IACM-Bulletin of November 6, 2011

Science — Cannabis provides additional pain relief in patients already treated with opioids

A clinical study was conducted at the San Francisco General Hospital, USA, to investigate the effects of inhaled cannabis on 21 patients with chronic pain, on a regimen of twice-daily doses of morphine or oxycodone. Participants were admitted to hospital for 5 days. They were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. They inhaled 0.9 grams of cannabis (3.56 per cent THC) with a Volcano vaporizer of the company Storz & Bickel. Blood sampling was performed at 12-h intervals on days 1 to 5. The extent of chronic pain was also assessed daily.

Pharmacokinetic investigations revealed no significant changes in blood concentrations of morphine or oxycodone after administration of cannabis. Pain was significantly decreased by an average of 27 per cent by cannabis inhalation. On a pain scale from 0 to 100 average pain intensity was 39.6 at baseline and 29.1 on day 5. Researchers concluded "that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects."

(Source: Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-Opioid Interaction in Chronic Pain. Clin Pharmacol Ther. 2011 Nov 2. [in press])

Science — An inhibitor of fatty acid amide hydrolase was well tolerated in the first clinical study

Researchers of the pharmaceutical company Pfizer in the USA investigated the pharmacokinetics and tolerability of an irreversible inhibitor of FAAH1 (fatty acid amide hydrolase 1) called PF-04457845 in healthy subjects. Double-blind, randomised, placebo-controlled single and multiple dose studies, and an open-label, randomised study on effects of food were conducted. Doses up to 40 mg (single dose) and up to 8 mg for 14 days were well tolerated.

PF-04457845 was rapidly absorbed with a median maximum blood concentration after 0.5-1.2 hours. Steady state was achieved by day 7. Less than 0.1 per cent of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (> 97 per cent) following doses of at least 0.3mg (single dose) and 0.5mg (multiple doses). Mean concentrations of fatty acid amides, among them endocannabinoids, increased 3.5- to 10-fold to a plateau then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. Authors concluded that "PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides."

(Source: Li GL, Winter H, Arends R, Jay GW, Le V, Young T, Huggins JP. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol. 2011 Nov 2. [in press])

Science — Large clinical trials demonstrate the benefit of the cannabis extract Sativex in patients with multiple sclerosis

Full results from three phase III studies with Sativex with altogether 1,500 MS patients were presented at the ECTRIMS congress in Amsterdam from 19 - 22 October. These studies provide evidence of the long term efficacy of this cannabis extract (2.7 mg THC and 2.5 mg CBD per puff) in symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication. These data have led to the approval of Sativex in the UK, Spain, Denmark, Germany and the Czech Republic.

Professor Hans Peter Hartung, director of the Clinic of Neurology at the University of Dusseldorf, Germany, and chairman of a symposium during the ECTRIMS meeting, commented: “Sativex has proven to reduce the severity of symptoms and improve patients’ quality of life and functional status, in patients with spasticity in multiple sclerosis, meaning that they can undertake everyday tasks more easily. Also, importantly, clinical experience to date has demonstrated that the tolerability profile of this medicine is favourable, with limited relevant adverse effects and - particularly reassuring - the drug does not appear to lead to withdrawal effects if patients suddenly stop using it.”

(Source: Press release by GW Pharmaceuticals of 24 October 2011)

News in brief

Canada — Medicinal cannabis

As of 30 September 12,216 people in Canada held authorization to possess cannabis for medical purposes, the Health Ministry (Health Canada) said. Currently there is a discussion on the proposal by Health Canada to remove itself as the final arbiter in approving or rejecting applications by patients to possess cannabis and to leave the approval process entirely up to the doctors. The Canadian Medical Association said that would put doctors in the position of controlling access to a largely untested and unregulated substance that hasn't gone through the normal regulatory drug review process. (Source: UPI of 31 October 2011)

Science — Physical exercise

According to research at the Free University Brussels, Belgium, physical exercise increases the concentration of BDNF (brain-derived neurotrophic factor) and the endocannabinoid anandamide (AEA). BDNF is a protein helping to support the survival of nerve cells and has been proposed to be implicated in depression, Alzheimer's disease and other conditions. Researchers concluded that "acute exercise represents a physiological stressor able to increase peripheral levels of AEA and that BDNF might be a mechanism by which AEA influences the neuroplastic and antidepressant effects of exercise." (Source: Heyman E, et al. Psychoneuroendocrinology. 2011 Oct 24. [in press])

Science — Genetic information of cannabis

Researchers of the University of Toronto, Canada, sequenced the complete genome (genetic information) of two cannabis strains, one producing high THC concentrations (Purple Kush) and the other low THC producing fibre hemp (Finola). The genome consists of 30,000 genes. Comparison of the genome of Purple Kush and Finola revealed that many genes for cannabinoid and precursor pathways are more highly expressed in Purple Kush. Researchers hope that the availability of the genome "will further the development of therapeutic marijuana strains with tailored cannabinoid profiles and provide a basis for the breeding of hemp with improved agronomic characteristics." (Source: van Bakel H, et al. Genome Biol. 2011 Oct 20;12(10):R102. [in press])

In an interview the President of Colombia Juan Manuel Santos suggested that the legalisation of cannabis, if done globally, could be a way forward in the fight against drug trafficking and the use of hard drugs such as cocaine and heroin. (Source: Metro World News Bogota of 23 October 2011)

Science — Cancer

According to research at the Catholic University of Louvain, Belgium, the antitumor properties of endocannabinoids were increased by the addition of a FAAH inhibitor (FAAH = fatty acid amide hydrolase) in experiments with cells of neuroblastoma, a common cancer in children. FAAH catalyses the degradation of some endocannabinoids and an inhibitor of this enzyme increases endocannabinoid concentration. (Source: Hamtiaux L, et al. PLoS One. 2011;6(10):e26823.)

Science — Social anxiety disorder

According to research at Rhode Island Hospital in Providence, USA, people with social anxiety disorder who also used cannabis are more likely to have a lifetime diagnosis of posttraumatic stress disorder and were more likely to report better physical health. The scientists compared 700 patients with social anxiety disorder without cannabis use and 173 with social anxiety disorder with cannabis use. They concluded that "there may be a unique relationship" between social anxiety disorder and cannabis use disorders. (Source: Tepe E, et al. J Psychiatr Res. 2011 Oct 31. [in press])

Science — Psychosis

According to research at the University of Manchester, UK, with 160 subjects with psychosis and cannabis use and 167 patients with psychosis and other substance use there was no significant association between cannabis use and psychotic symptoms and a small effect on psychosocial functioning. The cannabis using subgroup was examined prospectively with repeated measures of substance use and psychopathology at baseline, 12 months, and 24 months. They also observed that cessation or reduction of cannabis use did not always result in symptomatic improvements. (Source: Barrowclough C, et al. Schizophr Bull. 2011 Oct 29. [in press])

Science — Hyperactivity disorder

According to researchers from Italy and the United States the CB1 receptor is involved in ADHD (attention deficit/hyperactivity disorder). They used a mouse model of ADHD. They concluded that "therapeutic strategies aimed at interfering with the ECS [endocannabinoid system] might prove effective in this disorder." (Source: Castelli M, et al. Eur J Neurosci 2011;34(9):1369-1377.)

Science — Pain

According to animal research at the University of Barcelona, Spain, the pain reducing effects of a synthetic CB2 receptor agonist (JWH-015) administered to the painful site were reversed by an opioid receptor blocker. From their investigations the scientists concluded that "the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are (…) mediated by endogenous opioids." (Source: Negrete R, et al. PLoS One. 2011;6(10):e26688.)

Science — Stroke

According to animal research of Spanish scientists activation of the CB2 receptor resulted in neuroprotective effects following reduced blood supply to the brain. In a mouse model of stroke administration of the CB2 receptor agonist JWH-133 reduced the activation of immune cells and inflammation in the brain. (Source: Zarruk JG, et al. Stroke. 2011 Oct 20. [in press])