Psychedelic Medicine: Worth the Trip?

Bret S. Stetka, MD; David J. Nutt, MD, FRCP, FRCPsych, FMedSci


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Psychedelic compounds have been used medicinally for millennia. Ancient Chinese, African, and South American healers prescribed them for various primarily psychiatric ailments, as did early Ayurvedic practitioners in India and possibly far older prehistoric cultures. One recent study[1] cites the possible influence of psychedelics on 40,000-year-old Paleolithic cave art. Despite extensive early 20th century interest in hallucinogens as therapy, modern medicine mostly abandoned research into their therapeutic potential, as governments worldwide criminalized agents such as LSD, psilocybin, and mescaline in reaction to their counterculture use in the 1960s. But scattered clinical curiosity over the years and a recent renewed interest in psychedelic treatments have hallucinogens again emerging as possible psychiatric therapies, or at least as pharmacologic leads on related and potentially helpful compounds.

What Are Psychedelics?

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Psychedelics are defined as compounds that alter the mind in ways very different from those of other psychoactive drugs. They can have profound effects on perception, cognition, and self-awareness, without effects on memory, coordination, or alertness. A modern milestone in psychedelic research came in 1938 when LSD was first synthesized by Swiss chemist Albert Hofmann (pictured) in an unsuccessful search for a circulatory and respiratory stimulant. Five years later he revisited the agent, accidently absorbed some through his fingertips, and set out on a lifetime of medicinal psychedelic advocacy, alongside other prominent spokesmen such as Harvard psychologist Timothy Leary. Early on, psychedelic drugs were used as psychotomimetics, as adjuncts to psychotherapies, and were self-administered for various experimental purposes by plenty of curious researchers.

Turn On, Tune In, Turned Off

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Psychedelic research for therapeutic benefit was vigorously pursued in the 1950s and the early 1960s, with over 40,000 patients studied and approximately 1000 papers published. However, as increasing recreational use became associated with the young antiwar and antiestablishment culture of the 1960s, the classic hallucinogens were made illegal by most western governments, rapidly leading to a practically complete halt in medical research that has mostly continued until today.[2]

Enter MDMA
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With LSD off the table, psychedelic researchers and therapists in the late 1960s through the 1980s turned to the empathogen methylenedioxymethamphetamine (MDMA), or ecstasy. In 1985, with the DEA rallying to regulate the compound, a meeting was called, in part by the Esalen Institute in Big Sur, California, to bring together MDMA-experienced clinicians and researchers to evaluate the agent's potential therapeutic role.[3] Study subjects at the gathering took MDMA and were monitored, and the differences between the agent and LSD were discussed. Overall, the efficacy and safety of the drug were reported to be positive. As was shown previously, the most striking reported benefit of MDMA was its apparent ability to allow retrieval of traumatic memories, such as child or sexual abuse encounters, without excessive negative emotions; patients could gain cognitive control over their trauma-related emotions. On May 31, 1985, because of growing recreational popularity, MDMA was classified in the United States as a schedule I controlled substance, a decision subsequently made in all other western countries. As with other, more traditional psychedelics, this meant that MDMA research also largely stopped.

A Psychedelic Renaissance

Research into psychedelic therapy limped on but has recently surged again in the face of a somewhat stagnant psychotropic pipeline and the limited efficacy and long-term side effects of many approved psychiatric medications. Of particular interest is the anesthetic ketamine, used for years in humans and animals as a dissociative anesthetic. The drug has long-established street value and acts as a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist. Now it's being taken seriously in treating addiction and as an acutely effective antidepressant.

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A study published in the Journal of Psychoactive Drugs in 1997[4] found that adding ketamine to established treatments for alcoholism resulted in drastically improved 1-year abstinence rates (66% vs just 24%) in patients who received standard treatment. More recent work has shown ketamine to be a remarkably effective antidepressant. In 2012Medscape reported findings[5] showing the agent to be rapidly effective in treatment-resistant depression. Researchers from the same group this year confirmed ketamine's efficacy in a larger study, reporting in the American Journal of Psychiatry[6] that it improved depression in 64% of patients within 24 hours of administration; by comparison, the anesthetic midazolam only improved symptoms in 28% of patients. Experts, including the study investigators, acknowledge that it is too early to recommend a major change in practice, but these results are encouraging in terms of understanding the biology of depression and representing a potential therapeutic approach worth further study.

Three 2013 studies furthered the understanding of ketamine's therapeutic potential. Findings published in the May issue of the Journal of Psychopharmacology[7] honed ketamine dosing: Serial infusions at lower doses than are commonly used are more effective than single infusions in treating depression symptoms. Other work[8] identified biomarkers that can potentially predict the antidepressant effects of ketamine, while a small study[9] of 15 adults with moderate to severe obsessive-compulsive disorder (OCD) showed a 50% responder rate for OCD symptoms 7 days after receiving a single intravenous ketamine infusion; a 40% responder rate was reported 2 weeks post-treatment.

Magic Mushrooms

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Along with LSD, "magic mushrooms" are a particularly resonant icon of psychedelia, drawing their hallucinogenic effects from psilocybin, a chemical cousin of the neurotransmitter serotonin. Hallucinogenic mushrooms were used religiously and medicinally in numerous ancient cultures. So perhaps it's not surprising that religious, hallucinogen-naive participants in a 2006 study[10] out of Johns Hopkins School of Medicine reported that administration of pure psilocybin resulted in meaningful personal experiences with spiritual significance. Moreover, they reported sustained positive attitude and behavior changes consistent with evaluations by community observers. A follow-up study 2 years later[11] found that at 14 months out, participants considered their psilocybin experience among the most spiritually significant and personally meaningful of their lives. It should be noted that along with effects perceived as positive, psilocybin also produced transient increases in blood pressure and lability in mood, including increased measures of anxiety.

Another 2006 study[12] evaluating psilocybin, published in the Journal of Clinical Psychiatry, was undertaken due to anecdotal reports that hallucinogens relieve the symptoms of OCD. Investigators assessed the safety, tolerability, and efficacy of pure psilocybin in patients with DSM-IV defined OCD. The study was small, with only 9 people enrolled, but the compound was deemed safe and was associated with acute reductions in OCD symptoms which lasted beyond 24 hours. Of note, despite the aforementioned link between psilocybin and anxiety in some people, work published in the Archives of General Psychiatry in 2011[13] found the agent to be safe in treating patient with advanced cancer and anxiety with some data suggesting improvements in mood and anxiety.

MDMA Returns

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Recreational MDMA use exploded with nightclub and rave culture in the 1980s and '90s, leading to its criminalization and slowing most medical research on the compound. A 2010 study, though, followed up on 1980s work on MDMA's potential benefits in post-traumatic stress disorder (PTSD).[14] Twenty patients with chronic PTSD refractory to both psycho- and pharmacotherapy were randomly assigned to receive psychotherapy plus either MDMA therapy or placebo. The treatment group showed significantly greater reductions in PTSD Scale scores, with no serious adverse events reported. It is important to note that the MDMA group received only 2 doses of the drug, about 3 weeks apart, each in an in-depth psychotherapy session in which the traumas were re-encountered and overcome. This effect was enduring, and most of the patients who entered remission were well for many years; none experienced any significant adverse effects. Recent fMRI research has revealed that MDMA does indeed reduce brain activation to negative memories in regions such as the insula.[15]

A Miracle Cure for Withdrawal?

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The newly controversial drug ibogaine, the subject of a number of recent press investigations, is reportedly able to stave off withdrawal from alcohol, opioids, and cocaine. The problem is that it comes with an intensely dissociated, hallucination-filled "trip." The compound is found in multiple plants, including the rainforest shrubTabernanthe iboga, and has been used in African spiritual ceremonies for centuries. It caught the interest of 19th century French and Belgian explorers, who brought it back to Europe where it was ultimately isolated and synthesized. The CIA studied ibogaine in the 1950s, and soon after it was promoted by American researcher and reformed heroin addict Howard Lotsof for its antiaddictive properties. However, the agent proved too potent to be embraced by and approved of by most medical communities. In the late '60s, the World Health Assembly deemed ibogaine likely to cause dependence and threaten human health, while the FDA slapped it with a schedule I classification.

With ibogaine banned for recreational use in the United States and in many countries abroad, research into the agent stalled. But scattered studies over the years demonstrated its antiaddictive properties. A 1998 study[16] established the safety of the drug for treating cocaine dependency, while subsequent work[17] supports its efficacy at reducing symptoms of opioid withdrawal. Although not yet subject to traditional double-blind trials, many centers now use ibogaine as part of a psychotherapeutic regimen for addiction withdrawal and therapy. In recent years it has become a legal medication in New Zealand. The psychedelic component of ibogaine is concerning to some authorities, so attempts are being made to find a nonpsychedelic alternative, with current emphasis on noribogaine.

One of the most noteworthy newer studies on the potential of psychedelics as therapy was published this year in PLoS One.[18] Researchers from Norway looked at over 21,000 adult psychedelic drug users and found no significant link between the use of LSD, psilocybin, mescaline, or peyote and risk for mental illness. In fact, use of these drugs was associated with a lower rate of psychiatric illness. This suggests that, at the very least, these drugs do not contribute to mental illness, calling into question their illegal status and providing some support for the results of earlier therapeutic trials.

Another recent study supports psilocybin as a potential tool to enhance recall of important memories of potential personal and clinical benefit, while a 2012 meta-analysis looking at older studies suggests that LSD may be helpful in treating alcohol misuse.[19,20] No recent data exist on this approach, however. Citing addiction as one of our biggest public health issues, researchers from the University of New Mexico reviewed the evidence on the therapeutic potential of hallucinogens, concluding that, "...existing evidence provides a convincing rationale for further research on the effects of classic hallucinogens in the treatment of addiction."[21]

Drawbacks and Future Role

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Psychedelics, with profound effects on the brain, are intriguing drugs with major therapeutic potential. Treatment options are currently hard to explore because of legal restraints on most of these drugs, which is disproportionate to their actual harms (which in most cases are less than those of alcohol).[2] It is possible that these potential benefits one day may be realized, but like all drugs, psychedelics have adverse effects that need to be understood and prevented. Some people can experience "bad trips" from psychedelics, and ketamine can lead to bladder damage. Occasionally MDMA can lead to an allergic hepatitis. The production and supply of safer versions of these agents should help reduce these risks.