Psychedelics Back in the Spotlight

But will it be any different this time?

Two papers on the use of psychedelics for the treatment of mood disorders surfaced last week in the prestigious journals Science and Nature. The articles have garnered a great deal of publicity, especially the results having to do with the effect of ketamine on depression. I cannot pretend to offer more insightful coverage than the posts and articles listed below have already done, but I do think it’s profitable to take a closer look at the Nature piece by Franz X. Vollenweider and Michael Kometer. This paper looked at both dissociative anesthetics, like PCP and ketamine, AND “classical hallucinogens,” like psilocybin and LSD.

Traditionally, LSD has been thought of as a relentlessly serotonin-active drug, while ketamine was more actively involved with NMDA and other glutamate receptors. There is accumulating evidence, the researchers believe, that a common mechanism undergirds the operations of both kinds of psychedelics. “Despite their different primary modes of action,” they write, “classical hallucinogens and dissociative anesthetics both modulate glutamatergic neurotransmission in the prefrontal-limbic circuitry that is implicated in the pathophysiology of mood disorders.”

It’s worth noting that Vollenweider and Kometer maintain that almost all depressed patients relapse within two weeks after a single dose of ketamine. In studies of patients with advanced cancer, say the authors, psilocybin improves mood just as effectively, and lasts longer, than ketamine.

While there are significant differences between the subjective effects of ketamine and LSD, there is also “a set of overlapping psychological experiences.” The two trips are different, but not completely different—they share effects such as distortion of perception, visual and auditory hallucinations, a sense that the boundaries of self have softened, and often an ecstatic experience or sense of profound unity. The serotonin-glutamate connection leads the authors to assert that “classical hallucinogens are potent modulators of prefrontal network activity that involves a complex interaction between the serotonin and glutamate systems in prefrontal circuits.”

Alternately, these drugs can trigger a classic “bad trip” in certain users--time, place, circumstance, and innate biology depending.  As the authors put it: “The same hallucinogen might produce a pleasurable loss of ego boundaries combined with feelings of oneness or might lead to a more psychotic ego dissolution that involves fear and paranoid ideation.”

And there you have it: In the case of psychedelics, there are certain extenuating factors which may forever limit the use of these substances for therapeutic purposes. The primary problem is that the drugs are clinically unreliable. With psychedelics, it is always, in a sense, the Lady or the Tiger.  “The strongly dissociative effects of ketamine may limit clinical use despite its reported efficacy,” the researchers conclude. Which is, I think, putting it mildly--and which brings the authors to suggest that pharmacology-assisted psychotherapy might require some tweaks.

Specifically, the hunt is now on for psychedelics that are, well, less psychedelic. In the same way that pharmacologists seek to dial down the euphoric effects of pain medication to lessen the chances for black market abuse, researchers are now looking for ways to tone down the mental fireworks often associated with the use of ketamine, LSD, or psilocybin, on the assumption that these represent nothing but unwanted side effects, rather than the core of the experience that alleviates depression, OCD, and addiction—at least for awhile. These drugs are among the most powerful mind-altering compounds on the planet. So good luck with that project. Studying the behavioral effects of these drugs in the first place is a bit like trying to pin down a writhing fire hose with a pair of tweezers.

Curing or successfully treating chronic ailments like depression and addiction with a power psychoactive medication is both an old and an exciting idea. The Nature opinion piece also documents studies, beginning in the 1960s, which showed that psilocybin and LSD were effective treatments for Obsessive-Compulsive Disorder (OCD).  Other studies have shown alleged successes using low-dose ketamine for heroin addiction. And some of the earliest LSD studies of all showed impressive results when LSD and psychotherapy were combined as a treatment for alcoholism.

 By 1965, the authors claim, there were more than 1,000 published clinical studies on the therapeutic effects of psychedelics.  But many, if not most, of the early studies were marred by procedural problems, lack of control groups, and the fact that researchers from a dozen different disciplines, representing a dozen different experimental methods, predictably emphasized different kinds of experiential results.  The authors suggest that novel neuroimaging techniques combined with an increased understanding of molecular mechanisms of action mean that it will be different this time. If the only real result of the ketamine studies is increased funding for research on psychedelic drugs after a long hiatus, that is still progress, and it’s long overdue.

Resources

David Biello, Scientific American

Maia Szalavitz, New Scientist

and MSN Health and Fitness

Scicurious at Neurotic Physiology

Neuroskeptic at Neuroskeptic

Eugene Rubin, Psychology Today

Jonah Lehrer at Frontal Cortex

Photo Credit: http://cherished79.wordpress.com/

Some Background on the Psychedelic Renaissance

Ecstasy, MAPS, and Post-Traumatic Stress Disorder.

The psychedelic drugs, new and old, are not only among the most powerful ever discovered, but are also tremendously difficult to study and utilize responsibly. By the mid-1990s, rumors about Ecstasy (MDMA) toxicity were everywhere. Unlike Prozac, but very much like LSD, Ecstasy not only blocks serotonin uptake, but also causes the release of additional serotonin, much the way cocaine and amphetamine cause the release of extra dopamine.

A study conducted by neurologist George Ricaurte at John Hopkins University under NIDA sponsorship seemed to show conclusive evidence of neurotoxic damage to the serotonin 5-HT receptors in the brains of monkeys given large doses of MDMA. A follow-up study of 30 MDMA users (existing users, since researchers didn’t have government permission to give MDMA to test subjects) showed 30 per cent less cerebrospinal serotonin, compared to a control group. However, the Johns Hopkins team did not have any baseline measurements for the MDMA users, and other neurologists raised technical objections about various aspects of the study, including dosage levels. As was often the case in such studies, the monkeys had been given a whopping dose, compared to the typical raver’s dose. Ricaurte insisted that the amount of MDMA consumed by a typical user in one night of raving was possibly enough to cause permanent brain damage. The government estimates that 10 million Americans have taken Ecstasy.

That would seem to be the end of the story, and a sobering lesson for today’s youth—but that is not how it turned out. A few years later, Dr. Charles Grob, psychiatry professor at the UCLA School of Medicine, received the first FDA approval ever given for the administration of MDMA to human volunteers. The result of Grob’s testing was that none of the volunteers showed any evidence of neuropsychological damage of any kind. In testimony before the U.S. Sentencing Commission, which was considering harsher penalties for MDMA possession in 2001, Dr. Grob seriously questioned the methodology of the Ricaurte studies: “It is very unfortunate that the lavishly funded NIDA-promoted position on so-called MDMA neurotoxicity has inhibited alternative research models which would better delineate the true range of effects of MDMA, including its potential application as a therapeutic medicine.” Science retracted its coverage of the Ricaurte findings.

It was eventually discovered that Dr. Ricaurte’s monkeys had been injected with amphetamine, not with MDMA—a discovery that also nullified four other published papers. Dr. Ricaurte explained that some labels had been switched, and a Johns Hopkins spokesperson called the whole thing “an honest mistake.” The basic questions about Ecstasy remain unanswered. Is there a line that separates a conceivably therapeutic dose of Ecstasy for mental ills or addictive ills from a possibly brain-damaging run of several dozen high-dosage trips? Perhaps the permanently altered receptor arrays, if they exist, don’t affect cognition or emotions in any significant way over the long run. Still, the risks of overindulgence appear to be at least potentially higher than the risks of overindulging in LSD or Ibogaine. All of the psychedelics tend to be more self-limiting than other categories of psychoactive drugs, anyway. After two or three days, even the most die-hard raver or LSD head is usually ready to take a break.

Rick Doblin and others at  the Multidisciplinary Association for Psychedelic Studies (MAPS) are now working with government investigators to pursue MDMA for the treatment of post-traumatic stress disorder. There are reports that very low doses of LSD sometimes have an antidepressant effect. One thing we know for certain is that people on SSRI medications or MAO inhibitors report that their experiences on LSD or Ecstasy are shorter and far less powerful than is typically the case.  There appears to be some competition for receptor sites when Zoloft meets LSD. In contrast to the diminished psychedelic experience while on SSRIs, the older norepinephrine-active tricyclics like Tofranil and Norpramine reportedly serve to potentiate the LSD or MDMA experience. None of these combinations is a wise idea, due to uncertainties about the interactions.

Even DMT, which experienced trippers compared to being shot out of a cannon, has returned as a legitimate study subject. Dr. Rick Strassman, then with the University of New Mexico’s School of Medicine, received approval for clinical testing of DMT. Strassman was drawn to the subject because of the molecule’s natural occurrence in the brain (which makes every man, woman, and child in America a drug criminal, chemically speaking). He gave DMT to 60 human volunteers over a study period of five years. Strassman was primarily interested in near-death experiences and mystical experiences. None of the supervised DMT sessions evidently resulted in any detectable harm to the participants. Strassman presents his views on the medical use of DMT in his book, DMT: The Spirit Molecule.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008, 2009.

Graphics Credit: http://hightimes.com/

Three Drug-Related Posts (Good Ones)

And a plea for your vote.

The DrugMonkey blog, written by an anonymous NIH-funded biomedical researcher,  takes on the question of why doctors dislike narcotics abusers but tolerate drinkers and smokers, and investigates whether there is something about opiates that “turns you into a jerk" in a post titled “Does one drug cause the user to be more annoying?”

Also at DrugMonkey this month, “UK Bans Mephedrone” is  a succinct summation of the dizzy panic going on in the UK over a new party drug that has similarities to the African drug khat. Did Britain institute a hasty and ill-considered ban on the substance based on political rather than scientific concerns?

Over at the Neuroskeptic blog, a British neuroscientist presents some intelligent background to the renewed interest in psychedelic research in his post, “Serotonin, Hallucinations & Psychosis.”

And lastly--although this couldn't possibly be any more off topic--my favorite tourist village--Ely, Minnesota--is currently leading the contest for "American's Coolest Small Town" at Budget Travel magazine's online site HERE.

If you are at all familiar with Ely (Gateway to the Boundary Waters Canoe Area Wilderness, Land of Sky Blue Waters, Canoe Capital of America, Summer Home to Ten Thousand Paddling Boy Scouts) vote early and vote often! Contest closes May 9.

Photo Credit: http://www.aglabs.com/