cannabinoids, variable trichome content, with resultant varying aroma, taste, appearance, and possibly varying effects, distinguishes hundreds of distinct chemotypes or strains. Most, if not all, cannabis terpenoids also occur in other plants and have well-documented pharmacological effects. Effects on recreational cannabis users are largely anecdotal with strong support from animal studies. Russo examines potential synergy between common cannabis terpenoids and cannabinoids. For example, THC is a known bronchodilator. α-Pinene, a bicyclic monoterpene present in cannabis, is also bronchodilatory in humans at low levels. A synergistic effect is postulated. α-Pinene levels in cannabis are reduced by drying and storage, but it occurs in some strains at levels sufficient to produce a strong pine (Pinus spp.) aroma. α-Pinene expresses more in flowers than in leaves. It is the terpenoid found most widely in nature, in evergreens, and many plant EOs, where it repels insects. α-Pinene is a major constituent of Sideritis spp. and Salvia spp. EOs, both highly active against methicillin-resistant Staphylococcus aureus (MRSA). α-Pinene appears to be a broad-spectrum antibiotic. It is anti-inflammatory via prostaglandin E-1 (PGE-1). An acetylcholinesterase inhibitor, it may counteract short-term memory deficits associated with THC. D-Limonene is the second most common terpenoid in nature, found in cannabis but mostly in citrus (Citrus spp.) EOs, and is the precursor to other monoterpenoids. It is a potent anxiolytic and antidepressant. It causes apoptosis in breast cancer cells and has been investigated in Phase II clinical trials. Its hepatic metabolite, perillic acid, has potential anticancer effects. A patent has been submitted for D-limonene to treat gastroesophageal reflux disease. EOs with D-limonene are effective against dermatophytes; some with terpenoid profiles similar to cannabis' are strong free radical scavengers. D-Limonene is highly bioavailable, rapidly metabolized, and highly nontoxic. Russo theorizes that α-pinene may have synergistic effects with THC in bronchodilation and enhance CBD's, CBG's, and CBN's anti-MRSA activities. Both α-pinene and D-limonene may be synergistically neuroprotective with THC and boost CBD's acne-fighting effects. D-Limonene's antioxidant activity complements THC's, while its anticancer and antidepressant effects could add to those of CBD, CBG, and CBN. Among other cannabis terpenoids, β-myrcene reduces inflammation via prostaglandin E-2 (PGE-2). It blocks liver carcinogenesis by aflatoxin. In Germany, it is found in hops (Humulus lupulus) sedative preparations (hops is a member of the Cannabaceae plant family). With strong evidence as a potent sedative, β-myrcene may be synergistic with THC in the lassitude ("couch lock syndrome") experienced with some cannabis use. Cannabis' D-linalool, a lavender (Lavandula spp.) monoterpenoid alcohol, is a known anxiolytic. Lavender EO is used in traditional aromatherapy to relieve burns without scarring. D-Linalool has local anesthetic effects equal to procaine and menthol. Post-gastric banding surgery patients who inhaled lavender used less morphine compared to those who inhaled placebo. In mice, D-linalool is antinociceptive at high doses via ionotropic glutamate receptors, anticonvulsant, and antiglutamatergic, as well as antileishmanial. β-Caryophyllene is usually the most common sesquiterpenoid in cannabis. It attracts insects that prey on insect pests of cannabis. β-Caryophyllene also occurs in black pepper (Piper nigrum) and copaiba (Copaifera officinalis). It has anti-inflammatory effects equivalent to phenylbutazone and protects against stomach cancer. β-Caryophyllene is a selective full agonist at cannabinoid receptor 2 (CB 2 ), the first known phytocannabinoid outside the Cannabis genus. Nerolidol, a cannabis sesquiterpene alcohol found in citrus peels, has known sedative effects. It inhibits fungal growth and enhances skin penetration of 5-flourouracil, so could be useful in treating fungal infection. It is an antimalarial and antileishmanial. β-Caryophyllene oxide, also found in lemon balm (Melissa officinalis) and eucalyptus (Eucalyptus globulus), is a cannabis sesquiterpenoid oxide. It serves the plant as an insecticidal antifeedant and broad spectrum antifungal. In a model of clinical onychomycosis, it was as efficacious as ciclopiroxalamine and sulconazole. It has antiplatelet aggregating effects. Russo adds that this terpenoid is used to identify cannabis by drug-sniffing dogs. Phytol, a diterpene in wild lettuce (Lactuca spp.) and green tea (Camellia sinensis), may be responsible for their relaxing effects as well as some of cannabis' by increasing gamma-aminobutyric acid (GABA) expression. A breakdown product of chlorophyll and tocopherol, phytol inhibits conversion of retinol to the harmful vitamin A metabolite all-trans-retinoic acid. For all of these terpenoids, Russo proposes plausible synergistic effects with cannabinoids. Terpenoids mentioned are Generally Recognized As Safe (GRAS) by the US Food and Drug Administration (FDA) and other regulatory agencies and are non-sensitizing to skin when used fresh. Synergy is the still unexplained but widely reported phenomenon that combined effects of two or more compounds may be greater than expected cumulative effects of each compound alone. The human ECS may use active and inactive synergists as the cannabis plant uses its phytocannabinoids and terpenoids, a process lending weight to arguments that whole plants and their complex preparations are better drugs than individual compounds isolated from them. Cannabis terpenoids are expressed in complex, variable mixtures, with marked structural diversity, serving various ecological roles. A unique mix of mono- and sesquiterpenoids determines viscosity and thus insect-trapping capacity. Insecticidal phytocannabinoid acids join to create a synergistic mechanical and chemical defense. For conventional Western medicine, reliant on single-compound drugs, most of them synthetic analogs of plant or other natural compounds, synergy presents challenging issues of verification, quantification, standardization, and more. Fortunately, these are issues that traditional systems of medicine worldwide, relying on complex plants, extracts, and plant/extract mixtures, have long considered, and at last some synergy appears to be emerging among researchers from diverse traditions towards experimental validation of traditional therapies. Basic mechanisms of synergy have now been proposed (exertion of multi-target effects, pharmacokinetic effects such as improved bioavailability, interactions affecting bacterial resistance, and modulation of adverse effects). Experimental results for synergy among cannabis compounds are mixed. In some studies, whole-plant cannabis extracts had effects two to four times greater than THC alone; in others, no differences were seen. Many experimental issues remain unresolved, such as the quality of cannabis available to researchers. Terpenoid yields from vaporization of US street cannabis were 4.3-8.5 times those obtained from US National Institute on Drug Abuse (NIDA) cannabis. Cannabis is remarkably free of serious adverse effects; in fact, one of the most serious from the viewpoint of conventional medicine is the very effect sought by recreational users: euphoria. For those who are naive to its effects, or whose emotional sensitivity is inopportunely enhanced, self-limiting panic reactions or toxic psychosis may ensue. No pharmacological intervention is generally needed. Russo cites historical methods of countering cannabis intoxication that also suggest possible terpenoid synergy. Acidic fruits were first mentioned by a 10th century C.E. Persian physician as preventing harm from eating cannabis seeds or hashish (a preparation of compressed trichomes); lemon (Citrus x limon) was specifically used in the 1800s as a remedy for both acute intoxication and morning-after effects (the latter suggesting a much more intoxicating form of cannabis than is currently available, apparently high-dose cannabis extracts), and "literary icons" consistently recommended the lemon cure at least until prohibition was enacted in the 1930s in the US. Ayurvedic tradition mentions calamus (Acorus calamus) root as neutralizing adverse side effects of smoking marijuana. This is supported by case reports of clearer thinking and improved memory with the cannabis-calamus combination.

Calamus contains β-asarone, an acetylcholinesterase inhibitor, providing a possible mechanism of action. α-Pinene also inhibits that enzyme, supporting the idea that cannabis contains its own antidote. This, too, is supported historically: Pliny wrote in the 1st century C.E. that pine nuts, with black pepper and honey in date palm (Phoenix spp.) wine, would drive away mental "phantoms" after imbibing cannabis with myrrh (Commiphora spp.) and wine, presumably grape (Vitis spp.). Russo discusses the ancient practice of storing wine in goatskins or clay pots, preserved with pine tar or terebinth resin from turpentine tree (Pistacia terebinthus). Both of these, and pine nuts, contain α-pinene; terebinth resin and pine nuts also contain D-limonene. Black pepper has α-pinene, β-myrcene, and β-caryophyllene, all with potential beneficial effects in panic or confusion. Experimental proof of these effects, with more exact descriptions of the cannabis effects modulated, would again add weight to arguments for synergy. Russo suggests a broad program of further study. This includes elucidation of mono- and sesquiterpenoid biosynthetic pathways in cannabis, high-throughput pharmacological screening of cannabis component combinations, investigation of biochemical targets of cannabis terpenoids and their mechanisms of action, investigation of terpenoid changes to phytocannabinoid signal transduction and trafficking, and more. Both cannabinoid and terpenoid production increase with light exposure but decrease with soil fertility, with higher yields when plants are deprived of nitrogen just before harvest. EO composition is more genetically than environmentally determined. Quality may be maintained despite cannabis' allogamy by vegetative propagation of high-performance plants in controlled conditions. Such techniques have been found to adhere tightly to the Good Manufacturing Practices (GMPs) required for pharmaceutical ingredients. Selective breeding has already produced chemotypes with no cannabinoids, some that express 97% of monoterpenoid content as β-myrcene, or 77% as D-limonene. Informed crossbreeding of selective high-terpenoid and high-cannabinoid chemotypes may lead to novel phytochemical combinations to improve therapeutic approaches to treatment-resistant depression, anxiety, drug dependency, dementia, insomnia, acne and many skin disorders, and to safer pesticides and antiseptics or treatments for antibiotic-resistant infections such as MRSA. —Mariann Garner-Wizard













