“Is this the best way we can grow our big orchards?” —Woody Guthrie $595 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 fra- grance. 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, fun- gal 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 inter- est 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! Copyright 2012 by O’Shaughnessy’s. All rights reserved. Address reprint requests to editor@@beyondthc.com —19— O’Shaughnessy’s • Autumn 2011 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