New Cannabis-like Drugs Could Block Pain Without Affecting Brain, Says Study

A new type of drug could alleviate pain in a similar way to cannabis without affecting the brain, according to a new study.

The research demonstrates for the first time that cannabinoid receptors called CB2, which can be activated by cannabis use, are present in human sensory nerves in the peripheral nervous system, but are not present in a normal human brain.

Drugs which activate the CB2 receptors are able to block pain by stopping pain signals being transmitted in human sensory nerves, according to the study, led by researchers from Imperial College London.

Previous studies have mainly focused on the other receptor activated by cannabis use, known as CB1, which was believed to be the primary receptor involved in pain relief. However, as CB1 receptors are found in the brain, taking drugs which activate these receptors can lead to side-effects, such as drowsiness, dependence and psychosis, and also recreational abuse.

The new research indicates that drugs targeting CB2 receptors offer a new way of treating pain in clinical conditions where there are currently few effective or safe treatments, such as chronic pain caused by osteoarthritis and pain from nerve damage. It could also provide an alternative treatment for acute pain, such as that experienced following surgical operations.

The new study showed that CB2 receptors work to block pain with a mechanism similar to the one which opiate receptors use when activated by the powerful painkilling drug morphine. They hope that drugs which target CB2 might provide an alternative to morphine, which can have serious side effects such as dependency, nausea and vomiting.

Praveen Anand, Professor of Clinical Neurology and Principal Investigator of the study from the Division of Neurosciences and Mental Health at Imperial College London, said: ”Although cannabis is probably best known as an illegal recreational drug, people have used it for medicinal purposes for centuries. Queen Victoria used it in tea to help with her period pains, and people with a variety of conditions say that it helps alleviate their symptoms.

“Our new study is very promising because it suggests that we could alleviate pain by targeting the cannabinoid receptor CB2 without causing the kinds of side-effects we associate with people using cannabis itself.”

The researchers reached their conclusions after studying human sensory nerve cells in culture with CB2 receptor compounds provided by GlaxoSmithKline, and also injured nerves from patients with chronic pain.

The researchers are now planning to conduct clinical trials of drugs which target CB2 in patients with chronic pain at Imperial College Healthcare NHS Trust, which has integrated with Imperial College London to form the UK's first Academic Health Science Centre.


Journal Reference:

  1. Anand et al. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain, 2008; 138 (3): 667 DOI: 10.1016/j.pain.2008.06.007

Medicinal Marijuana Effective For Neuropathic Pain In HIV, Study Finds

In a double-blind, placebo-controlled clinical trial to assess the impact of smoked medical cannabis, or marijuana, on the neuropathic pain associated with HIV, researchers at the University of California, San Diego School of Medicine found that reported pain relief was greater with cannabis than with a placebo.

The study, sponsored by the University of California Center for Medical Cannabis Research (CMCR) based at UC San Diego, will be published on line, August 6 in the journal Neuropsychopharmacology.

Led by Ronald J. Ellis, M.D., Ph.D., associate professor of neurosciences at UCSD School of Medicine, the study looked at 28 HIV patients with neuropathic pain not adequately controlled by other pain-relievers, including opiates. They took part in the controlled study as outpatients at the UCSD Medical Center. The proportion of subjects achieving pain reduction of 30 percent or more was greater for those smoking cannabis than those smoking the placebo.

"Neuropathy is a chronic and significant problem in HIV patients as there are few existing treatments that offer adequate pain management to sufferers," Ellis said. "We found that smoked cannabis was generally well-tolerated and effective when added to the patient's existing pain medication, resulting in increased pain relief."

Each trial participant participated in five study phases over seven weeks. During two five-day phases, randomly selected participants smoked either cannabis or placebo cigarettes made from whole plant material with cannabinoids (the psychoactive compound found in marijuana) removed, both provided by the National Institute on Drug Abuse. Outcome was tested by standardized tests measuring analgesia (lessened pain sensation), improvement in function and relief of pain-associated emotional distress.

Using verbal descriptors of pain magnitude, cannabis was associated with an average reduction of pain intensity from 'strong' 'to mild-to-moderate' in cannabis smokers, according to Ellis. Also, cannabis was associated with a sizeable (46% versus 18% for placebo) proportion of patients reporting clinically meaningful pain relief.

The study's findings are consistent with and extend other recent research supporting the short-term efficacy of cannabis for neuropathic pain, also sponsored by the CMCR.

"This study adds to a growing body of evidence that indicates that cannabis is effective, in the short-term at least, in the management of neuropathic pain," commented Igor Grant, M.D., professor of psychiatry and director of the CMCR.

Grant noted that this is the fourth CMCR sponsored study to provide convergent evidence that cannabis can help in relieving these types of pain. The previous studies were conducted with CMCR support by Donald I. Abrams, M.D., Professor of Clinical Medicine at UCSF, who reported efficacy in short-term treatment of HIV neuropathy (Neurology, 2007, 68:515-521); by Mark Wallace, M.D., Program Director for the UCSD Center for Pain Medicine, who found that normal volunteers subjected to chemically induced pain which mimics neuropathy also responded to medium doses of cannabis (Anesthesiology, 2007, 107(5):785-796); and by Barth Wilsey, M.D., Director of the UC Davis Analgesic Research Center, who also reported benefit from smoked cannabis in a group of patients with neuropathy of multiple origins (Journal of Pain, 2008 Jun;9(6):506-21).

Additional contributors to the study, all from the UCSD School of Medicine, include Will Toperoff, RN, FNP, Department of Neurosciences; Florin Vaida, Ph.D., Family and Preventive Medicine; Geoff van den Brande, RN, Medicine; J. Gonzales, Pharm.D., Pharmacy; Ben Gouaux, Heather Bentley, CCRA, and J. Hampton Atkinson, M.D., Psychiatry.


Journal Reference:

  1. Ellis et al. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. Neuropsychopharmacology, 2008; DOI: 10.1038/npp.2008.120

Can Cannabis Compounds Slow The Progression Of Multiple Sclerosis?

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study at the Peninsula Medical School in Plymouth has reached an important milestone with the news that the full cohort of 493 people with multiple sclerosis (MS) has been recruited to the study.

CUPID is a clinical trial which will evaluate whether tetrahydrocannabinol (THC), one of many compounds found in the in the cannabis plant (and the main active ingredient) is able to slow the progression of MS.

This is an important study for people with MS because current treatments either target the immune system in the early stages of MS, or are aimed at easing specific symptoms such as muscle spasms or bladder problems. At present there is no treatment which slows progression of the disease.

The CUPID trial follows an earlier study — Cannabinoids and Multiple Sclerosis (CAMS) — which suggested a link between THC and the slowing of MS. The CAMS trial saw participants take THC for a year — the CUPID trial will last for longer and aims to assess the effect of THC on progressive MS.

It has taken two years to recruit the 493 participants who will each take part in the trial for three years, and in some cases three and a half years. After data cleaning and analysis the results should be available by spring/early summer 2012.

Professor John Zajicek from the Peninsula Medical School, who heads the team carrying out the CUPID study, said: "We are delighted to have achieved the correct number of patient participants for this trial. Patients have been recruited from 27 sites across the UK. If we are able to prove beyond reasonable doubt the link between THC and the slowing down of progressive MS, we will be able to develop an effective therapy for the many thousands of MS sufferers around the world."

The CUPID trial is funded by the Medical Research Council, the Multiple Sclerosis Society and the Multiple Sclerosis Trust.

Chris Jones, chief executive of the MS Trust, commented: "The MS Trust is delighted to be supporting this study on behalf of people with MS. The ability to halt progression in MS is what we dream of – the Holy Grail for those whose condition deteriorates year on year. This study should give us the definitive answer as to whether cannabinoids will prove to be such an agent."

Dr Laura Bell, research communications officer for the MS Society, said: "People affected by MS are keen to know whether there's any truth in the suggestion that elements of the cannabis plant can help ease the symptoms and slow down progression of the condition.

"The MS Society is supportive of safe clinical trials investigating the medicinal properties of cannabis and it's great news that this trial is going ahead. We look forward to the results of this exciting study."

Weeding Out The Highs Of Medical Marijuana

Research exploring new ways of exploiting the full medicinal uses of cannabis while avoiding unwanted side-effects will be presented to pharmacologists on July 15 by scientists attending the Federation of European Pharmacological Societies Congress, EPHAR 2008.

Cannabis is a source of compounds known as cannabinoids, one of which, THC — the main chemical responsible for the 'high' — has long been licensed as a medicine for suppressing nausea produced by chemotherapy and for stimulating appetite, for instance, in AIDS patients.

More recently, the cannabis-based medicine Sativex was licensed both for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. Sativex contains approximately equal amounts of THC and the non-psychoactive plant cannabinoid, cannabidiol.

"THC works by targeting molecules in our bodies called cannabinoid receptors" said Roger Pertwee, Professor of Neuropharmacology at the University of Aberdeen, who is co-chairing the cannabis symposium.

"So some current research is focused on designing drugs that only target cannabinoid receptors in the part of the body relevant to the disease in question and not the receptors in the central nervous system involved in the unwanted effects of cannabis."

A further approach to avoiding the psychoactivity caused by THC involves harnessing the body's own cannabis, called 'endocannabinoids'.

"We don't have cannabinoid receptors just in case we come into contact with plant-derived chemicals that activate them but rather because we have our own molecules that do this," said Christopher Fowler, Professor of Pharmacology at Umea University, in Sweden, and co-chair of the meeting.

"The neat thing about endocannabinoids is that they are often produced only when we need them, such as when our bodies are damaged in some way; pain, for example, leads to a release of endocannabinoids in a region of the brain that is involved with pain control.

"The problem with this natural protective 'endocannabinoid system' is that it is too short-lived to be of great benefit — enzymes in our bodies quickly breakdown or metabolise the endocannabinoids negating their effect. It's a bit like a bathtub without a plug — the water is turned on but rapidly disappears down the plughole. This suggests an immediate target: block the plughole and the water will stay longer.

"Since the release of endocannabinoids is local, levels in other parts of the brain, stay low. This approach is under intense investigation and programmes for the development of new drugs targeting pain and possibly other disorders such as anxiety and depression are currently underway."

Speakers will report on promising studies that show improved strategies for targeting the endocannabinoid system, not only for pain relief, but also for treating other conditions, including stroke, liver diseases and, ironically, nicotine addiction and obesity.

Thus, as the conference will hear, there are some disorders in which endocannabinoid release appears to be detrimental to our health, one example being obesity, which can be treated with Acomplia*, a licensed synthetic medicine that acts by blocking cannabinoid receptors.

Professor Pertwee added: "THC in cannabis is of course well known for its ability to induce 'the munchies' and, as mentioned, is used in clinics to boost appetite. But my research group has discovered that another constituent of cannabis, THCV, acts in a similar way to Acomplia, blocking one of the cannabinoid receptors, so providing an alternative — and potentially better — treatment route in the fight against obesity.

"The conference will hear about some of the possible advantages THVC has over current obesity treatments, as well as data on the potential of cannabinoids to treat other conditions, including neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's disease."

*Acomplia has been a licensed medicine for obesity in the UK and Europe for about two years and was accepted by the National Institute for Clinical Excellence (NICE) on June 28, 2008.

Schizophrenia Linked To Dysfunction In Molecular Brain Pathway Activated By Marijuana

Alterations in a molecular brain pathway activated by marijuana may contribute to the cognitive symptoms of schizophrenia, according to a report in the July issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Expression of the cannabinoid 1 receptor (CB1R), the site of action of the main chemical ingredient of marijuana, is significantly reduced in the brains of individuals with schizophrenia. Activation of CB1R impairs signaling by gamma-aminobutyric acid (GABA), an important neurotransmitter essential for core cognitive processes such as working memory. The use of marijuana in individuals with schizophrenia appears to worsen this deficit in GABA synthesis.

Since reduced GABA is known to be present in schizophrenia, these findings suggest possible new drug targets that could help to improve function in people with the mental illness, University of Pittsburgh School of Medicine researchers report.

"Heavy marijuana use, particularly in adolescence, appears to be associated with an increased risk for the later development of schizophrenia, and the course of illness is worse for people with schizophrenia who use marijuana," said David A. Lewis, M.D., corresponding author of the study and UPMC Endowed Professor in Translational Neuroscience, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. "We wanted to understand the biological mechanisms that could explain these observations, and with this study, I believe that we can narrow down at least part of the 'why' to CB1R, the receptor for both tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, and the brains own cannabinoid chemical messengers."

Dr. Lewis and his colleagues examined specimens of brain tissue collected after death from 23 people with schizophrenia and 23 normal comparison subjects matched for a number of factors, including age and sex. The researchers evaluated levels of CB1R messenger RNA and protein, and also measured levels of glutamic acid decarboxylase (GAD-67), an enzyme that makes GABA, and cholecystokinin (CCK), a neuropeptide released from GABA neurons that, among other actions, regulates the production of the brain's own cannabinoids.

"CB1R levels were significantly 15 percent lower in the subjects with schizophrenia," Dr. Lewis said. "We measured these biochemical messengers using three techniques, and each time got the same answer — less CB1R in people with schizophrenia." This reduction, he noted, appears to be the brain's way of compensating for lower levels of GABA, and the use of marijuana defeats this compensation.

"These findings may provide insight into the biological basis of why cannabis use worsens schizophrenia, and, as a result, identify a novel target for new drug development that could improve treatments available for schizophrenia," said Dr. Lewis.

Other authors include Stephen M. Eggan, Ph.D., and Takanori Hashimoto, M.D., Ph.D., both of the Department of Psychiatry, University of Pittsburgh School of Medicine.

The study was funded by the National Institutes of Health. Additional funding support for Dr. Eggan came from the University of Pittsburgh's Andrew Mellon Predoctoral and Scottish Rite fellowships.

Body's Own 'Cannabis (Marijuana)' Is Good For The Skin, Scientists Find

 Scientists from Hungary, Germany and the U.K. have discovered that our own body not only makes chemical compounds similar to the active ingredient in marijuana (THC), but these play an important part in maintaining healthy skin.

This finding on "endocannabinoids" just published online in, and scheduled for the October 2008 print issue of, The FASEB Journal could lead to new drugs that treat skin conditions ranging from acne to dry skin, and even skin-related tumors.

"Our preclinical data encourage one to explore whether endocannabinoid system-acting agents can be exploited in the management of common skin disorders," said Tamás Biró, MD, PhD, a senior scientist involved in the research. "It is also suggested that these agents can be efficiently applied locally to the skin in the form of a cream."

Biró and colleagues came to this conclusion by treating cell cultures from human sebaceous glands (the glands that make the oil on our skin) with various concentrations of endocannabinoids (substances produced by the body that are similar to the active ingredient in marijuana).

Then they measured the production of lipids (fat cells, such as those in skin oil), cell survival and death, and changes in gene expression and compared these outcomes to those in an untreated control group.

"This research shows that we may have something in common with the marijuana plant," said Gerald Weissmann, MD. "Just as THC is believed to protect the marijuana plants from pathogens, our own cannabinoids may be necessary for us to maintain healthy skin and to protect us from pathogens ."

United States Has Highest Level Of Illegal Cocaine And Cannabis Use

A survey of 17 countries has found that despite its punitive drug policies the United States has the highest levels of illegal cocaine and cannabis use. The study, by Louisa Degenhardt (University of New South Wales, Sydney, Australia) and colleagues, is based on the World Health Organization's Composite International Diagnostic Interview (CIDI).

The authors found that 16.2% of people in the United States had used cocaine in their lifetime, a level much higher than any other country surveyed (the second highest level of cocaine use was in New Zealand, where 4.3% of people reported having used cocaine). Cannabis use was highest in the US (42.4%), followed by New Zealand (41.9%).

In the Americas, Europe, Japan, and New Zealand, alcohol had been used by the vast majority of survey participants, compared to smaller proportions in the Middle East, Africa, and China.

The survey found differences in both legal and illegal drug use among different socioeconomic groups. For example, males were more likely than females to have used all drug types; younger adults were more likely than older adults to have used all drugs examined; and higher income was related to drug use of all kinds. Marital status was found to be related to tobacco, cannabis, and cocaine use, but not alcohol use (the never married and previously married having higher odds of lifetime cocaine and cannabis use than the currently married; tobacco use is more likely in people who have been previously married while less likely among the never married).

Drug use "does not appear to be simply related to drug policy," say the authors, "since countries with more stringent policies towards illegal drug use did not have lower levels of such drug use than countries with more liberal policies." In the Netherlands, for example, which has more liberal policies than the US, 1.9% of people reported cocaine use and 19.8% reported cannabis use.

Data on drug use were available from 54,068 survey participants in 17 countries. The 17 countries were determined by the availability of research collaborators and on funding for the survey. Trained lay interviewers carried out face-to-face interviews (except in France where the interviews were done over the telephone) using a standardized, structured diagnostic interview for psychiatric conditions and drug use. Participants were asked if they had ever used alcohol, tobacco, cannabis, or cocaine.

The study's main limitations are that only 17 countries were surveyed, within these countries there were different rates of participation, and it is unclear whether people accurately report their drug use when interviewed. Nevertheless, the findings present comprehensive data on the patterns of drug use from national samples representing all regions of the world.


Journal Reference:

  1. Degenhardt et al. Toward a Global View of Alcohol, Tobacco, Cannabis, and Cocaine Use: Findings from the WHO World Mental Health Surveys. PLoS Medicine, 2008; 5 (7): e141 DOI: 10.1371/journal.pmed.0050141