Hallucinogenic mushroom Psilocybe Cubensis, variation Ecuador. (Photo: afgooey74)More than 35 years ago, the United States Food and Drug Administration (FDA), along with similar agencies around the world, imposed a crushing stranglehold on legitimate research with psychedelic drugs. The move was rationalized as an appropriate response to irresponsible pseudoscientists such as Timothy Leary who spawned a counterculture in which a whole generation of young people left their brains behind them in the 1960s and early 70s. Now, almost four decades later, drug regulatory agencies are beginning to allow research with lysergic acid diethylamide (LSD), psilocybin, 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), and other mood- and consciousness-altering drugs as evidence accrues of their therapeutic efficacy.

To first approximation, the terms “psychedelic” and “hallucinogen” mean roughly the same thing. They may affect perception and cognitive (thinking) processes – and, of course, they produce hallucinations: auditory, visual or both. The hallucinogens are among the most powerful drugs on earth: a minute drop of LSD on a sugar cube can exert a profound effect on a person’s existential sense of consciousness.

In the 1950s and 60s, there was a great deal of psychiatric research with LSD. Psychiatrists thought they had a “model” for producing the symptoms of schizophrenia. Unfortunately, they were wrong: LSD primarily produces visual hallucinations, while schizophrenics mainly hear voices. Nevertheless, many psychiatrists had interesting experiences trying LSD on themselves. But if the LSD/schizophrenia connection was a bust, some psychiatrists pursued another line of research that may prove to be relevant today. Before the FDA closed the gates, a number of psychiatrists had conducted small-scale studies which found that LSD is effective for treating end-of-life anxiety and depression in cancer and other sufferers. That’s why physicians are watching a small, American-sponsored study that’s being conducted by Peter Gasser, a medical doctor in Switzerland.

The anxiety associated with the fear of dying is notoriously treatment resistant to conventional medications like Valium. The Multidisciplinary Association for Psychedelic Studies, an American organization known by the acronym MAPS, is sponsoring a study by Dr. Gasser into the efficacy of LSD for treating end-of-life anxiety in conjunction with psychotherapy, using audio and visual recording of the interviews with patients. Gasser’s goal is to replicate those decades-old studies, using modern techniques of psychiatric evaluation. Though the study comprises only 20 dying subjects, it will make a major contribution if the outcome is successful, because it will spur larger, definitive LSD studies.

LSD was discovered in 1943 by the Swiss chemist Dr. Albert Hofmann, who experienced hallucinations while conducting experiments with fungi. Psilocybin, another powerful hallucinogen, was used for centuries by American Indian tribes as part of their religious rituals. It was ingested by eating certain species of wild mushrooms, but today the active ingredient has been extracted and purified. Psilocybin does not pack the punch of LSD, but it is nothing to be sneezed at and is currently being used in psychiatric research. It produces changes in mood and perception more prominently than hallucinations. The two psychedelics are thought to affect the brain serotonin system, though the mechanism of action remains to be worked out. Serotonin is one of the major brain chemicals, along with noradrenaline, dopamine and others that facilitate the transmission of nervous impulses. LSD and psilocybin may enhance our understanding of the way serotonin works and may prove to be useful therapeutic agents in psychiatry and neurology.

One psychiatric illness that is probably mediated by serotonin – although we don’t know how – is obsessive-compulsive disorder (OCD), a seriously disabling condition marked by repetitive thoughts and rituals such as repeated hand-washing. People with OCD may spend hours on end washing their hands, and, unfortunately, the available drugs for treating OCD leave much to be desired. One such drug is clomipramine (Anafranil), a tricyclic antidepressant which raises the concentration of serotonin in the brain. The others are known as specific serotonin reuptake inhibitors (SSRIs) and include such drugs as Zoloft and Prozac. Though they elevate the brain serotonin concentration, the mechanism of action is not that simple; one theory is that these drugs enhance the sensitivity of serotonin receptors. LSD and psilocybin may work the same way, but with greater effectiveness. There are now a number of small-scale studies on the topic on the Internet, all of which show that psilocybin is much more effective than conventional drugs for treating OCD. Several psychiatrists with whom I spoke* are hopeful that the FDA will eventually approve psilocybin for OCD.

Psilocybin, like LSD, has been found to be effective for treating anxiety in patients with advanced-stage cancer and for cluster headache (1), an excruciating headache that is localized around the eyeball or one side of the head, so there is indeed hope that psilocybin may find its way into the American pharmacopoeia. One cannot write with the same degree of hopefulness about MDMA unless it shows remarkable promise.

It may yet do exactly that.

MDMA is a synthetic psychotropic related to methamphetamine (or “crystal” in drug-abusing circles). But while the parent compound is a stimulant, MDMA is a powerful anti-anxiety agent. This impact is attributed to its serotonergic properties. What is more, while stimulants tend to evoke hostility, MDMA is a “socializing” drug, which is attributed to its effect on the oxytocin (“love drug”) neurotransmitter in the brain.

Dr. Michael Mithoefer, a South Carolina psychiatrist in private practice, is studying MDMA for the treatment of post-traumatic stress disorder (PTSD). The core element of PTSD is fear, and Mithoefer’s idea is to block fear with MDMA, then gradually expose the patient to the frightening stimulus. Recently, the soft-spoken Southerner, working with a technician, but no academic affiliation, published the results on his pilot study of ten patients (2), and he showed that MDMA is dramatically effective. Mithoefer told me that he is about to begin a larger study comprising exclusively veterans with PTSD. If the second study is as impressive as his pilot study, Mithoefer’s research may change some minds about MDMA because there is no effective drug currently available for PTSD.

Dr. Charles Grob, a professor of psychiatry at UCLA and one of the leading American researchers in psychedelic drugs, finds Mithoefer’s initial work very encouraging, and explained to me why MDMA is so controversial. Back in the 1980s and 90s, MDMA was very fashionable in the sex-club scene. However, the party was tainted by deaths that medical examiner reports found were caused by overheating in hot tubs, but for which MDMA took the rap. The clubs were padlocked and the FDA banned MDMA. Worse yet, there is an ongoing controversy regarding whether MDMA causes brain damage. All of this is complicated by the fact that ecstasy is seldom pure MDMA, but rather a mixture of an amphetamine, cocaine, aspirin and impurities from the synthetic process, so it’s difficult to know what’s doing the damage. However, animal experiments using pure MDMA suggest that the substance causes degeneration of brain cells. This may not be applicable to the clinical situation in studies such as Mithoefer’s, where the patients receive only two doses of MDMA spaced a week apart, while the animals are exposed chronically.

Not every drug with psychedelic properties is illegal. The most prominent example is ketamine, which is used to anesthetize animals and, less frequently these days, human beings. Ketamine, which is chemically and pharmacologically related to phencyclidine (a k a “angel dust”) is a “dissociative” anesthetic. It does not knock you out; instead, it scrambles your brains so that you do not experience painful stimuli. Ketamine also differs from conventional anesthetics in that it supports, rather than depresses, breathing and blood pressure, making it a safer agent. It also excites rather than sedates, and has hallucinatory properties. It is a favorite spree drug among anesthesiologists and veterinarians.

Ketamine is administered intravenously. A number of small-scale studies (3) have found that one ketamine infusion has lasting antidepressant properties. Ketamine is sometimes used to anesthetize people undergoing electric shock for the treatment of their depression.(4) In one imaginative experiment (5), the clinicians compared depression scores for patients who were anesthetized with ketamine or propofol, a conventional anesthetic like barbiturates, halothane and others. It proved possible to improve symptoms of depression earlier by using ketamine.

There is a common denominator to the drugs discussed in this article, and for others for which space does not permit, or which are “me too” drugs. The psychedelics require only a couple of doses to bring about a lasting psychological effect, such as relief of end-of-life anxiety or PTSD. This is in sharp contrast to conventional psychiatric drugs – anxiolytics, antidepressants, antipsychotics – which must be administered at least once a day. How can psychedelics exert an effect that persists for months? One theory is that these agents bring about a spiritual, transcendent change in the personality. Investigators at Johns Hopkins University have been studying this rigorously and found just such a lasting psychological change. However, it is less clear whether such a change in spirituality is responsible for, say, relief from OCD. What is more, asserting that the drugs cause a psychological change only restates the problem: we still do not know what changes a person’s psychodynamic structure on the biological level.

A new wave of research into psychedelic drugs began recently. So far, there have been several important implications for the treatment of PTSD, OCD, and end-of-life anxiety and depression. One important fact is clear: these drugs work differently from conventional psychotropic agents. Why they work the way they work remains to be discovered.

*including Roland R. Griffiths, PhD, Johns Hopkins; Charles S. Grob, MD, UCLA and Michael C. Mithoefer, MD, (private practice) Mount Pleasant, South Carolina.

1. Delgado PL, Moreno FA. Hallucinogens, serotonin and obsessive-compulsive disorder. J Psychoactive Drugs 1998;30(4):359-366 and Sewell AR, Halpern JH, Pope HC. Response of cluster headaches to psilocybin and LSD. Neurology June 27, 2007; 66(12):1920-1922.

2. Mithoefer, J Pharmacol 2011 25:439-452.

3. For example, Berman RM, Cappiello A, Anand A et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, February 15, 2000; 47(4):351-4.

4. Rasmussen KG, Jarvis MR, Zorumski CF. Ketamine anesthesia in electroconvulsive therapy. Convulsive Therapy, 1996; 12(4):217-23.

5. Okamoto N, Nakai T, Sakamoto K et al. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. Journal of ECT, September 2010; 26(3):223-227.