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IACM-Bulletin of 11 January 2015

Science/Human: Nabilone reduces nightmares in patients with posttraumatic stress disorder

Nabilone reduced nightmares in 10 patients with posttraumatic stress disorder (PTSD) in a controlled study with 10 patients, researchers of the Canadian Forces Health Services Group Headquarters in Ottawa, Canada, wrote in the journal Psychoneuroendocrinology. Canadian male military personnel with PTSD, who despite standard treatment continued to experience trauma-related nightmares, received double-blind treatment with 0.5mg nabilone or placebo, and then titrated to the effective dose (nightmare suppression) or reaching a maximum of 3.0 mg. Subjects were followed for 7 weeks and then, following a 2-week washout period, were titrated with the other study treatment and followed for an additional 7 weeks. Nabilone is a synthetic derivative of THC with similar effects.

Ten subjects were included. The mean reduction in nightmares as measured by a standardized questionnaire were -3.6 (nabilone) and -1.0 (placebo). Mean global improvement as measured by another questionnaire was 1.9 (i.e. much improved) and 3.2 (i.e. minimally improved) in the nabilone and placebo groups, respectively. Researchers concluded that in this small sample nabilone “provided significant relief for military personnel with PTSD, indicating that it shows promise as a clinically-relevant treatment for patients with nightmares and a history of non-response to traditional therapies.”

Jetly R, Heber A, Fraser G, Boisvert D. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 2015;51:585-8.

Science/Human: Cannabis extract did not reduce cancer pain in clinical study

The cannabis extract Sativex of the British company GW Pharmaceuticals failed to alleviate pain in cancer patients as hoped in a clinical study. GW, which is developing Sativex for pain in collaboration with the Japanese company Otsuka, said the first of three large trials found no statistically significant difference between subjects using its product and those given a placebo. This placebo-controlled study recruited a total of 399 patients at centres in the U.S., Mexico and EURope. It evaluated Sativex at a dose range of 3-to-10 sprays per day (containing 8.1-27.0 mg of THC) over a 5-week treatment period with an additional 5-to-14 day stabilization period at the beginning of the trial and a one week follow up at the end of the trial.

Justin Gover of GW Pharmaceuticals said the findings were both disappointing and surprising, given encouraging results in earlier tests, but the company's scientists had not given up hope. Results from two further Phase III trials are due later this year and, if positive, could still allow the drug to be submitted for treating pain in patients with advanced cancer, where it is designed to be given on top of opioids. "Although we missed the primary endpoint in this trial, based upon the positive data seen in the Phase II programme, we remain confident in the ability for Sativex to relieve cancer pain in this patient population,” Gover said.

Reuters of 8 January 2015

Press release by GW Pharmaceuticals of 8 January 2015

Science/Human: Tetrahydrocannabivarin may be helpful in obesity

The natural cannabinoid tetrahydrocannabivarin (THCV) altered the nerve response to pleasant and unpleasant stimuli in a way that it “suggests therapeutic activity in obesity,” researchers of the Universities of Reading and Oxford, UK, wrote in the International Journal of Neuropsychopharmacology. THCV is a neutral CB1 receptor antagonist. Researchers hypothesized that THCV would, unlike the CB1 receptor antagonist rimonabant, leave intact neural reward responses but augment aversive responses. Rimonabant was approved in some EURopean countries for some time for the treatment of obesity, but was associated with severe side effects, such as suicidal ideation. 20 healthy volunteers received a single dose of THCV (10mg) and placebo on two separate occasions.

We measured the neural response to rewarding (sight and/or flavour of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional Magnetic Resonance Imaging. There were no significant differences between groups in subjective ratings. However, THCV increased responses to chocolate stimuli in several brain regions (midbrain, anterior cingulate cortex, caudate, and putamen). THCV also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen.

Tudge L, Williams C, Cowen PJ, McCabe C. Neural Effects of Cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) on Food Reward and Aversion in Healthy Volunteers. Int J Neuropsychopharmacol. 2014 Dec 25. [in press]

News in brief

USA: Cannabis use increased in Colorado after legalisation
As cannabis legalization took hold in Colorado, the estimated percentage of regular cannabis users increased according to a study by the National Survey on Drug Use and Health. Monthly use in Colorado increased to 12.7 per cent — a 22 per cent increase. Nationally, monthly cannabis use by people 12 and older increased by about 4 percent to 7.4 percent. "This is not surprising, given what's going on the medical side," Dr Mark Kleiman, a University of California-Los Angeles professor who studies cannabis policy, said of the increase, referring to the uptick in medical marijuana patients in Colorado in the same period. "I don't think this tells us about the long-term impacts of legalization."
Denver Post of 26 December 2014

Science/Human: Cannabis use is associated with lower fat mass and better glucose metabolism in Inuit
Researchers analysed data on 786 Inuit adults and found that the use of cannabis was associated with lower body mass index (BMI), lower fat mass, lower fasting insulin, and lower HOMA-IR, which is a measure of glucose metabolism.
CHU de Québec Research Center, Canada.
Ngueta G, et al. Obesity (Silver Spring). 2014 Dec 31. [in press]

Science/Cells: Anandamide activates cell death in skin tumour cells
Non-melanoma skin cancer and other epithelial tumours contain more of the enzyme cyclooxygenase-2 (COX-2), differentiating them from normal cells. New research suggests that the endocannabinoid anandamide (AEA) “will be selectively toxic in tumor cells that overexpress COX-2 (…). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2.“
Brody School of Medicine, Pharmacology and Toxicology, East Carolina University, Greenville, USA.
Soliman E, et al. Mol Carcinog. 2015 Jan 3. [in press]

Science/Cells: Fenofibrate, a drug against high blood cholesterol, binds to both cannabinoid receptors
In studies with a piece of the intestine taken from guinea pigs researchers demonstrated that fenofibrate, which is used to reduce blood cholesterol acted as an agonist at the CB2 receptor and a partial agonist at the CB1 receptor. Authors wrote that “fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary“ target, which is the PPAR receptor.
University of Nottingham Medical School, UK.
Priestley RS, et al. FASEB J. 2014 Dec 30. [in press]

Science/Animal: Cannabinoids may protect damage to the kidneys in diabetes
High blood glucose increases the risk of developing diabetic nephropathy (kidney damage). The number of CB1 and GPR55 receptors in certain parts of the kidney (proximal tubules) is “altered in response to exposure to elevated levels of glucose and albumin.” Researchers suggest investigating “if these receptors are effective physiological targets for the treatment and prevention of diabetic nephropathy.”
College of Health and Biomedicine, Victoria University, Melbourne, Australia.
Jenkin KA, et al. Clin Exp Pharmacol Physiol. 2014 Dec 29. [in press]

Science/Animal: Cannabinoid receptor activation in the brain may protect from brain injury
Researchers investigated certain brain areas (hippocampus) of mice after traumatic brain injury and found a protective effect of cannabinoid receptor activation.
Children's Hospital of Philadelphia, USA.
Johnson BN, et al. Front Cell Neurosci 2014;8:435. eCollection 2014

Science/Animal: Reduced brain function after traumatic brain injury is improved by a CB2 receptor inverse agonist
Motor, visual and emotional deficits in mice after mild traumatic brain injury were alleviated by the synthetic CB2 inverse agonist SMM-189. An inverse agonist binds to the same receptor as an agonist (for example THC to the CB2 receptor) but induces an effect opposite to that agonist.
The University of Tennessee Health Science Center, Memphis, USA.
Reiner A, et al. Int J Mol Sci 2014;16(1):758-87.

Science/Human: Adverse effects of opioids during surgery may depend on genetic variation of the enzyme responsible for endocannabinoid degradation
In a study with 259 healthy children between 6 and 15 years of age undergoing tonsillectomy who received an intraoperative dose of morphine adverse effects depended on the function of fatty acid amide hydrolase (FAAH). FAAH is responsible for the degradation of the endocannabinoid anandamide. If FAAH did not work properly due to a gene defect there were more opioid related side effects, for example postoperative nausea and vomiting.
Cincinnati Children's Hospital Medical Center, USA.
Sadhasivam S, et al. Pharmacogenomics J. 2015 Jan 6 [in press]

Science/Human: Kind of medical cannabis law in the USA influences cannabis use
Researchers of RAND investigated previous inconsistencies identified in the literature regarding the relationship between medical cannabis laws and recreational cannabis use by closely examining the importance of policy dimensions (registration requirements, home cultivation, dispensaries, etc.). They concluded that not all “laws are the same” and have not the same consequences.
RAND Corporation, Santa Monica, USA.
Pacula RL, et al. J Policy Anal Manage 2015;34(1):7-31.

Science/Cells: The endocannabinoid system is involved in the analgesic effects of metamizol
Both blockade of the cannabinoid-1 receptor and the vanilloid receptor reversed effects of metamizol (dipyrone) in certain cells, “suggesting that the endocannabinoid/endovanilloid system takes part in the analgesic effects of dipyrone.”
Endocannabinoid Research Group at the Department of Experimental Medicine, The Second University of Naples, Italy.
Maione S, et al. EUR J Pharmacol. 2014 Dec 31. [in press]

Science/Animal: Both central and peripheral cannabinoid receptors are involved in the reduction of muscle pain by THC
Research with rat models of acute muscle pain shows that both central and peripheral cannabinoid receptors are involved in the reduction of muscle pain by THC. Researchers suggest “that THC could be a future pharmacological option in the treatment of muscle pain. The local administration of THC could be an interesting option to treat this type of pain avoiding the central adverse effects.”
Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
Bagüés A, et al. EUR J Pharmacol 2014;745:69-75.

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