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

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