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The Journal of Cannabis in Clinical Practice
“Is this the best way we can grow our big orchards?”
Project CBD Update—
starts on page 7
Some 35 strains containing more than 4% Cannabidiol have been identi ed by labs serving the medical cannabis industry in the U.S.
The Society of Cannabis Clinicians has begun collect- ing patients’ responses to CBD-rich products.
Martin A. Lee lays out what scientists have learned about the mechanism of action by which CBD exerts its effects.
Lawrence Ringo (below) has bred plants that produce seeds with a one-in-four chance of containing 10-11% CBD (and 6-7% THC)!
Ethan Russo reviews the evidence
Terpenoids, ‘minor’ cannabinoids
contribute to ‘entourage effect’
of Cannabis-based medicines
By Fred Gardner
• CBD-Rich Strains Abound
The chemical structure of tetrahyrdocannabinol (THC) was determined in 1964 by Raphael Mechoulam and Yechiel Gaoni. For more than three decades thereafter, the blatant psychoactivity of THC induced scientists to de ne it as the active ingredient in the plant.
predominate. They tend to be volatile molecules that read- ily evaporate, and they’re very potent —all it takes is a few reaching the nose to announce their presence.
Experienced marijuana smokers who tried the drug Ma- rinol (pure, synthetic THC) when it became prescribable in the mid-1980s reported that the effects were dissimilar. But it wasn’t until the late 1990s that the research estab- lishment acknowledged that another compound, cannabi- diol (CBD), also exerted effects when present in signi - cant amounts.
• How CBD Works
In 1999 a British start-up, GW Pharmaceuticals, began clinical trials of a whole-plant extract containing rough- ly equal amounts of THC and CBD. Multiple Sclerosis patients found the combination extract —dubbed “Sa- tivex”— more effective in reducing pain and spasticity than a high-THC extract devoid of CBD, and less psycho- active.
Hergenrather expects Russo’s talk to “gener- ate great interest in terpenes among medical cannabis users as well as physicians.”
• “Sour Tsunami” Stabilized
Sativex has now been approved for use by MS patients in England, Canada, New Zealand, and a growing list of European countries. CBD is no longer referred to as a “minor cannabinoid” at scienti c conferences and in the literature.
Both terpenoids and cannabinoids are secreted inside the Cannabis plant’s glandular trichomes, and they have a par- ent compound in common (geranyl pyrophosphate). More than 200 terpenoids have been identi ed in Cannabis. The most common and most studied include limonene, myr- cene, alpha-pinene, linalool, beta-caryophyllene, caryo- phyllene oxide, nerolidol and phytol. Anecdotal evidence suggests that pinene is alerting, limonene “sunshine-y,” and myrcene sedating.
Several cannabinoids still considered “minor” —tet- rahydrocannabavarin (THCV), cannabigerol (CBG) and cannabichromene (CBC)— also show therapeutic prom- ise, according to recent studies. Plants with high levels of each have been grown out in GW Pharmaceuticals’ glass- houses for research purposes.
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 avor and fragrances manufacturers have investigated their proper- ties over the years. But the terpenoids “remain understud- ied” in terms of therapeutic potential, according to Russo.
Wake up and smell the terpenes!
His paper mustered all the evidence —proof in some cases, hints in others— that cannabinoids and terpenoids
• Harlequin, Omrita Rx3 Clones Released
Scientists are now formally acknowledging something else that Cannabis consumers have long taken for granted: aroma is associated with effect.
The aroma of a given plant depends on which terpenoids predominate.
Plant cannabinoids —21-carbon molecules found only in Cannabis— are odorless. It’s the terpenoids —compo- nents of the plant’s “essential oils”— that create the fra- grance. 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 owers, aromatic barks and woods.
To expedite patient access to CBD-rich medicine, the developers of two remarkable strains have chosen to make clones available (rather than provide only owers) to dispensaries participating in Project CBD.
Evidence that “phytocannabinoid-terpenoid interac- tions” enhance the therapeutic effects of cannabis was pre- sented by Ethan Russo, MD, at a conference in Israel last fall and published in the August 2011 British Journal of Pharmacology. Russo, a neurologist and ethnobotanist, is senior medical adviser at GW Pharmaceuticals.
• SCC Launches Survey
• ICRS 2011: CBD Research Accelerates
The aroma of a given plant depends on which terpenoids
can work in concert to abate symptoms of pain, in amma- 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.
Ethan Russo, RaphaEl MEchoulaM, and YEchiEl Gaoni
continued on page 19
bRacts on cannabis flowERs are sites of most abundant trichome production.
Copyright 2012 by O’Shaughnessy’s. All rights reserved. Address reprint requests to editor@@beyondthc.com
at the “Cannabinoids in Biology and Medicine” workshop held at Hebrew University in Jerusalem last November. The event honored Mechoulam on his 80th birthday. His many accomplishments include helping to discover the structure of CBD (with Shvo in 1963), THC (with Gaoni in 1964), and anandamide, the neurotransmitter that THC mimics (with Devane in 1992). A 1998 paper by Shimon Ben-Shabatt, co-authored by Mechoulam, proposed that endocannabinoids (made in the body) act in concert with other compounds to exert an “entourage effect.” Russo, a senior medical advisor with GW Pharmaceuticals, applied the entourage concept to phytocannabinoids (made by the plant). photo bY luMiR hanus
alEssia liGREsti’s icRs talk described “Mechanisms of the anti-cancer effects of cannabidiol and other non- psychotropic cannabinoids on human prostate carcino- ma.” Her team studied 12 cannabinoids in pure form and in “relative enriched extracts” (in each of which a different cannabinoid was predominant). They ob- served, “Generally, among all pure compounds tested, CBD was the most ef cacious at reducing cell viability... and in many cases the [extracts] were more potent than pure compounds.” CBC and CBG were also found to be effective, but “to a lesser extent.” Prostate cancer cells are killed, Ligresti reported, “through several concur- ring molecular mechanisms.” An entourage effect!
GlandulaR tRichoMEs (globules atop stalks) contain specialized cells that secrete both can- nabinoids and terpenoids.
“CBD was the star of the show on opening day here at ICRS, demonstrating potent anti-cancer effects in a vari- ety of cancer types.” —Jahan Marcu, on the Internation- al Cannabinoid Research Society meeting in early July.
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.
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