What we know and don’t know about a new category of psychiatric medications
Medications used for the treatment of psychiatric illnesses like depression, bipolar disorder, and schizophrenia have been proven to work in countless randomized controlled studies and should be considered for the treatment of any of these conditions. Yet it is also clear that they are only partially effective for many patients and totally ineffective for others. Scientists, therefore, continue to search for medications for illnesses like major depression and posttraumatic stress disorder that will be more effective than currently available agents and that will work for more people who suffer from these conditions.
Curiously, some of the greatest excitement in psychopharmacology circles right now comes from drugs that have long been considered drugs of abuse. Specifically, a version of ketamine is already approved for the treatment of depression. Both MDMA, also known as ecstasy, and psilocybin, aka magic mushrooms, are being developed for mood and anxiety disorders. Not so long ago it would have been unthinkable to consider these agents as candidates for licensed psychopharmacological agents. Why are they now being studied so intensively and greeted with such excitement?
Which Drugs Are Being Studied?
Ketamine is now given as the FDA-approved inhaled agent esketamine to people suffering from a major depressive episode. Some centers also administer ketamine intravenously for depressed patients. Its benefit compared to traditionally available antidepressants like the SSRIs is that ketamine works almost immediately—some patients feel better within minutes of receiving a first ketamine dose and stay well for as long as two weeks. It is also effective for patients who have not responded to other treatments for depression.
On the street, however, ketamine is known as “Special K.” Ketamine has dissociative properties that can cause an “out of body” experience that some people find pleasurable. Hence, long before ketamine was ever used to treat depression it was an abused drug.
Ecstasy, sometimes called “Molly,” is the street name of a drug that also causes a dissociative experience, sometimes accompanied by hallucinations and other distortions of reality. Right now, it is an illegal drug, but in a landmark paper published in the prestigious journal Nature Medicine earlier this year, it was shown to be an effective treatment for post-traumatic stress disorder (PTSD) when accompanied by manualized psychotherapy. In that study, 90 patients with PTSD were randomized to receive either psychotherapy plus MDMA or psychotherapy plus placebo. Active MDMA was associated with robust improvement in PTSD compared to placebo and the investigators reported few adverse side effects from MDMA.
A psychedelic drug now under study for the treatment of a psychiatric disorder is psilocybin, the active ingredient in “magic mushrooms.” With effects similar to LSD, magic mushrooms have long been used to induce a “trip” that includes hallucinations and euphoria. Nevertheless, last April investigators reported in the New England Journal of Medicine on a study that compared psilocybin to the SSRI antidepressant escitalopram (brand name: Lexapro) for the treatment of major depression. In that study, 59 patients with depression were randomized to receive either psilocybin or escitalopram and all also received “psychological support.” There was no measurable difference in outcome between psilocybin and escitalopram, but psilocybin was superior to the SSRI on several secondary measures such as the percentage of patients who were judged to have improved and the speed at which that improvement took place. There were no statistically significant differences in adverse side effects.
Is It Okay to Repurpose Drugs of Abuse?
Ketamine, MDMA, and psilocybin are thus now being looked upon as psychiatric medications capable of improving depression, PTSD, and other disorders. Some commentators have been nearly breathless in describing these drugs as breakthroughs for the treatment of psychiatric illness, suggesting we’re on the cusp of a new era in psychopharmacology.
It would be helpful if we could say that these drugs are addressing some underlying abnormalities in conditions like depression and PTSD. We do have information about the biological mechanisms of action of all three of them. Ketamine works mainly through an interaction with the brain’s glutamate neurotransmission system and also has effects on opioid receptors. Both MDMA and psilocybin work mainly through the enhancement of the brain’s serotonin receptor system, the same system that is affected by SSRI-type antidepressants like Prozac and Lexapro.
Unfortunately, however, we still have no firm idea if derangements in any of these neurotransmitter systems are actually the cause of any mood or anxiety disorder. There are many theories linking abnormal glutamate neurotransmission to depression, for example, and some solid data from animal studies suggesting such a link, but no definitive proof that any abnormality in glutamate neurotransmission is part of depression yet exists. We cannot say that any of these drugs work by remediating a known abnormality in the brains of people with psychiatric illnesses any more than we can say that about any of the traditional psychiatric medications.
One thing we can say is that most of the currently approved medications for depression and PTSD are usually not abused, sold on the street, or addictive. There is no evidence that Prozac, Lexapro, or Zoloft are abusable drugs. By contrast, ketamine, psilocybin, and MDMA all have long histories as street drugs and can be addictive for some people. The questions raised by this simple fact are as philosophical as they are scientific. Clinical trials will tell us whether or not drugs like ketamine, psilocybin, and MDMA work to relieve conditions like depression and PTSD: as noted, some studies already exist. Are we ready, then, to have such drugs go into wide use for the treatment of psychiatric illness? What does it mean that drugs once considered dangerous and addictive are now being looked upon as potentially effective treatments for mental health disorders?
Some people find that drinking alcohol improves their mood, and it is possible that a clinical trial could show that alcohol works better than a placebo in making people with depression feel better. Of course, no one would ever suggest that we consider alcohol as a treatment for any psychiatric illness. The adverse side effects of alcohol would be considered too serious to warrant its use as an antidepressant or anti-anxiety agent. After all, alcohol is a potentially addictive substance that some people abuse.
Proponents of the use of drugs like ketamine, psilocybin, and MDMA would vehemently reject the analogy with alcohol. In the clinical trials done so far with these agents, adverse side effects seem to be minimal and, in the doses and manner in which they are given, addiction unlikely. Furthermore, some widely used, FDA-approved psychiatric drugs can be misused. The anti-anxiety agents called benzodiazepines, like Valium, Xanax, and Klonopin, for instance, can be abused, as can the psychostimulant medications used to treat Attention Deficit Hyperactivity Disorder (ADHD), such as Ritalin and Vyvanse. There is precedent, therefore, for our use of potentially abused drugs as treatments for psychiatric illnesses.
Is psychiatry going in the direction of approving the use of “mind-altering” street drugs as medications? Or are we simply following solid science in recognizing that once tainted drugs indeed have useful properties to help people suffering from severe illnesses get better? These are questions with which we will have to wrestle, even as clinical trials examining the utility of medications once considered drugs of abuse continue to show their effectiveness for psychiatric disorders.