Decades after psychedelic drugs became popular agents for recreational use and were subsequently made illegal, a select group of researchers is revisiting their therapeutic potential for mental illness.

Psilocybin, the active ingredient in "magic mushrooms," lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), ketamine, mescaline, and other substances have been the subject of recent and ongoing research as potential treatments for psychiatric disorders, including severe depression, addiction, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD), among others, with promising results.

Among the most fascinating aspects of drugs such as psilocybin, LSD, and MDMA is that the potential therapeutic benefits are not the result of taking a daily pill for months or years but rather can come from a single treatment lasting several hours ― yet described by many as being so intensely profound as to be life-changing.

"In one recent study [of psilocybin], conducted at Johns Hopkins in normal volunteers, approximately 3 out of 4 participants described the experience as the single or top 5 most profoundly meaningful experience of their life," said Stephen Ross, MD, director of addiction psychiatry, New York University (NYU) Tisch Hospital, and principal investigator on the NYU Psilocybin Cancer Project.

"It is a tremendously interesting model that a single dose can have therapeutic utility for months. That is a novel development in mental health," he told Medscape Medical News.

Dr. Ross has also been evaluating the effects of psilocybin in cancer patients ― terminal and nonterminal ― with severe existential distress and death anxiety.

For the study, patients received a dose of 0.3 mg/kg of psilocybin. They also were given highly targeted psychotherapy prior to the treatment session and afterwards to help recall and remember the experience and to integrate it with the patients' lives.

Among 32 cancer patients involved in the 9-month phase 2 clinical trial, most have emerged from the approximately 6- to 8-hour therapy session reporting that they had an out-of-body experience.

"The majority of the subjects describe stories of having had symbolic encounters with their cancer, such as visualizing a black cloud of cancer leaving their body, having encounters with transcendental forces, near-death experiences, journeys to earlier parts of their life, journeys into the future or into highly symbolic landscapes," he said.

Common themes described by the patients include a sense of profound calmness and serenity, being in touch with sacred elements, having a sense of universal love, having connectivity between their consciousness and the universe ― having "mystical experiences," Dr. Ross said.

Dr. Stephen Ross

"People will say things like, 'I realize now that the only thing in the universe that matters is love,' and they will feel a heightened awareness of things they need to do and a pressing need to go and make amends with people in their lives."

One patient described having envisioned his own death during the treatment, but not in a manner that involved anxiety or fear.

"[The patient] came from the experience saying, 'I am not scared of death anymore because I have experienced it ― there's nothing more to fear,' " Dr. Ross explained.

"Some of these experiences are kind of hard to conceptualize or understand, but without a doubt, what we have seen is significant clinical improvement with our patients in the aggregate," he added.

None of the patients in the study experienced severe side effects or anxiety, which is consistent with the bulk of clinical studies with psilocybin. Importantly, exclusion criteria for the study included any history or family history of schizophrenia, psychosis, or bipolar disorders.

"There have been 450 doses of psilocybin administered in research settings in the US in the last decade, and there have been 0 serious adverse psychological events," said Dr. Ross. "No one has become psychotic or addicted or needed any medication for anxiety during a session."

Data on the study are still under evaluation, but Dr. Ross noted that the effects of psilocybin in improving patients' depression lasted from several weeks to as long as 1 year.

Continued analysis will determine whether any patient characteristics are associated with improved response, but Dr. Ross said a strong correlation was observed between the intensity of patients' mystical experience and their clinical improvement.

"We are still trying to understand whether it is a biological effect or a more powerful psychological experience, but in looking at 25 of the 32 patients so far, it definitely looks like there is a very significant treatment effect."

What is crucial to psilocybin treatment is that the drug is administered in a highly controlled, calm, and comfortable setting. Dr. Ross said the one downside of the treatment is the concern of its desirability as a recreational drug.

Dr. Ross is one of only 4 researchers in the United States currently using psilocybin in clinical trials. His laboratory has a research license for Schedule I drugs, and he obtains synthetic psilocybin from Organix Inc, of Woburn, Massachusetts, which is also licensed by the federal government to produce the compound.

"It worries me that young people could see this research and say, 'Oh, psilocybin is safe ― I can just go out and do this.' The fact is, this will never be a drug that you can go out and get at the pharmacy and take by yourself," he said.

"It will only be available in a specially licensed center, administered by specially licensed therapists with training and under a lot of supervision to patients who have been very carefully screened. That is the only way it could be clinically administered and feasible, from my perspective."

The NYU laboratory works in tandem with other research teams at the Univeristy of California, Los Angeles (UCLA), and Johns Hopkins University, which has been studying the effects on cancer patients with depression as well as for smoking cessation, and the University of New Mexico, which is studying psilocybin for alcohol dependence.

Although the number of centers are few, these efforts have already pushed psilocybin research well beyond what might be called a "re-emerging" stage, said Dr. Ross.

"Ten years ago, there were only 2 people, and 15 years ago, only 1, so it may still be a tiny group of us who have taken this on, but it is a growing group, and I think the re-emergence of the field has already occurred," he said.

"I think we're in the next phase, where we will soon see a new kind of explosion of research into this, because the applicability therapeutically is incredibly broad."

The Psilocybin Therapy Session To achieve the most productive and positive therapeutic value and to avoid the kinds of negative experiences or "bad trips" that gave psychedelic drugs a bad name, psilocybin or MDMA is administered under the most rigorously controlled conditions ― with lots of preparation beforehand, lots of support during the treatment session, and lots of reinforcement afterward. In researching psilocybin for the treatment of depression in cancer patients at New York University's Psilocybin Cancer Project, the therapy begins weeks before the drug is administered. The patient, under the guidance of a therapist, undergoes a "life review" ― a detailed narrative of the patient's life. The patients also provide a narrative of their cancer and how it has affected them. Even a spiritual history is requested. "A spiritual history is taken because these drugs can induce a spiritual state," said Stephen Ross, MD, director of addiction psychiatry at New York University Tisch Hospital and principal investigator of the project. The drug is administered in a relaxed, comfortable, living room setting, where the patient is attended for the entire session by 2 therapists. Throughout the session, preselected, soothing, inspirational music with no lyrics is played. Prior to taking the psilocybin, there is almost a ritualistic preparation in which the patient stands and states his or her goals for the experience, somewhat consistent with the traditional use of the therapy in indigenous cultures. "The 2 therapists and the patient stand and hold hands, and the patient is asked to state their intention, which is usually something like, 'I want to rid myself of the fear of this cancer,' " said Dr. Ross. As the drug begins to take effect, the patient lies down, is provided with eyeshades, and is asked to focus internally while the 2 therapists sit by the bed to offer any support. The therapists do not offer guided imagery but allow the patients to follow their own chosen intentions. "It is the patient's stated focus that sets the stage for the drug to have a therapeutic effect," Dr. Ross said. The session typically lasts for 2 to 4 hours. When the session ends, patients are asked to recount the experiences they had, and the rest of the day is spent as an extended psychotherapy session. "The patient is still somewhat in an altered state and has greater access to their unconscious material, so we have them sort of free-associate during this time," Dr. Ross said. Patients are sent home at the end of the day and are asked to record as much of the experience as they can remember. They come back the next day for more integrative psychotherapy to help put the experience of the therapy in the context of their life. "We have them write it down, and we go back to the experience again and again. We really want them to imprint the memory." Therapy sessions in the weeks or months following the treatment session continue to reinforce the lessons and insights learned from the psilocybin experience. Dr. Ross reports no relevant financial relationships.

Psilocybin for Addiction

Beginning in 2014, Dr. Ross and his team will collaborate with researchers at the University of New Mexico in a multicenter, double-blind trial examining psilocybin as a potential treatment for alcohol dependence. The trial is funded by the Heffter Research Institute.

Dr. Michael Bogenschutz

This study is based on results from a pilot study conducted by investigators at the University of New Mexico suggesting that the drug may help decrease alcohol consumption in dependent patients.

The pilot study included 10 alcohol-dependent patients who received 2 doses of psilocybin after 4 weekly sessions of motivational enhancement therapy to prepare for the experience and psychosocial treatment before and after the second treatment.

The 12-week study included psilocybin sessions at 4 and 8 weeks. The investigators found no decrease in drinking in the first 4 weeks prior to the psilocybin treatment, but significant decreases in the second and third months following the treatment.

"This suggests that the psilocybin may have had a beneficial effect, but the finding is only suggestive, since there was no control group in this pilot study," said lead investigator Michael P. Bogenschutz, MD, professor and vice-chair for addiction psychiatry and clinical research at the University of New Mexico Health Sciences Center's Department of Psychiatry.

Nevertheless, he added, the results showed important patterns similar to those observed by Dr. Ross's group, including the correlation between the intensity of the experience and the extent of the treatment effect ― in this case, a decrease in craving and an increase in confidence to remain sober at week 5.

"This supports the idea that the subjective experience is important in mediating therapeutic benefit of psilocybin in alcohol dependence," he told Medscape Medical News.

Unconventional, Not Novel

Although the idea of a mystical experience providing measurable therapeutic benefits is somewhat unconventional, it is not novel, Dr. Bogenschutz said.

"We know that people can have sudden and dramatic changes in behavior following singular and intensely meaningful experiences," he said.

Clinical data elucidating the neurochemical basis for the therapeutic benefits of psychedelics such as psilocybin in addiction are lacking, but animal models showing that decreases in serotonin 2A receptor activity are associated with decreases in response to cocaine cues and in impulsivity offer some clues, Dr. Bogenschutz added.

"Psychedelics such as psilocybin act at serotonin 2A receptors and generally downregulate them in the short term. So there is a plausible model for relatively brief antiaddictive effects, but no direct evidence at present."

Whereas longer-term effects of a therapy are generally attributed to neuroplastic changes, the idea of a psychological experience causing such changes in brain structure and function is not unheard of ― as evidenced with PTSD.

"We already have a model for this in PTSD, where a traumatic experience can cause persisting negative changes in the brain," Dr. Bogenschutz said.

"Here we are investigating the possibility that another kind of experience could lead to persisting positive changes in the brain."

MDMA for PTSD

Similarly, MDMA, also known by the street name 'Ecstasy,' is also showing therapeutic promise in PTSD.

Also classified as a Schedule I controlled substance, although not until 1985, the drug has been evaluated as a treatment in highly controlled research settings with several weeks of psychotherapy sessions before and after the the drug is administered.

In what was the first clinical trial to evaluate MDMA as a therapeutic adjunct, researchers found an 83% decrease in PTSD scores in an active treatment group of 12 patients with severe PTSD, compared with a 25% decrease in symptoms scores among in 8 PTSD patients in the placebo group (J Psychopharmacol. 2011;25:439-52).

All patients had previously failed to respond to psychotherapy and/or psychopharmacology; treatment sessions involved an initial dose of MDMA (125 mg) or placebo, given by capsule.

As with Dr. Ross's study, the drug was administered in a comfortable, aesthetically pleasing living room–type setting, and patients closed their eyes or were given nightshades while relaxing.

An optional second dose of 62.5 mg of MDMA or placebo was administered 2 to 2.5 hours after the initial dose if the investigators found it to be safe and the participants agreed to it. In 22 of the 23 sessions, the additional dose was administered.

The sessions lasted 8 to 10 hours, and patients stayed overnight.

Dr. Michael C. Mithoefer

No drug-related adverse events or adverse neurocognitive effects were reported.

A long-term follow-up study of PTSD patients who received MDMA showed that on average, patients maintained improvement in PTSD symptoms, and none reported harm from participation in the study.

Although patients improved after just 1 treatment, the MDMA model may involve subsequent treatments, said lead author Michael C. Mithoefer, MD, a psychiatrist based in Mt. Pleasant, South Carolina.

"We have seen big improvements in Clinician-Administered PTSD Scale (CAPS) scores after 1 treatment with MDMA," he told Medscape Medical News.

"The optimal number of treatments is probably more than 1 for many people, but the main point is the same ― it's not a model of taking a drug every day or chronically, it's a model of just a few doses at monthly intervals to catalyze a therapeutic experience that gets at resolving the problem, rather than a drug that is taken continuously to decrease symptoms."

In terms of the treatment approach, there is a great deal of overlap between MDMA and psilocybin, but MDMA has effects that are different from and in some ways better than other psychedelic drugs, Dr. Mithoefer said.

"I would say that MDMA differs from psilocybin and LSD by not causing hallucinations and being somewhat less likely to be associated with anxiety and strong transpersonal experiences," he said.

Dr. Mithoefer’s research has primarily focused on MDMA's safety and efficacy in PTSD rather than its therapeutic mechanisms, but he noted that neuroimaging studies of normal volunteers who received MDMA have shown decreased activity in the left amygdala and increased activity in the prefrontal cortex as well as other areas.

"This is consistent with what we observe in research sessions, that MDMA appears to decrease levels of anxiety and defensiveness when people are processing trauma, while also decreasing emotional numbing, so that people are in touch with their feelings but not overwhelmed by them."

"This is sometimes referred to as the 'optimal arousal zone' or 'window of tolerance,' in which people are able to process experience effectively without being either overaroused or underaroused."

Dr. Mithoefer's group continues to focus on PTSD, but he noted that other centers, including UCLA and Stanford University, are embarking on the therapeutic potential of MDMA for social anxiety in adults with autism spectrum disorders.

"Based on reports from when MDMA was used legally by therapists before it was placed in Schedule I, there is reason to think it may be useful for other anxiety disorders and couples therapy," he said.

Ketamine for Depression

Recent research has also raised interest in ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, as a treatment for severe depression, and although the effects may not be long-lasting, they do appear to be very fast-acting, providing a rapid, antidepressive effect that can be particularly important for people with suicidal ideation.

The anesthetic has been used recreationally for its psychedelic effects. However, its therapeutic value at lower doses for depression is not in the experience of the effects, as with psilocybin and MDMA. In fact, the hallucinations and dissociation that the drug is known for are seen as potentially adverse effects in the treatment depression.

In a recent study, which was the largest clinical trial to date to evaluate the efficacy of ketamine in depression, the dose was low (0.5 mg/kg), and the psychedelic effects minimal.

The study involved 72 patients with treatment-resistant major depression who were administered either a single 40-minute IV infusion of ketamine (n = 47) or midazolam (0.045 mg/kg) as an active placebo.

The response rate in the ketamine group was 63.8%, compared with 28% in the midazolam arm (P = .006).

"Ketamine is known to cause transient psychoticlike symptoms and dissociation for a brief period while the drug is being administered," lead author James Murrough, MD, told Medscape Medical News at the time.

"In our study, we observed increases in measures of dissociation during the infusion of ketamine, which returned to normal levels within 4 hours of the start of the infusion and in most cases within minutes of the end of the infusion," said Dr. Murrough, who is an assistant professor of psychiatry and neuroscience and associate director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai, in New York City.

"However, we observed very little in the way of psychoticlike effects, probably because the dose we are using is very low."

Only 1 patient experienced the increased blood pressure and heart rate that can occur with ketamine, and the patient was fine after a night of monitoring.

In a further analysis, published in the International Journal of Neuropsychopharmacology, the authors found that patients who had responded to ketamine had significantly higher levels of brain-derived neurotrophic factor (BDNF), a biomarker of treatment response in depression, at 240 minutes, 24 hours, 48 hours, and 78 hours postinfusion.

"These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response," the authors noted.

In addition, a previous study from the same team, also reported by Medscape Medical News, that used the same dose showed improvement in depression lasting more than 2 weeks.

The need for such a fast-acting drug for severely depressed patients who may be in a desperate, suicidal state is pressing, according to the authors of a recent review in Nature Reviews Neuroscience of the potential therapeutic role of ketamine and other psychedelic drugs.

"In particular, patients with depression who are suicidal might benefit from such a rapid and marked effect, as their acute mortality risk is not considerably diminished with conventional antidepressants, owing to their long delay in onset of action (usually 2-3 weeks)," the authors noted.

In addition to its potential role in severe depression, ketamine is currently being tested in the treatment of bipolar disorder, and it has also been evaluated in previous research for treatment of heroin addiction.

In a randomized clinical trial, 70 heroin addicts were treated either with a high dose (2.0 mg/kg) or a low dose of ketamine (0.2 mg/kg). Participants in the high-dose group showed significantly greater abstinence in the 2 years of follow-up, with greater and longer-lasting reduction in craving or heroin use.

Recreational Use Data

Although most researchers echo Dr. Ross's emphasis that psychedelic drugs should only be used therapeutically in well-controlled clinical conditions, recreational use has at least led to some important insights.

A recent review of more than 21,000 psychedelic drug users published in PLoS One in August and reported by Medscape Medical News at that time showed no increased risk for mental health problems relating to the substance use, including "flashbacks," panic attacks, or psychosis.

"We found no relation between lifetime use of psychedelics and any undesirable past year mental health outcomes, including serious psychological distress, mental health treatment (inpatient, outpatient, medication, felt a need but did not receive), or symptoms of panic disorder, major depressive episode, mania, social phobia, generalized anxiety disorder, agoraphobia, posttraumatic stress disorder, or non-affective psychosis," the authors wrote.

They added that the classical serotonergic psychedelic drugs in fact have long been regarded as more benign than most drugs of abuse.

"LSD and psilocybin are consistently ranked in expert assessments as causing less harm to both individual users and society than alcohol, tobacco, and most other common recreational drugs," they wrote.

Stigma, Lack of Research Funds

However, despite such evidence, psychedelic drugs are stigmatized, as indicated by a continued lack of research funding.

A big part of the problem lies in the suggestion that the research of Schedule I drugs somehow contributes to their abuse, said David J. Nutt, MD, of the Centre for Neuropsychopharmacology, Division of Brain Sciences, at Imperial College, in London, United Kingdom.

Dr. David Nutt

"[The argument is] that by using illegal drugs, doctors and researchers are somehow condoning recreational use, which is absurd, since morphine and ketamine are 'legal' drugs that are also abused," he told Medscape Medical News.

Also stigmatizing is the fact that the drugs cause an altered mental state, but again, psychedelics are not the only agents to do so, said Dr. Nutt.

"In part, people are still irrationally scared of 'mind-altering' drugs, even though they happily alter their minds with alcohol."

In an article published in Nature Reviews Neuroscience in June, Dr. Nutt discussed the obstacles that Schedule I drug laws present for neuroscience research into psychedelic agents.

Moving such substances from Schedule I to Schedule II in the United States would improve accessibility for research purposes, he said, but for MDMA and psilocybin, the move may not accomplish much because the 2 agents are also listed on Schedule I of the United Nations 1971 convention.

"Thus, changing their status requires approval by a majority of United Nations Member States, and the United Nations conventions have proved to be extremely resistant to any such changes," Dr. Nutt writes.

In the meantime, Dr. Nutt and colleagues suggested that neuroscience communities could push for greater access to psychedelic drugs for research purposes.

He noted the fact that highly addictive drugs such as heroin and methamphetamine are commonly used in animal research in an effort to better understand the neurologic aspects of addiction and relapse.

If these substances are allowed in the laboratory despite their high potential for addiction, "would it not make sense to encourage research on other psychotropic drugs that have less strong or even no addictive properties?" said Dr. Nutt.

Dr. Ross, Dr. Mithoefer, Dr. Nutt, and Dr. Bogenschutz report no relevant financial relationships. Dr. Bogenschutz has ongoing studies funded by National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the Lundbeck Foundation, and the Heffter Research Institute.