An Open Mind: Psychedelic Drugs as Treatments for Depression

Any mention of psychedelic drugs probably conjures up images of Timothy Leary (Richard Nixon's "most dangerous man in America"), the 1969 Woodstock festival, and the Grateful Dead. There is, however, a tradition of non-recreational use for these medications starting around the turn of the 20th century. As early as 1874, psychologist William James argued for the use of nitrous oxide (aka laughing gas) as a mind-expanding drug, which he believed could help people access great truths of religion and philosophy. Drugs like mescaline and peyote had of course been used much earlier in religious ceremonies for exactly that purpose. But legitimate scientific research on psilocybin at Harvard University in the 1960s intersected with the growing New Age movement to create a cultural phenomenon tied to psychedelic drug use, and tainted the reputation of this kind of medication for years to come. In 1963 the Harvard faculty involved in psychedelic research were either fired or resigned, and by 1968 both LSD and PCP were illegal throughout the U.S.

After a long dry spell in psychedelic treatment research, the field is enjoying a resurgence. Harvard has started a new psychedelic research center nearly 60 years after its previous effort. And Johns Hopkins University in Maryland has undertaken a large number of studies since 2000 to examine the use of psychedelics in treating a wide range of mental health disorders. In part because of the new data, there is a movement in some cities and states to re-legalize psilocybin, and drug companies are sponsoring multiple clinical trials with the endgame of FDA approval. The number of studies of psychedelic drugs in medical journals has skyrocketed just in the years since 2015. And all of this science is bringing psychedelic medications back into the mainstream: In it's November 2021 issue, Good Housekeeping magazine ran an article touting the benefits of psychedelic drugs. Who would have been able to imagine that happening back in 1968?

Some of the most promising recent findings have been seen in the treatment of depression. Benefits have been seen for patients with major depressive disorder, with additional studies showing reductions in anxiety as well. Patients who have depressed mood as a secondary diagnosis connected to serious physical health conditions like cancer, Alzheimer's disease, or Lyme disease also seem to benefit. The second-strongest set of evidence is for patients with alcohol use disorder, at least some of whom who show reduced cravings and lower amounts of alcohol use after 1-2 treatment sessions with psychedelics. Other individual studies have shown promising findings for smoking cessation, opioid use disorders, post-traumatic stress symptoms, chronic pain, and anorexia.

There is one FDA-approved medication that broadly falls into the category of psychedelic drugs, ketamine, which is also used by hospitals as an anesthetic. It's one approved psychiatric use is for "treatment resistant depression," in which other antidepressant medications have failed to have an effect. But it's also true that once a medication is legally available for one health condition, prescribers can use it off-label to treat any health condition that they think is appropriate. So ketamine is now available from at least some psychiatric practitioners in many parts of the country, and is potentially being used for more than just depression. Potential side effects include neurological or cognitive problems (e.g., continuing to feel dissociated from reality), and elevated heart rate or blood pressure, so the treatment is not without risks. As with other psychedelics, ketamine is also being studied in the treatment of substance use disorders, and is sometimes used off-label for this purpose.

A secondary finding from these studies would have been right up William James's alley: People's level of improvement is directly correlated with the degree to which they report a mystical experience during their use of psychedelic medication. A mystical experience sounds like a pretty out-there concept, but it can be measured using a standardized 30-item questionnaire, the MEQ30. This demonstrates that psychologists can take any human experience, no matter how deep or rich, and reduce it to a boring paper-and-pencil survey. In the psychedelic treatment studies people's scores on the MEQ30 right after their drug experience were a strong predictor of their level of symptom improvement over the following weeks. When psychedelics are used to treat other substance use problems, the evidence also suggests that they work mainly by reducing a person's emotional rather than physical dependence on the drug.

Studies of ketamine's effects on the brain show reduced activity in several low-brain areas associated with Intuitive mind functions, and specifically with negative emotions. For instance, ketamine suppresses activity in the nucleus accumbens which is part of the brain's reward system and is known to misfunction in addictive disorders, in the lateral habenula which is involved in pain and avoidance learning and has been characterized as an "anti-reward center," in the bed nucleus of stria terminalis (BNST) which is connected to the amygdala and linked to negative emotions. Interestingly, it also reduces neural activity in the the cingulate cortex (specifically the subgenual cingulate cortex or sgACC), which is believed to have a role in consciousness. In general ketamine might be expected to have anesthetic effects that suppress brain function, although in some cases it has been shown to increase connectivity or synchronization between brain regions, e.g. strengthening synchronization between other brain regions and the prefrontal cortex (PFC, tied to Narrative mind functions). According to general resonance theory, synchronized activity is the hallmark of conscious experience. Alternately, Kastrup argues that the generally activity-reducing effects of psychedelic drugs on the brain demonstrate that these medications are actually suppressing individual mental activity and allowing a greater connection to a "universal mind." In one way or another, the neural effects of psychedelic drugs are generally consistent with patients' reports of helpful mystical experiences.

One of the most interesting findings about psychedelic treatment is that repeated doses may not be required for people to see improvement. A single experience in some cases seems sufficient to produce a kind of "transformational" or "second-order" change, in which the patient experiences him- or herself as being qualitatively different from before. This is the same kind of fundamental shift that people sometimes experience after a serious illness, a near-death experience, or the type of religious conversion that William James wrote about at the turn of the 20th century. People with depression and anxiety are often focused inward, thinking about their personal risks or perceived failures. Psychedelic medications might be one way (perhaps safer than major illness or injury) for people to experience what the Stoics called "the view from above," the world seen from the perspective of eternity. A more expansive view of life might lead people suffering from excessively self-focused anxiety or depression to see that personal things matter much less than they had originally believed. This kind of insight might provide relief from suffering at the level of Intuitive experience, in a way that people's Narrative minds alone cannot convince them to accept.

There are certainly risks associated with psychedelics, and more research still needs to be done. The greatest source of risk may not come from the medications themselves, but from the context in which they are used and in particular from the actions of unscrupulous treatment providers. New York Magazine ran a recent podcast series titled "Power Trip," about the ways in which therapists might exploit or abuse clients who are in the highly suggestible state induced by some psychedelic drugs. Some of the reports include people who want to become treatment providers themselves, and are told that they must undergo the treatment before beginning to provide it. That's not something expected in any other area of medical practice; this and many other aspects of psychedelic treatment have more in common with the practices of charismatic gurus or teachers than with legitimate psychological care. The drugs' pharmacological effects seem to be much less of a problem than the actions of some drug dispensers who feel that they don't have to abide by the usual code of ethics for mental health. 

In general, the more risky a treatment is likely to be and the more vulnerable the patient, the stronger our ethical protections and oversight should be around that treatment. With appropriate oversight, psychedelics do seem to have a great deal of potential to help people who haven't benefitted from conventional medications or psychotherapies. But we need to be sensitive to people's heightened vulnerability when using these medications, and remain aware that greater potential for harm might also come along with their greater potential for benefit.