Tuesday, April 24, 2018

Cannabinoid receptor research outlines why pot may work as medicine

Almost a decade ago, Palmetto resident Ryan Roman started using pot to cope with the effects of a rare spinal cancer that spread to his brain. Beating his doctors' predictions, the 31-year-old is still alive. He credits marijuana that he inhales through a vaporizer or ingests in concentrate form.

Roman and other advocates view marijuana as almost a miracle plant, capable of treating a grab-bag of maladies like pain, MS, PTSD, nausea, skin cancer and Lou Gehrig's disease — sweeping claims reminiscent of old-time patent medicine hucksters.

But in the case of pot, biology does offer theoretical support for this array of effects.

Years ago, scientists trying to find out why marijuana affects humans as it does discovered an extensive system of "cannabinoid receptors," little on-off switches that are critical to how some cells function.

These receptors — which pot can activate — are heavily concentrated in areas of the brain that control motion, anxiety, memory, judgment, sensation, vomiting and hunger.

The same mechanisms that make pot smokers crave snacks might help an AIDS patient regain appetite. Substances that make recreational imbibers mellow might also reduce pain, anxiety or spasticity.

Scientists disagree about the wisdom of treating illness with pot, but they rave about the possibility that learning about cannabinoid receptors might lead to life-saving breakthroughs.

"It is enormously important to our basic knowledge of the brain as well as our bodies' physiology,'' said Aron Lichtman, a Virginia Commonwealth University pharmacology professor. "It tells us about marijuana's effects, but more importantly about the possibility of developing new medication.''

Puzzle pieces

More than two decades ago, scientists injected lab rats with a radioactive version of THC, the primary chemical ingredient in marijuana. Distinct portions of the rat brains lit up like hotels on the Las Vegas strip.

The THC had sparked activity by plugging into previously undiscovered receptors on brain cell membranes. That's a common way cell networks operate. One cell sends out molecules that plug — like puzzle pieces — into receptors on other cells, giving them instructions.

"It turns out the brain is simply teeming with receptors, consistent with marijuana having wide-ranging influences on mental function,'' Eckerd College biology professor Gregory Gerdeman writes in The Pot Book: A Complete Guide to Cannabis.

But the body does not produce THC. So scientists reasoned it must produce something with a very similar chemical structure that would activate the receptors during normal operations of the body. When scientists finally isolated these natural signaling molecules, they labeled them cannabinoids, harkening back to the cannabis plant and the original search for THC's effects.

Cannabinoid receptors show up in the brain, the immune system and a few organs, often acting to calm down the body's responses before they get out of control.

Cut your finger and the immune system sends out cells to fight infection. That causes inflammation, which is harmful if it gets out of hand. Finding bear spoor on a forest trail should cause anxiety so you know to get away from danger. But if brain cells panic for hours, they will damage themselves.

When a cell that contains cannabinoid receptors gets excited, it sends messages to other cells to get something done. Those receiving cells send back cannabinoid molecules that plug into the receptors to calm the transmitting cell down. It's like saying, "Whoa, That's enough input, slow down now,'' Gerdeman writes.

This push-pull communication creates balance, lays down memories and helps the brain adapt to change, Gerdeman said. Bad things can happen without it. Mice with blocked cannabinoid receptors cannot function under stress. Neurons involved in some forms of epilepsy are loaded with cannabinoid receptors, suggesting that seizures may stem from impaired cannabinoid signaling.

In Florida, parents of children with severe epilepsy are pushing for legalization of a noneuphoric pot derivative known as Charlotte's Web. This illustrates the theory behind medical marijuana: When the body cannot maintain health on its own, pot's ingredients can plug into cannabinoid receptors and make things better.

The Legislature has given Charlotte's Web a sympathetic ear, raising the prospect that one limited form of medical marijuana will become legal before voters decide in November whether to legalize pot for all debilitating medical conditions.

Complexity, hope

Kevin Sabet, director of the University of Florida's Drug Policy Institute, agrees that the cannabinoid system offers promising targets for medical research.

But that "doesn't justify smoking marijuana any more than the research around morphine justifies smoking opium or shooting heroin,'' Sabet said.

Pot's shotgun approach creates many harmful side effects, he said. "Herbal marijuana doesn't provide the standardized, reliable dosage we have come to expect from modern medicine.''

To get there, scientists are experimenting with cannabinoids in pot and the body's natural cannabinoid system.

GW Pharmaceuticals, a British company, purifies pot extracts after cross-breeding strains to accentuate certain chemicals. Sativex, a nasal spray, is already approved in Europe for treatment of multiple sclerosis and is well along in the testing process in the United States.

Getting from field to pharmacy is not easy. Full-blown clinical trials are hugely expensive and pot presents legal as well as scientific challenges, including the varied functions of cannabinoid receptors.

After receptors were found on fat cells, a European company won approval in 2006 to block them with a drug. Sure enough, people lost weight, even without reducing food intake. U.S drug companies, hoping for a new obesity drug, launched their own research.

But the drug was yanked from the market after patients with blocked receptors started getting depressed and even suicidal. That's consistent with smoked pot's ability to create a temporary sense of well-being. No receptors, no well-being.

More than a decade ago, studies indicated that THC might inhibit the progression of some brain cancers, said Sean McAllister, of the California Pacific Medical Center Research Institute. But test subjects dropped out because THC's psychoactive nature — it can affect mood, behavior and cognition — bothered them so much.

McAllister's group has now found that large amounts of cannabidiol — pot's second most common ingredient — reduce the spread of aggressive breast cancer cells in lab dishes and mice.

Cannabidiol, called CBD for short, is not psychoactive but it also does not trigger any known cannabinoid receptor, leaving scientists to wonder how it works and what organs it might affect.

McAllister is eager to raise $500,000 and take the next step investigating CBD and breast cancer — a small, controlled study in humans. He is already receiving emails from people eager for a cure "and that motivates us,'' he said. "But with clinical trials, it's all guesswork.''

Ryan Roman thinks that if pot can help sick people they shouldn't have to wait on drug companies, the Food and Drug Administration and the rigors of traditional medicine. He has joined the Florida Cannabis Action Network to lobby the Legislature to legalize all medical marijuana.

"That's the one main reason I'm still here.''

Stephen Nohlgren can be reached at [email protected]

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