The increasing social and economic burden of depressive disorders and the significant percentage of patients with treatment-resistant depression together highlight the need to explore more therapeutic options — including psychedelics, argues a new paper.
Unipolar mood disorders are on track to become the second leading cause of disability worldwide by 2020, and up to a third of patients do not achieve remission, according to some research. That reality, combined with the reticence of pharmaceutical companies to invest in further development of mental health therapeutics, underscores the importance of not dismissing any reasonable avenue of research — particularly with low-toxicity substances and that do not require chronic use, as with psychedelics, suggest James Rucker, MD, MRCPsych, PhD, of the King’s College London Institute of Psychiatry in the UK and his colleagues.
“Psychedelics deserve to be investigated in modern, controlled trials if we are to know whether they are useful treatments in psychiatry, or not,” Rucker said. “At the moment there isn’t enough high quality evidence to make that judgment.”
Past Studies Lack Strong Methodology
Rucker’s team reviewed the existing research in psychedelics for mood disorders, which, though dated, hints at the possibility of therapeutic use. A systematic search of PsychINFO and MEDLINE databases for studies from 1940 through 2000 yielded 21 studies, published between 1949 and 1973 and involving a total of 423 patients. Most of the studies included a dozen or fewer participants — sample sizes ranged from 5 to 77 — and only 4 used control groups (only one of which was adequately selected and described). Patients were frequently described as “depressives,” or having “depressive neuroses,” “psychoneuroses,” or “depressive reaction neuroses,” making it difficult to distinguish between depression and anxiety in the study patients.
Lysergic acid diethylamide (LSD) was the most commonly tested substance, but several studies explored mescaline, often in conjunction with LSD. None explored psilocybin, the psychoactive substance in some mushroom species, perhaps because it was not isolated until 1959, when LSD was already widely in research use.
There were 2 main types of studies: the psycholytic approach of periodic low-dose psychedelic use combined with psychotherapy and the psychedelic approach of a large dose administered in a single session, typically in a group or with a psychiatrist as a “companion” during the experience. Doses of LSD ranged from 20 to 1500 micrograms and mescaline doses ranged from 200 to 400 mg.
Most of the studies looked at inpatients, but a handful investigated outpatient use. Nearly all the studies found clinical benefit, often with quite large effect sizes in the range of 70% to 90% of patients showing “improvement,” although that improvement was poorly defined and purely subjective.
“Similarly, the trial participants are probably quite a self-selecting group, who probably also believe in psychedelics’ power to heal more than most,” Rucker said. Further, “all trials using drugs that have a psychoactive effect are confounded by the fact that people can tell whether they are on the drug,” Rucker added. “They are then essentially unblinded and all their expectations and preconceptions then come into play. It’s hard to get around this.”
In addition to the vague outcome measures and lack of controls, other significant shortcomings of the studies included the use of anecdotal evidence, inadequate assessment procedures, insufficient follow-up, and naïve statistical treatment. None of these limitations suggest that psychedelics have no place in psychiatry but rather establish why it’s important to conduct new, rigorous studies that explore their potential.
“Many in the clinical community would welcome research into any new, safe treatments for mood disorders,” said Michael V. Genovese, MD, JD, former chief medical officer at Sierra Tucson in Arizona and currently chief medical advisor of the Acadia Healthcare Recovery Division in Tucson, Arizona. Genovese was not involved in this study but agrees that the lack of research precludes the ability to draw any conclusions one way or another about psychedelics’ potential utility in psychiatry.
“Even with all of our current treatment modalities major depressive disorder remains the number one cause of disability in the United States,” Genovese said. “That’s reflective of the need to explore new and better treatment options.”
Research Needed to Elucidate Mechanisms, Ideal Patients
One particularly pressing reason for research into psychedelics is the lack of research into other therapeutics.
“In psychiatry we don’t have much of an understanding of the biological basis of what we are treating, so developing drugs is similar to trying to play darts in the dark when you don’t know where the target is,” Rucker said. “The antidepressants and antipsychotics represented the ‘low hanging fruit’ I expect. Until we have some sort of new biological hypothesis to aim at in different psychiatric disorders, I doubt big pharma is going to be interested.”
Companies are unlikely to show interest in psychedelics either because they aren’t patentable and are taken in single rather than repeated doses, removing financial motives for development.
The potentially beneficial mechanisms of LSD and other psychedelics remains similarly mysterious without further investigation. Although both LSD and psilocybin stimulate the 5-HT2a receptor, thereby causing the core psychedelic effect, LSD lasts longer and is more potent than psilocybin, Rucker explained.
“One of the primary goals of clinical research would be to determine the precise mechanism by which these compounds effectuate benefit,” Genovese said. “Once we understand the specific mechanism of action then we can look at similar compounds, metabolites, or isomers that render therapeutic benefits and minimize or eliminate adverse effects.”
In one study reviewed, the researchers “suggest that its therapeutic effect is in part due to the reliving of early experiences and release of repressed feelings.” Rucker added that a group at Johns Hopkins University in Baltimore has published research linking “long-lasting beneficial change with the degree of mystical/spiritual experience under the drug.”
That jibes well with the less structured older studies in which a psychiatrist provided more emotional support than formal psychotherapy during a patient’s psychedelic experience.
“This state may be linked to emotionally profound shifts in perspective on an individual’s life and relationships with self and others,” Rucker surmised. “At the biological level the psychedelics seem to ‘deconstrain’ patterns of neural activity: bits of the brain that do not usually communicate with each other appear to do so under the influence of psychedelics.”
This “clinically fascinating observation” leads Rucker to wonder whether psychedelics might “in the right set and setting, help people ‘change their minds,’ or their ‘perspectives,’ on all sorts of things.”
Further, determining who might benefit from these treatments is further reason to conduct studies. “Our mind first goes to those who may have failed traditional treatment methods,” Genovese said, but beyond that it’s difficult to know.
Modern research suggests excluding patients with a history of bipolar disorder or psychosis or first-degree relatives with psychosis, Rucker said. Others to exclude would be pregnant women, individuals with histories of self-harm or suicide attempts, and people with current drug or alcohol problems.
That said, some of the older research suggested a benefit in treating alcoholism, and a significant advantage of psychedelics is the lack of the risk of dependence. Psychedelics would not be used long-term, like current antidepressants and antipsychotics, but would instead be taken as a single dose.
“In fact, the brain becomes completely tolerant to the biological effect of psychedelics within about 72 hours, so there is no scope for long-term use,” Rucker said. “This is why psychedelics have no risk of dependence — there is nothing to be dependent ‘on,’ as it were, after 72 hours, and there is no withdrawal effect when you stop.”
Psychedelics are similarly safe physiologically, Rucker said, even compared with the least toxic current prescription drugs, such as fluoxetine. He did note that they can be “psychologically toxic,” potentially leading to tragic, if rare, events such as accidental death, suicide, or homicide if taken irresponsibly in recreational settings. But the most clear adverse physical events with psychedelics were short-term nausea, anxiety and disorientation.
“You would need to eat many, many kilograms of magic mushrooms before the dose of psilocybin you ingested with them was harmful to your body,” Rucker said. “Psychedelics are much, much safer than opiates, which are routinely used in medical practice and kill thousands of people every year from overdose, but they are more legally restricted. It is quite a perverse situation, really, and certainly not an evidence-based one.”
Research Barriers and Challenges Remain Substantial
The biggest barrier to psychedelic use in psychiatry remains the lack of research. Even the potential stigma associated with their use and the government resistance to their research is itself a result of not having an adequate evidence base.
“Much of the stigma likely stems from recreational use of these substances as well as the lack of good science currently available,” Genovese said.
Yet in a catch-22, legal obstacles hamper research because they are classified as Schedule I drugs.
“This imposes a very large burden of security and bureaucracy on anyone who wants to make or handle the drugs,” Rucker said. “Most companies don’t bother, because it is too difficult and not profitable.”
Even if those obstacles are overcome, further challenges remain. One is the relative impossibility of using a placebo control or blinding because of the clearly identifiable effects induced by psychedelics. Further, the psychological state of patients and the setting during therapy are inseparable from therapeutic effects.
A purely logistical challenge for study of psilocybin is the difficulty in obtaining sources of psilocybin that meet the standards required in clinical trials, Rucker added. But the bottom line remains that we cannot know how useful they might be if we don’t study them.
“I think everyone in this field is interested in one thing — that psychedelics get a fair hearing by Western medicine by undergoing well-funded, well-designed controlled trials,” Rucker said. “Then we will know whether they have any benefit, and we can judge whether this benefit is suitably balanced against any harm they might do. Until then we won’t know, and that is a worse state of affairs than knowing, in my opinion.”
Rucker J, Jelen L, Flynn S, Frowde K, and Young A. Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacol. 2016;30(12):1220-1229.