Medical marijuana could help patients reduce pain with opiates

December 6, 2011

Science Daily/University of California - San Francisco

A UCSF study suggests patients with chronic pain may experience greater relief if their doctors add cannabinoids -- the main ingredient in cannabis or medical marijuana -- to an opiates-only treatment. The findings, from a small-scale study, also suggest that a combined therapy could result in reduced opiate dosages.

More than 76 million Americans suffer from chronic pain -- more people than diabetes, heart disease and cancer combined, according to the National Centers for Health Statistics.

"Pain is a big problem in America and chronic pain is a reason many people utilize the health care system," said the paper's lead author, Donald Abrams, MD, professor of clinical medicine at UCSF and chief of the Hematology-Oncology Division at San Francisco General Hospital and Trauma Center (SFGH). "And chronic pain is, unfortunately, one of the problems we're least capable of managing effectively."

In a paper published this month in Clinical Pharmacology & Therapeutics, researchers examined the interaction between cannabinoids and opiates in the first human study of its kind. They found the combination of the two components reduced pain more than using opiates alone, similar to results previously found in animal studies.

Researchers studied chronic pain patients who were being treated with long-acting morphine or long-acting oxycodone. Their treatment was supplemented with controlled amounts of cannabinoids, inhaled through a vaporizer. The original focus was on whether the opiates' effectiveness increased, not on whether the cannabinoids helped reduce pain.

"The goal of the study really was to determine if inhalation of cannabis changed the level of the opiates in the bloodstream," Abrams said. "The way drugs interact, adding cannabis to the chronic dose of opiates could be expected either to increase the plasma level of the opiates or to decrease the plasma level of the opiates or to have no effect. And while we were doing that, we also asked the patients what happened to their pain."

Abrams and his colleagues studied 21 chronic pain patients in the inpatient Clinical and Transitional Science Institute's Clinical Research Center at SFGH: 10 on sustained-release morphine and 11 on oxycodone. After obtaining opiate levels from patients at the start of the study, researchers exposed them to vaporized cannabis for four consecutive days. On the fifth day, they looked again at the level of opiate in the bloodstream. Because the level of morphine was slightly lower in the patients, and the level of oxycodone was virtually unchanged, "one would expect they would have less relief of pain and what we found that was interesting was that instead of having less pain relief, patients had more pain relief," Abrams said. "So that was a little surprising."

The morphine group came in with a pain score of about 35, and on the fifth day, it decreased to 24 -- a 33 percent reduction. The oxycodone group came in with an average pain score of about 44, and it reduced to 34 -- a drop of 20 percent. Overall, patients showed a significant decrease in their pain.

"This preliminary study seems to imply that people may be able to get away perhaps taking lower doses of the opiates for longer periods of time if taken in conjunction with cannabis," Abrams said.

Opiates are very strong powerful pain medicines that can be highly addictive. They also can be deadly since opiates sometimes suppress the respiratory system.

As a cancer doctor, Abrams was motivated to find safe and effective treatments for chronic pain. Patients in the cannabis-opiates study experienced no major side effects such as nausea, vomiting or loss of appetite.

"What we need to do now is look at pain as the primary endpoint of a larger trial," he said. "Particularly I would be interested in looking at the effect of different strains of cannabis."

For instance, Delta 9 THC is the main psychoactive component of cannabis but cannabis contains about 70 other similar compounds with different effects. One of those is cannabidiol, or CBD. It appears to be very effective against pain and inflammation without creating the "high" created by THC.

"I think it would be interesting to do a larger study comparing high THC versus high CBD cannabis strains in association with opiates in patients with chronic pain and perhaps even having a placebo as a control," Abrams said. "That would be the next step."

Abrams is the lead author of the paper; co-authors are Paul Couey, BA, and Mary Ellen Kelly, MPH, of the UCSF Division of Hematology-Oncology at SFGH; Starley Shade, PhD, of the UCSF Center for AIDS Prevention Studies; and Neal Benowitz, MD, of the UCSF Division of Clinical Pharmacology and Experimental Therapeutics.

The study was supported by funds from the National Institutes on Drug Abuse (NIDA), a subsidiary of the National Institutes of Health (NIH).

Major Components of Cannabis

·     Delta-9 Tetrahydrocannabinol (Delta-9 THC)-- It is the main psychoactive component of cannabis with mild to moderate painkilling effects. It also helps treat nausea associate with cancer chemotherapy and to stimulate appetite. It induces feelings of euphoria. Potential side effects include accelerated heartbeat, panic, confusion, anxiety and possible paranoia.

·     Cannabidiol (CBD)- It is a major, non-psychoactive component of cannabis that helps shrink inflammation and reduce pain without inducing the euphoria effects of THC. It has been used to treat rheumatoid arthritis, inflammatory bowel diseases, psychotic disorders and epilepsy. Larger amounts of CBD can relax the mind and body without causing negative side effects associated with THC.

·     Cannabinol (CBN)-- It is a secondary psychoactive component of cannabis. It is not associated with painkilling effects of THC or CBD. CBN is formed as THC ages. Unlike the euphoria effects of THC, CBN can induce headaches and a sense of lethargy.

·     Tetrahydrocannabivarin (THCV) -- It is found primarily in strains of African and Asian cannabis. THCV heightens the intensity of THC effects and the speed in which the component is delivered, but also causes the sense of euphoria to end sooner.

https://www.sciencedaily.com/releases/2011/12/111206151448.htm

Weeding Out the Highs of Medical Marijuana

July 15, 2008

Science Daily/University of Manchester

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.

https://www.sciencedaily.com/releases/2008/07/080714192555.htm

Yeast produce low-cost, high-quality cannabinoids

February 27, 2019

Science Daily/University of California - Berkeley

Synthetic biologists have created an enzymatic network in yeast that turns sugar into cannabinoids, including tetrahydrocannabinol and cannabidiol, but also novel cannabinoids not found in the marijuana plant itself. The yeast factories would be more environmentally friendly and less energy intensive than growing the plant and separating out the psychoactive and non-psychoactive ingredients. They may also yield cannabinoid derivatives with unexpected medical uses.

University of California, Berkeley, synthetic biologists have engineered brewer's yeast to produce marijuana's main ingredients -- mind-altering THC and non-psychoactive CBD -- as well as novel cannabinoids not found in the plant itself.

Feeding only on sugar, the yeast are an easy and cheap way to produce pure cannabinoids that today are costly to extract from the buds of the marijuana plant, Cannabis sativa.

"For the consumer, the benefits are high-quality, low-cost CBD and THC: you get exactly what you want from yeast," said Jay Keasling, a UC Berkeley professor of chemical and biomolecular engineering and of bioengineering and a faculty scientist at Lawrence Berkeley National Laboratory. "It is a safer, more environmentally friendly way to produce cannabinoids."

Cannabis and its extracts, including the high-inducing THC, or tetrahydrocannabinol, are now legal in 10 states and the District of Columbia, and recreational marijuana -- smoked, vaped or consumed as edibles -- is a multibillion-dollar business nationwide. Medications containing THC have been approved by the Food and Drug Administration to reduce nausea after chemotherapy and to improve appetite in AIDS patients.

CBD, or cannabidiol, is used increasingly in cosmetics -- so-called cosmeceuticals -- and has been approved as a treatment for childhood epileptic seizures. It is being investigated as a therapy for numerous conditions, including anxiety, Parkinson's disease and chronic pain.

But medical research on the more than 100 other chemicals in marijuana has been difficult, because the chemicals occur in tiny quantities, making them hard to extract from the plant. Inexpensive, purer sources -- like yeast -- could make such studies easier.

Plus, he added, there is "the possibility of new therapies based on novel cannabinoids: the rare ones that are nearly impossible to get from the plant, or the unnatural ones, which are impossible to get from the plant."

Keasling, the Philomathia Foundation Chair in Alternative Energy at Berkeley, and his colleagues will report their results online Feb. 27 in advance of publication in the journal Nature.

Plugging chemical pathways into yeast

Cannabinoids join many other chemicals and drugs now being produced in yeast, including human growth hormone, insulin, blood clotting factors and recently, but not yet on the market, morphine and other opiates.

One of the pioneers of synthetic biology, Keasling has long sought to exploit yeast and bacteria as "green" drug factories, eliminating the expensive synthetic or extractive processes common in the chemical industry and the often toxic or environmentally- damaging chemical byproducts.

Cannabis cultivation is a prime example of an energy-intensive and environmentally-destructive industry. Farms in northwest California have polluted streams with pesticide and fertilizer runoff and helped drain watersheds because marijuana plants are water-hungry. Illegal grows have resulted in clear-cutting and erosion.

Indoor cultivation under grow lights with ventilation fans uses a lot of energy, accounting for a growing percentage of annual power consumption. One study estimated that California's cannabis industry accounted for 3 percent of the state's electricity usage. Indoor grows have caused blackouts in some cities, and energy consumption can add more than $1,000 to the price of a pound of weed.

Hence Keasling's interest in finding a "green" way to produce the active chemicals in marijuana.

"It was an interesting scientific challenge," he admitted, that was akin to other challenges he and his team have successfully overcome in yeast: producing an antimalarial drug, artemisinin; turning plant waste into biofuels; synthesizing flavors and scents for the food and cosmetics industries and chemical intermediates for making new materials. "But when you read about cases of patients who have seizures and are helped by CBD, especially children, you realize there is some value in these molecules, and that producing cannabinoids in yeast could really be great."

With approval and oversight by the U.S. Drug Enforcement Agency -- cannabis is still illegal under federal law -- Berkeley postdoc Xiaozhou Luo and visiting graduate student Michael Reiter, who led the project, started assembling in yeast a series of chemical steps to produce, initially, the mother of all cannabinoids, CBGA (cannabigerolic acid). In both marijuana and yeast, the chemical reactions involve the acid form of the compounds: CBGA and its derivatives, THCA and CBDA. They readily convert to CBG, THC and CBD when exposed to light and heat.

Turning yeast into chemical factories involves co-opting their metabolism so that, instead of turning sugar into alcohol, for example, yeast convert sugar into other chemicals that are then modified by added enzymes to produce a new product, such as THC, that the yeast secrete into the liquid surrounding them. The researchers ended up inserting more than a dozen genes into yeast, many of them copies of genes used by the marijuana plant to synthesize cannabinoids.

One step, however, proved to be a roadblock for Keasling's group and competing groups: an enzyme that performs a key chemical step in making CBGA in the marijuana plant didn't work in yeast.

Rather than engineer a different synthetic pathway, Berkeley postdoc Leo d'Espaux and graduate student Jeff Wong went back to the plant itself and isolated a second enzyme, prenyl transferase, that does the same thing, and stuck it in the yeast.

"It worked like gangbusters," Keasling said.

Once they had yeast-producing CBGA, they added another enzyme to convert CBGA to THCA and a different enzyme to create a pathway to CBDA. Though the products the yeast produce are predominantly THC or CBD, Keasling said, each must still be separated from other chemicals present in tiny quantities.

They also added enzymes that made the yeast produce two other natural cannabinoids, CBDV (cannabidivarin) and THCV (tetrahydrocannabivarin), whose effects are not well understood.

Surprisingly, Xiaozhou and Michael discovered that the enzymatic steps involved in making CBGA in yeast are flexible enough to accept a variety of starter chemicals -- different fatty acids in place of the one used by the marijuana plant, hexanoic acid -- that generate cannabinoids that do not exist in the plant itself. They also got the yeast to incorporate chemicals into cannabinoids that could later be chemically altered in the lab, creating another avenue for producing never-before-seen, but potentially medically useful, cannabinoids.

Keasling subsequently founded an Emeryville, California, company, Demetrix Inc., which d'Espaux and Wong later joined, that licensed the technology from Berkeley to use yeast fermentation to make cannabinoids.

"The economics look really good," Keasling said. "The cost is competitive or better than that for the plant-derived cannabinoids. And manufacturers don't have to worry about contamination -- for example, THC in CBD -- that would make you high."

https://www.sciencedaily.com/releases/2019/02/190227131838.htm

Cannabis: A new frontier in therapeutics

February 15, 2015

Science Daily/McGill University Health Centre

While debate about recreational marijuana use continues, researchers are investigating the effectiveness of cannabis for treating pain, spasticity, and a host of other medical problems. In a symposium organized by the McGill University Health Centre (MUHC) as part of the 2015 American Association for the Advancement of Science Annual Meeting held this week in San Jose, California, experts from North America and the U.K. share their perspectives on the therapeutic potential of medical cannabis and explore the emerging science behind it.

"We need to advance our understanding of the role of cannabinoids in health and disease through research and education for patients, physicians and policy-makers," says Dr. Mark Ware, director of clinical research at the Alan Edwards Pain Management Unit at the MUHC, in Canada.

As a pain specialist Dr. Ware regularly sees patients with severe chronic pain at his clinic in Montreal, and for some of them, marijuana appears to be a credible option. "I don't think that every physician should prescribe medical cannabis, or that every patient can benefit but it's time to enhance our scientific knowledge base and have informed discussions with patients."

Increasing numbers of jurisdictions worldwide are allowing access to herbal cannabis, and a range of policy initiatives are emerging to regulate its production, distribution, and authorization. It is widely believed that there is little evidence to support the consideration of cannabis as a therapeutic agent. However, several medicines based on tetrahydrocannabinol (THC), the psychoactive ingredient of cannabis, have been approved as pharmaceutical drugs.

Leading British cannabis researcher Professor Roger Pertwee, who co-discovered the presence of tetrahydrocannabivarin (THCV) in cannabis in the 70's, recently published with collaborators some findings of potential therapeutic relevance in the British Journal of Pharmacology. "We observed that THCV, the non-psychoactive component of cannabis, produces anti-schizophrenic effects in a preclinical model of schizophrenia," says Pertwee, professor of Neuropharmacology at Aberdeen University. "This finding has revealed a new potential therapeutic use for this compound."

Neuropsychiatrist and Director of the Center for Medicinal Cannabis Research (CMCR) at the University of California, San Diego Dr. Igor Grant is interested in the short and long-term neuropsychiatric effects of marijuana use. The CMCR has overseen some of the most extensive research on the therapeutic effects of medical marijuana in the U.S. "Despite a commonly held view that cannabis use results in brain damage, meta analyses of extensive neurocognitive studies fail to demonstrate meaningful cognitive declines among recreational users," says Dr. Grant. "Bain imaging has produced variable results, with the best designed studies showing null findings."

Dr. Grant adds that while it is plausible to hypothesize that cannabis exposure in children and adolescents could impair brain development or predispose to mental illness, data from properly designed prospective studies is lacking.

https://www.sciencedaily.com/releases/2015/02/150215070209.htm