How Brain Science Began

Civilization’s debt to opium.

The history of brain science probably began about 4,000 B.C., somewhere in Sumeria, when human beings first discovered the extraordinary effects of the unripened seed pods of the poppy plant. Modern neuroscience owes a great debt of gratitude to this tame-looking plant drug and its sticky, incredibly potent byproduct called opium. Neuropharmacology—the study of the action of drugs on the nervous system—would never have advanced so quickly without it.

Historically, the emphasis has been on opium’s cash value, not its value to science. A trade staple on the Silk Route for centuries, opium was very nearly the perfect business. The present-day drug companies, known collectively as Big Pharma, are not the first capitalists in the world to exert an unprecedented grip on drug retailing.

From roughly 1720 to the late 1800s, the merchants of the British East India Company ran a brisk and lucrative opium business with the Oriental “heathens.” In 1839, the British went to war with China to maintain unlimited trading rights. The British won the war, retained the right to market opium in the Orient, and picked up the island of Hong Kong in the bargain.

Opium’s effects are concentrated at specific receptor sites, while alcohol’s range of action is more diffuse. Nonetheless, the two drugs have similar effects along the limbic reward pathway. Morphine comes right from the source, isolated from the crude opium resin found on Papaver somniferum—the opium poppy. Morphine is known as a “pure mu agonist,” meaning it locks securely into the “mu” subset of endorphin receptors, and activates them. This alters the transmission of pain messages, and induces a contented, euphoric state of relaxation. Codeine, another natural painkiller, is found in opium in very small concentrations. Most medical codeine is synthesized from morphine.

The body’s own opiates are referred to as endogenous opioids. Endorphins and enkephalins are interchangeable terms for these chains of amino acids. An important mechanism of action in this process is morphine’s inhibitive effect on GABA. By inhibiting the inhibitor, so to speak, neurotransmitter levels increase down the line, particularly in the nucleus accumbens. Hence, feelings of pleasure.

Alcohol stimulates the mu receptor as well, so we are back to the same basic chain of limbic activation triggered by drinking. GABA is the bridge that connects the alcohol high and the heroin high.

Rapid cellular tolerance is the hallmark of opiate addiction. Brain cells quickly become less responsive to the same doses of the drug. “The body’s natural enkephalins are not addicting because they are destroyed rapidly by peptide-degrading enzymes as soon as they act at opiate receptors,” writes Solomon Snyder. “Therefore, they are never in contact with receptors long enough to promote tolerance…. As analgesics, the enkephalin derivatives developed by drug companies have not been superior to morphine, or even as good as morphine.” Even the brain’s own morphine is not as good as morphine. Nothing is as good as morphine.

Recent evidence for the heritability of opiate addiction looks strong. “Harvard did some really superb studies using a huge cohort of military recruits in the U.S. Army,” according to Mary Jeanne Kreek, a specialist in opiate addiction at Rockefeller University in New York. “Heroin addiction has even a larger heritable component than any of the other addictions, so that up to 54% of heroin addictions seem to be on a genetic basis or a heritable basis.” Estimates of alcohol’s heritability generally run to 40 or 50 per cent.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction. (Spring 2009).

Salvia: The Mystery Drug

Tripping with the kappa opiate receptor.

Over the past few years, a little known and highly unusual psychedelic drug has claimed the interest of drug users and drug scientists alike. Salvia divinorum, a green, leafy plant native to the Mazateca region of Mexico, provides its users with a short but intense hallucinogenic experience. A member of the mint family, it is not among the ornamental garden plants sold under the name Salvia at local nurseries.

The high is unlike that from LSD or psychedelic mushrooms, users say, nor is it anything like the experience of smoking marijuana. Salvia is not currently controlled by federal law, but dozens of states have moved to outlaw cultivation and sale of the plant, which is currently freely available for purchase on the Internet.

As an herb with psychedelic properties, Salvia divinorum is of pharmaceutical interest because of its uncommon affinity for opium/endorphin receptors—specifically the kappa opioid receptor. Most drugs with classical “psychotomimetic” properties, like LSD and MDMA, are highly selective for the 5-HT(2A) serotonin receptor.

Salvia is not one of these. Like ibogaine, another hallucinogenic shrub with a weak affinity for kappa opiate receptors, Salvia’s active ingredient--Salvinorin A--causes psychoactive effects not usually associated with stimulation of the brain’s internal opioid system. Previous research had identified a few such compounds, such as enadoline, which produced similar hallucinogenic effects.

The pharmaceutical industry has already taken a look at the kappa-opioid agonists in the ongoing search for new painkillers, and has so far discovered the usual psychedelic trap of too many unpredictable side effects for a commercial medication.

Classified as an “atypical” psychedelic, the salvia high is intense, dream-like, and short-lived, tapering off after about 30 minutes. An ounce of salvia in leaf form sells for as little as $40, but more concentrated liquid extracts sell for as much as $60 per gram.

Salvia’s addictive potential is low to nonexistent. No hallucinogen such as LSD or peyote has ever been found to be addictive in the classical sense.

Nonetheless, fearing that the inexpensive plant might become “the next marijuana,” as an Associated Press report put it last month, 24 states have passed, or are considering, legislation to restrict access to salvia. Elsewhere, sale of the drug has been restricted in Spain, Italy, Sweden, Belgium, Australia, and other countries. In the AP article, a Florida state legislator alleged—with unintended irony: “As soon as we make one drug illegal, kids start looking around for other drugs they can buy legally. This is just the next one.”

There are many reasons why Salvia divinorum is not likely to be “the next one.” According to drug expert Rick Doblin of the Multidisciplinary Association for Psychedelic Studies (MAPS), salvia “tastes terrible” and is “not going to be extremely popular.” The popular drug information site EROWID describes salvia as “more scary than fun” for many users, concluding that, whether smoked or swallowed, the plant is “aversive for many who try it.” Like ibogaine, salvia is no party drug. It can result in confusion, dizziness, depersonalization, and all the other hallmarks of a “bad trip.”

A related question is the extent to which kappa opioid receptor boosters might reduce the craving for addictive drugs. Ibogaine has been touted for having precisely this effect on heroin addicts and others. However, an early study of kappa opioid receptor-active compounds did not find any reduction in self-administration of cocaine.

The National Institute of Drug Abuse (NIDA) is studying salvia. The Drug Enforcement Administration (DEA), citing salvia as a “drug of concern,” is evaluating it.

Photo Credit: http://www.salvia-divinorum-extract-now.com/