Terpenoids, 'Minor' Cannabinoids Contribute to 'Entourage Effect'

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O’Shaughnessy’sThe Journal of Cannabis in Clinical Practice Autumn 2011 Ethan Russo reviews the evidence Terpenoids, ‘minor’ cannabinoids contribute to ‘entourage effect’ Project CBD Update— of Cannabis-based medicines starts on page 7 By Fred Gardner • CBD-Rich Strains Abound The chemical structure of tetrahyrdocannabinol (THC) predominate. They tend to be volatile molecules that read- Some 35 strains containing more than 4% Cannabidiol was determined in 1964 by Raphael Mechoulam and ily evaporate, and they’re very potent —all it takes is a few have been identified by labs serving the medical cannabis Yechiel Gaoni. For more than three decades thereafter, the reaching the nose to announce their presence. industry in the U.S. blatant psychoactivity of THC induced scientists to define Evidence that “phytocannabinoid-terpenoid interac- • SCC Launches Survey it as the active ingredient in the plant. tions” enhance the therapeutic effects of cannabis was pre- The Society of Cannabis Clinicians has begun collect- Experienced marijuana smokers who tried the drug Ma- sented by Ethan Russo, MD, at a conference in Israel last ing patients’ responses to CBD-rich products. rinol (pure, synthetic THC) when it became prescribable fall and published in the August 2011 British Journal of • How CBD Works in the mid-1980s reported that the effects were dissimilar. Pharmacology. Russo, a neurologist and ethnobotanist, is Martin A. Lee lays out what scientists have learned But it wasn’t until the late 1990s that the research estab- senior medical adviser at GW Pharmaceuticals. about the mechanism of action by which CBD exerts its lishment acknowledged that another compound, cannabi- effects. diol (CBD), also exerted effects when present in signifi- Hergenrather expects Russo’s talk to “gener- • “Sour Tsunami” Stabilized cant amounts. ate great interest in terpenes among medical In 1999 a British start-up, GW Pharmaceuticals, began Lawrence Ringo (below) has bred plants that produce clinical trials of a whole-plant extract containing rough- cannabis users as well as physicians.” seeds with a one-in-four chance of containing 10-11% ly equal amounts of THC and CBD. Multiple Sclerosis CBD (and 6-7% THC)! patients found the combination extract —dubbed “Sa- Both terpenoids and cannabinoids are secreted inside the tivex”— more effective in reducing pain and spasticity Cannabis plant’s glandular trichomes, and they have a par- than a high-THC extract devoid of CBD, and less psycho- ent compound in common (geranyl pyrophosphate). More active. than 200 terpenoids have been identified in Cannabis. The Sativex has now been approved for use by MS patients most common and most studied include limonene, myr- in England, Canada, New Zealand, and a growing list of cene, alpha-pinene, linalool, beta-caryophyllene, caryo- European countries. CBD is no longer referred to as a phyllene oxide, nerolidol and phytol. Anecdotal evidence “minor cannabinoid” at scientific conferences and in the suggests that pinene is alerting, limonene “sunshine-y,” literature. and myrcene sedating. Several cannabinoids still considered “minor” —tet- The fact that most terpenoid compounds are common rahydrocannabavarin (THCV), cannabigerol (CBG) and components of the human diet and “generally recognized cannabichromene (CBC)— also show therapeutic prom- as safe” by the Food and Drug Administration has made ise, according to recent studies. Plants with high levels of research possible, and scientists employed by flavor and each have been grown out in GW Pharmaceuticals’ glass- fragrances manufacturers have investigated their proper- houses for research purposes. ties over the years. But the terpenoids “remain understud- Wake up and smell the terpenes! ied” in terms of therapeutic potential, according to Russo. • Harlequin, Omrita Rx3 Clones Released Scientists are now formally acknowledging something His paper mustered all the evidence —proof in some cases, hints in others— that cannabinoids and terpenoids To expedite patient access to CBD-rich medicine, the else that Cannabis consumers have long taken for granted: developers of two remarkable strains have chosen to aroma is associated with effect. make clones available (rather than provide only flowers) to dispensaries participating in Project CBD. The aroma of a given plant depends on • ICRS 2011: CBD Research Accelerates which terpenoids predominate. “CBD was the star of the show on opening day here at ICRS, demonstrating potent anti-cancer effects in a vari- Plant cannabinoids —21-carbon molecules found only ety of cancer types.” —Jahan Marcu, on the Internation- in Cannabis— are odorless. It’s the terpenoids —compo- al Cannabinoid Research Society meeting in early July. nents of the plant’s “essential oils”— that create the fragrance. Terpenoids contain repeating units of a 5-carbon Glandular trichomes (globules atop stalks) contain specialized cells that secrete both can- molecule called isoprene and are prevalent in smelly herbs nabinoids and terpenoids. such as mints and sage, citrus peel, some flowers, aromatic barks and woods. can work in concert to abate symptoms of pain, inflamma- The aroma of a given plant depends on which terpenoids tion, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA, which kills more Ameri- cans 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 sur- veys will seek to document which other cannabinoids and which terpenoids are associated with which effects. continued on page 19

Ethan Russo, Raphael Mechoulam, and Yechiel Gaoni at the “Cannabinoids in Biology and Medicine” workshop Alessia Ligresti’s ICRS talk described “Mechanisms held at Hebrew University in Jerusalem last November. of the anti-cancer effects of cannabidiol and other non- The event honored Mechoulam on his 80th birthday. His psychotropic cannabinoids on human prostate carcino- many accomplishments include helping to discover the ma.” Her team studied 12 cannabinoids in pure form structure of CBD (with Shvo in 1963), THC (with Gaoni and in “relative enriched extracts” (in each of which in 1964), and anandamide, the neurotransmitter that THC a different cannabinoid was predominant). They ob- mimics (with Devane in 1992). A 1998 paper by Shimon served, “Generally, among all pure compounds tested, Ben-Shabatt, co-authored by Mechoulam, proposed that CBD was the most efficacious at reducing cell viability... endocannabinoids (made in the body) act in concert with and in many cases the [extracts] were more potent than other compounds to exert an “entourage effect.” Russo, a pure compounds.” CBC and CBG were also found to be senior medical advisor with GW Pharmaceuticals, applied effective, but “to a lesser extent.” Prostate cancer cells the entourage concept to phytocannabinoids (made by the Bracts on cannabis flowers are sites of most abundant are killed, Ligresti reported, “through several concur- plant). photo by Lumir Hanus trichome production. ring molecular mechanisms.” An entourage effect!

Entourage Effect from page 1

The “Entourage Effect” “Very seldom is the biological and flavonoids may also increase cerebral Caryophyllene Oxide, Nerolidol, and Phy- The conference at which Russo present- activity of the active constituent blood flow, enhance cortical activity, kill tol. ed his paper was held at Hebrew Universi- respiratory pathogens, and provide anti- assayed together with inactive ‘en- 3. He notes which cannabinoid effects ty, Jerusalem, where Raphael Mechoulam inflammatory activity.” would be augmented by which terpenoids, directs a lab, in honor of Mechoulam’s tourage’ compounds.” A decade later, Russo is substantiating and which terpenoid effects would be aug- 80th birthday. —Raphael Mechoulam the molecular-teamwork hypothesis and mented by which cannabinoids. In 1999 Mechoulam co-authored a pa- expanding on it. His BJP paper, “Tam- There is a huge body of information to per with Shimon Ben-Shabat suggesting constituents. Very seldom is the biological ing THC: potential cannabis synergy and convey, and Russo’s style is compressed that cannabinoids made in the body work activity of the active constituent assayed phytocannabinoid-terpenoid entourage ef- —documented fact after documented fact by means of an “entourage effect.” They together with inactive ‘entourage’ com- fects,” contains 304 citations. after documented fact, with insights posi- had found that the endocannabinoid 2-AG pounds. Investigations of the effect of the Although the paper takes the form of a tioned fittingly. The slides he showed in (2-arachidonoylglycerol), when adminis- active component in the presence of its review of the literature, Russo’s perspec- Israel have been integrated into two full- tered with two related compounds, would ‘entourage’ compounds may lead to results tive is forward-looking and practical. The page tables for the BJP paper, listing the bind more readily at the cannabinoid re- that differ from those observed with the ac- paper can be read as a strategic guide for relevant studies and the cannabinoid-terpe- ceptors and exert more pronounced behav- tive component only.” breeding and/or blending Cannabis so as noid combinations likely to produce a de- ioral effect on mice. In 2001 John McPartland and Russo pub- to maximize specific medical effects. Its sired effect. The paper, online at http//on- To pharmacologists who customarily lished a paper in the Journal of Cannabis structure is straightforward: linelibrary.wiley.com/doi/10.111/j.1476- designed experiments aimed at finding Therapeutics applying the “entourage” 1. Russo cites studies documenting the 5381.2011.01238x/abstract, is well worth the active ingredient, this had heavy im- concept to the plant itself. “Good evidence beneficial effects of THC, CBD, CBC, reading. Our summary and the disjointed plications. Mechoulam spelled them out: shows that secondary compounds in can- THCV, CBDV, CBG and CBN (noting the highlights that follow cannot do justice to “Biochemically active natural products, nabis may enhance the beneficial effects of adverse effects attributed to THC). Russo’s carefully constructed thesis. from either plant or animal origin, are in THC... and reduce THC-induced anxiety, 2. He cites studies documenting the many instances accompanied by chemi- cholinergic deficits, and immunosuppre- beneficial effects of Limonene, α-Pinene, cally related though biologically inactive sion,” they wrote. “Cannabis terpenoids Myrcene, Linalool, β-Caryophyllene, continued on next page Phytocannabinoid Effects

9 Δ -tetrahydrocannabinol (THC) annabigerol C (CBG) Tetrahydrocannabivarin (THCV) • Anti-hypertensive • Next most effective phytocannabinoid vs. breast cancer after CBD • Inhibits keratinocyte proliferation (anti-psoriasis?) • Powerful activity against MRSA • Analgesic? • Analgesic via CB1, CB2 • GABA uptake inhibitor (more potent • Inhibits anandamide reuptake. • Antipruritic than THC or CBD) • TRPM8 antagonist (application in • CB1 antagonist at low doses, but • Neuroprotective/Antioxidant • Modest antifungal activity prostate cancer?) CB1 agonist at higher doses. • 20 times the anti-inflammatory • Antidepressant • Produces weight loss, decreased effect of aspirin body fat, increased energy expendi- • Twice the anti-inflammatory effect Cannabichromene (CBC) ture in obese mice. of hydrocortisone • Anti-inflammatory • Anticonvulsant in rodent cerebel- • Not a Cox-1 or Cox-2 inhibitor • Analgesic (less than THC) lum and pyriform cortex. • Reduces amyloid plaque build-up • Antibiotic/antifungal • Cancer cytotoxic agent Cannabidiol (CBD) • CBC extract antidepressant in rodents Cannabidivarin (CBDV) • Anandamide reuptake inhibitor

• Anticonvulsant in hippocampal slices • Neuroprotective antioxidant, strongly inhibits glutamate excitotoxicity; more potent antioxidant than Vitamins C, E • Inhibits uptake of anandamide, Cannabinol (CBN) weakly inhibits its breakdown • Alerting vs. THC • Anticonvulsant • Anti-anxiety • Cytotoxic in breast cancer and many other cancer cell lines; cytopreservative for normal cells • Antagonist at GPR55 and GPR18 • Antagonizes tumor necrosis factor • Sedative alpha in rodent rheumatoid arthritis. • Anticonvulsant • Not Cox-1 or Cox-2 inhibitor • Anti-inflammatory • Agonist at serotonin receptor (why it • Antibiotic, potent against MRSA may counter anxiety) • TRPV2 agonist of interest in burns • Reduces nausea • Inhibits keratinocyte proliferation • Improved cognition in hepatatic en- (utility in psoriasis?) cephalopathy • Stimulates recruitment of quiescent • Enhances adenosine receptor A2A mesenchymal stem cells in marrow, pro- signaling via inhibition of an adenosine moting bone formation transporter, suggesting anti-inflamma- Inhibited breast cancer resistance pro- tory and analgesic role tein. Megadoses might help treat breast • Prevents prion accumulation and tumors. neuronal toxicity • Powerful activity against MRSA

Phytocannabinoids and their effects were reviewed by Ethan Russo, MD, “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage at the International Workshop on the Cannabinoids in Biology and Medicine, held in effects” —online at http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01238.x/ Jerusalem, November 2010. Phytocannabinoids are odorless, 21-carbon molecules found abstract. GW Pharmaceuticals has developed cannabis cultivars in which CBC and only in the Cannabis plant and nowhere else in nature. Russo’s slides, excerpted above, THCV are predominant —and one in which the entire cannabinoid content is CBG. GW cited the studies by which each cannabinoid effect was determined. The relevant stud- Pharmaceuticals’ plant-breeding program is described on their website and in a four- ies are also cited in Russo’s paper in the August 2011 British Journal of Pharmacology, part series by Etienne de Meijer and co-workers in the journal Euphytica. —20— O’Shaughnessy’s • Autumn 2011

Entourage Effect from previous page The Cannabinoids cannabis chemotypes yields a high-CBC Every compound the plant pro- plants that are “highly predominant” in Formerly Known as Minor (CFKMs) ‘enriched trichrome preparation.’” THCV have been bred. The extensive breeding program directed Cannabigerolic acid (CBGA), the pre- duces has or had an evolutionary by GW Pharmaceuticals’ Etienne de Mei- cursor of THC, CBD, and CBC in their purpose. Terpene Factoids jer has yielded plants rich in CBD, CBC, acid forms, is usually found at low con- Whereas plant cannabinoids are found CBG, and THCV. centrations. “But recent breeding work the CB1 receptor at low doses, and acti- nowhere else in nature, terpenoids are pro- Cannabichromene (CBC) is produced has yielded cannabis chemotypes lack- vates it at high doses. GW Pharmaceuti- duced by countless plant species. Some early in the plant’s life cycle according to ing in downstream enzymes that express cals hopes that a THCV-rich extract will be 20,000 terpenoids have been identified by a paper published by de Meijer in 2009. 100% of their phytocannabinoid content as an effective appetite suppressant and will chemists; they constitute the largest group Citing de Meijer’s co-worker David Pot- CBG,” according to Russo. (More details counter the symptoms of metabolic syn- of plant chemicals. More than 200 have ter, Russo notes that “An innovative tech- are provided on GW Pharmaceuticals’ very drome. been found in cannabis. nique employing cold water extraction of informative website.) THCV is present in cannabis chemo- “Essential oil composition is much more immature leaf matter from selectively bred Tetrahydrocannabivarin (THCV) blocks types from southern Africa —from which genetically than environmentally deter- continued on next page Terpenoid Effects and Synergistic Cannabinoids

Limonene (also found in lemon) α-pinene (also found in pine needles)

• Antidepressant and immune stimula- tor in humans —CBD • Anti-inflammatory via prostaglandin • Anti-anxiety, antidepressant in mice E-1 mechanism —CBD via serotonin receptor. CBD • Bronchodilatory in humans —THC • Apoptosis of breast cancer cells • Acetylcholinesterase inhibitor, —CBD, CBG aiding memory —THC?, CBD • Effective against dermatophytes • Anti-MRSA et al —CBD, CBG, CBN —CBG • Wide-spectrum antibiotic • Gastro-esophageal reflux —THC

Myrcene (also found in hops) Linalool (also found in lavender) • Anti-anxiety —CBD, CBG? • Sedative on inhalation in mice —THC • Local anesthetic equal to procaine, men- thol —THC •Anticonvulsant/anti-gluta- • Blocks inflammation via prosta- mate —CBD, THCV, CBDV glandin E2 —CBD • Analgesic in mice • Analgesic in mice, antagonized by • May achieve these effects naloxone —CBD, THC by modulating glutamate and • Sedating; muscle relaxant; poten- GABA neurotransmission. tiated sleep time —THC • Blocks hepatic carcinogenesis by aflatoxin —CBD, CBG Phytol (also found in green tea)

eta caryophyllene Nerolidol (also found in orange) B - (also found in Echinacea)

• Counters mutagenic effect of Vitamin A • Blocks breakdown of GABA —CBG

• Sedative —THC, CBN • Skin penetrant —? • Inhibits fungal growth —CBC • Utility in contact dermatitis? • Anti-inflammatory via PGE-1 —CBD • Gastric cytoprotective —THC • Selective CB2 full agonist (anti-inflammatory, analgesic) —THC • Treatment of pruritus? —THC • Treatment of addiction? —CBD

Caryophyllene oxide (also found in lemon balm)

• Antifungal in onychomycosis — CBC, CBG • Insecticidal —THCA, CBGA

terpenoids common in cannabis, their effects, and synergistic cannabinoids terpene). Some 200 terpenoids have been identified in Cannabis, but only those shown as listed by Russo. Aromatic terpenes abound in smelly herbs such as mints and sage, here and a few others occur frequently in significant amounts. Russo specified which citrus peel, some flowers, barks and woods. In Cannabis, terpenoids and cannabinoids cannabinoids are likely to augment medically useful terpenoid effects and vice versa. are produced by secretory cells in the glandular trichomes. Terpenes contain repeating GW Pharmaceuticals has developed a cannabinoid-free cannabis cultivar, which should units of isoprene, a 5-carbon molecule. Terpenoid naming is based on 10-carbon units: facilitate investigation of terpenoid effects. See www.GWPharm.com and Meijer EPM monoterpenes contain 10 carbons, sesquiterpenes 15, diterpenes 20, etc. Monoterpenes de, Hammond KM, Sutton A. 2009, “The inheritance of chemical phenotype in Can- are lightest and evaporate most readily. Thus Cannabis extracts tend to lose myrcene, nabis sativa L. (IV): cannabinoid-free plants,” Euphytica 168: 95-112. pinene, and limonene (all monoterpenes) in proportion to beta-caryophyllene (a sesqui- —21— O’Shaughnessy’s • Autumn 2011

Entourage Effect from previous page mined,” Russo states. Every compound the Limonene, inhaled, is an immunostimu- plant produces has or had an evolutionary lant. In lab experiments it has killed breast Cannabis designer extracts are purpose. The bitter 15-carbon terpenoids cancer cells and acne bacteria. It is a poten- Is Irradiation Safe? Russo’s BJP paper contains an asser- in the fan leaves repel grazing animals, tial treatment for gastro-esophageal reflux. likely to yield safe, effective new tion, tangential to his theme, that seems while the predominantly monoterpene mix Alpha-pinene —as anyone who has treatments for a wide range of like a big story in and of itself: “Gov- in the flowers is unappealing to insects — walked into piney woods and breathed conditions ernment-approved cannabis supplied and, thanks to its stickiness, can also en- deeply can sense— is a bronchodilator. It to patients in national programs in the trap them. also has anti-bacterial and antibiotic prop- act synergistically. Netherlands and Canada is gamma- Alpha-pinene is the most common ter- erties. α-Pinene inhibits the enzyme that • They can work on separate targets. irradiated to sterilize coliform bacteria, penoid in the plant world; limonene is breaks down acetylcholine, a neurotrans- For example, if CBD were combined with but the safety of this technique for a second. Named for their strong presence mitter involved in memory. “This feature limonene as an acne treatment, the can- smoked and inhaled product has never in pine needles and lemons, respectively, could counteract short-term memory defi- nabinoid could penetrate the skin and in- been specifically tested.” (Emphasis they are monoterpenes, also prevalent in cits induced by THC intoxication,” Russo duce the cells that produce sebum to self- added by O’Shaughnessy’s.) cannabis. notes. destruct, while the terpenoid could inhibit Russo cites studies showing that Terpenoids may account for only 1% production of the key pathogen, Propion- “Gamma-irradiation significantly re- of the weight when cannabis is tested but Myrcene, combined with THC, bacterium acnes. (Linalool and alpha-pi- duced linalool titres in fresh cilantro, 10% of the weight within the trichome. nene also suppress P. acnes.) and myrcene and linalool in orange Monoterpenes evaporate more readily may produce the ‘couch-lock’ • They can interact to overcome bacterial juice.” than the di- and sesquiterpenes during dry- phenomenon of certain chemo- resistance. For example, CBD and CBG In other words, getting zapped with- ing, storage, and production of extracts, types. “powerfully inhibit MRSA,” according to gamma rays may not only make plants which results in a relatively higher propor- one study cited by Russo, while in another unsafe to inhale, it can reduce their nu- tion of caryophyllene. Myrcene, another monoterpene common study, an essential oil rich in pinene proved tritional value. in cannabis, is also abundant in the flow- “as effective against MRSA and other an- Beneficial Effects ers of humulus lupulus —hops— the only tibiotic resistant bacterial strains as vanco- How do terpenoids exert effects within other member of the Cannabinacae family. mycin.” The Research Agenda the body? Citing the relevant studies, In addition to its anti-inflammatory effect, • They can have an antagonistic effect, as Cannabis designer extracts are likely Russo explains that they are “lipophilic, Russo writes, “Myrcene is a recognized in the case of CBD countering THC’s abil- to yield safe, effective new treatments for interact with cell membranes, neuronal sedative as part of hops preparations, em- ity to promote an accelerated heartbeat, the a wide range of conditions, and —in due and muscle ion channels, neurotransmit- ployed to aid sleep in Germany... Myrcene munchies, drowsiness, and anxiety. course, it is hoped— to regulatory approval ter receptors, G-protein coupled (odorant) acted as a muscle relaxant in mice, and and sales. GW Pharmaceuticals has already receptors, second messenger systems and potentiated barbiturate sleep time at high Key role for CBD bred cannabis chemotypes with very high enzymes.” doses. CBD will play a key role in extracts de- fractions of myrcene and limonene, and we “Together, these data would support the signed for medical use. Although deemed assume they’re working on plants high in Limonene has been shown to hypothesis that myrcene is a prominent “non-psychoactive,” CBD reduces anxiety pinene, linalool and other terpenoids with decrease anxiety in mice via the sedative terpenoid in cannabis, and com- by affecting the serotonin receptors. It also therapeutic potential. As Russo puts it in bined with THC, may produce the ‘couch- reduces cravings —for heroin, cocaine, his BJP paper, “Selective cross-breeding serotonin receptors. lock’ phenomenon of certain chemotypes food, nicotine and other addictive sub- of high-terpenoid- and high-phytocannab- that is alternatively decried or appreciated stances. inoid-specific chemotypes has... become a The beneficial effects are wide-rang- by recreational cannabis consumers.” Russo describes a recent study that rational target.” ing and, in many cases, well established. “demonstrated the fascinating result” that Meanwhile back in California, research- Limonene, for example, has been shown Linalool has sedative and anti- stroke patients who had suffered damage to minded doctors, cannabis cultivators, dis- to decrease anxiety in mice via the sero- a part of the brain called the insula “were pensary and lab owners, have been think- tonin receptors. “Compelling confirma- convulsant properties. able to quit tobacco smoking without re- ing along similar lines. (The idea that can- tory evidence in humans,” Russo writes, lapse or urges.” nabis can be bred to maximize production was provided by a Japanese study of se- Linalool, which is abundant in laven- “In a provocative parallel,” he adds, of more than one compound is as obvious verely depressed hospital patients whose der, affects serotonin neurotransmission functional MRIs of patients given CBD as the association between aroma and ef- moods improved when exposed to citrus and counters anxiety, according to a study (600 mg p.o.) dramatically reduced activ- fect.) We don’t have the resources to do fragrance. (Nine of 12 were able to get off cited by Russo. Linalool has sedative and ity observed within the left insula “sug- high throughput pharmacological screen- antidepressants.) anti-convulant properties, and is also “the gesting the possibility that CBD could act ing or animal studies involving radioactive likely suspect in the remarkable therapeu- as a pharmaceutical surrogate for insular labeling, but we do have access to labs that Essential Resource tic capabilities of lavender essential oil to damage in exerting an anti-addiction thera- can identify the compounds in a cannabis alleviate skin burns without scarring.” peutic benefit.” bud, and we have our own senses to evalu- Beta-caryophyllene, which is found in Which terpenoid(s) would be comple- ate effects. black pepper, Echinacea, and marigolds, mentary? Citing a study in which inhaled- As O’Shaughnessy’s goes to press in late “is frequently the predominant terpe- vapor from an essential oil of black pep- August, we know of two labs in California noid in cannabis extracts, particularly if per reduced craving for cigarettes, Russo that have begun testing for terpenes and they have been processed under heat.” writes: “the terpene profile of black pepper others are maing plans to do so. (See story β-caryophyllene is anti-inflammatory and, suggests possible candidates: myrcene via on next page.) ProjectCBD.org and can- unlike other anti-inflammatories, protec- sedation, pinene via increased alertness, nabisclinicians.org will carry updates on tive of the stomach lining. or especially caryophyllene via CB2 ago- what we, collectively, are about to learn. In 2008 Swiss investigators led by Jurg nism.” Gertsch showed that β-caryophyllene ac- tivates 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 The Handbook of Essential Oils: applications.” Science, Technology and Applications Other terpenoids with therapeutic po- by K. Husnu Can Baser and Gerhard tential mentioned by Russo in his BJP pa- Buchbuaer, is a 975-page compendium per are nerolidol (found in citrus, it may published in 2010 By CRC Press, Boca have sedative and anti-fungal effects); Raton, FL. caryophyllene oxide (found in the herb Ethan Russo must have made good lemon balm, it repels insects); and phytol use of this book. Reviewing it in Herb- (a breakdown product of chlorophyll with algram, he wrote, “The antimicrobial relaxant properties that may be the reason activities of the terpenoids are handled that green tea, despite its caffeine content, with an introduction in which the activi- doesn’t jangle the nerves). ty of thymol (an ingredient in Listerine) In their landmark 2001 paper in the is stated as 10-fold stronger than phe- Journal of Cannabinoid Therapeutics, nol. This is followed by an astounding Russo and lead author John McPartland 177 pages of tables documenting previ- touched on the beneficial effects of euca- ous experimental work examining the lypytol, pulegone, alpha-terpineol and oth- effects of various agents.” er possibly efficacious terpenoids. These A chapter on aromatherapy points out compounds were not discussed in Russo’s Raphael Mechoulam in the fall of 2010, addressing scientists assembled in his the difficulty of conducting randomized 2011 BJP paper. clinical trials (RCTs) with substances honor. Ethan Russo paid homage to a 1999 paper in which Mechoulam used the term “entourage effect” to describe how compounds act in concert to activate receptors in the that have such obviously distinct smells. Designer Extracts body. Mechoulam commented in that paper, “This type of synergism may play a role in No RCTs, no “scientific validity.” Russo describes several mechanisms by the widely held (but not experimentally based) view that in some cases plants are better which terpenoids and/or cannabinoids can drugs than the natural products isolated from them.” Photo by Zach Klein