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Hallucinogens and Depression

Are potent hallucinogens coming soon to a psychiatric hospital near you?

Source: Wikimedia Commons
Source: Wikimedia Commons

Hallucinogens, or "psychedelics," are substances that induce a "non-ordinary" experience of consciousness. In use for thousands of years (at least), the medical potential for potent mind-altering substances has come in and out of vogue.

Mescaline was isolated in 1897 and used in experiments as a truth serum and for treatments of psychiatric disorders just after the second world war. LSD was made freely available to scientists by the pharmaceutical company, Sandoz, and widely used in medical research in the 1950s and 60s, with tens of thousands of patients (and researchers) giving it a try for conditions such as schizophrenia and alcohol dependence. LSD was also used in psychotherapy to "assist" patients in recovering from their neuroses, for severe pain patients, and in an experiment with theology students where it was found to induce mystical experiences. Albert Hoffman published the synthesis of psilocybin in 1959 and it too was studied for a variety of conditions. Surprisingly, little concern was raised about the safety of these hallucinogens in these early papers.

In 1966, the United States banned LSD at a time when medical science was applying far more methodological rigor to what was considered a proper clinical trial. Most psychedelic research was nearly worthless by the new standards, being mostly thousands of case studies with no controls and no objective measurements of symptoms (such as symptom rating scales). Researchers in the mid-60s using more modern research techniques and longer follow-up weren't able to replicate the glowing results of yore. With psychedelics illegal, research became much more difficult and enthusiasm for their treatment potential waned. Of the major modern hallucinogens (psilocybin, mescaline, DMT, ketamine, and MDMA), only ketamine is still legal and in general use as an anesthetic.

In today's medical practice, particularly in psychiatry, hallucinogens are considered possibly dangerous kindlers of ongoing psychotic disorders, particularly for people with personal or family histories of schizophrenia and bipolar disorder, and should be avoided. It would be malpractice (not to mention illegal) for a doctor to administer LSD to a schizophrenic patient today. However, the lack of success of almost any therapy, medicine or otherwise, for treatment resistant depression and some addiction disorders has led researchers to consider studying hallucinogens again, starting with ketamine.

All of these agents seem to act on a particular serotonin receptor, 5HT-2A, and ketamine additionally is an antagonist at the NMDA receptor. Activation of this serotonin receptor seems to influence "existential concepts of self, including moral values, self-identity, and purpose." It brightens the mood and makes people feel motivated to change. Interestingly, modern studies of ketamine for depression focus on low dose (typically 0.5mg/kg over 40 minutes in an IV, whereas 1-4.5mg/kg are typically used for anesthesia), and that the hallucinogenic properties of ketamine are minimized at this dose. However, some studies showed that the amount of dissociation symptoms measured during the infusion correlated with a longer antidepressant effect. All ketamine studies tend to be rather small, and some show no correlation between hallucinogenic effect and antidepressant effects.

The other hallucinogen with some promising modern research is psilocybin, derived from mushrooms. It too has a number of small studies for alcohol and tobacco addiction, end of life anxiety and depression, obsessive compulsive disorder, and treatment resistant depression. Scientists in London used fMRI to look for brain mechanisms in their study of psilocybin and depression. 19 patients were given psilocybin, and all 19 had their depression scores drop significantly (in fact, on average, depression scores were cut in half) a week after the dose. 47% still met the criteria for treatment response 5 weeks after the dose.

The fMRIs were interesting too, showing decreased blood flow in the amygdala (the "fear" center of the brain) correlating with antidepressant effects. fMRI can measure the overall "connectivity" of the brain, or how much communication is going on between the different parts. Increased connectivity of some parts of the prefrontal cortex and parietal lobe predicted treatment response at 5 weeks, as did decreased connectivity between the parahippocampal and prefrontal cortices.

In all these modern studies, carefully done in controlled conditions with medical and psychological support, psychedelics seem to immediately reduce depressive symptoms and also promote positive change. The side effects of ketamine include vital sign changes, and some folks who take ketamine and psilocybin experience distressing hallucinations and dislike feelings of dissociation (others seem to like this feeling). Given that the only other end-of-line treatment that works very quickly for depression and, especially, acute suicidality, is electroshock therapy, the risks and benefits of psychedelics in this context is a different (currently experimental) conversation than for standard outpatient treatment. It seems likely, unless larger studies take a surprising turn, that ketamine, especially, is going to be used more in general practice, particularly in closely monitored settings such as locked inpatient psychiatric units and emergency rooms. This is not the optimism of a 1950s researcher who likes to dabble in LSD with his patients...this is science.

The major down side to these agents is that they don't seem to work for very long in some people, but it may be we need to figure out mechanisms, dosage, and how to space re-treatments if necessary. As their study widens, we will undoubtedly find more cases of induced psychosis or mania and learn more about the patients in which to avoid hallucinogens entirely.

In the mean time...I strongly recommend you don't try this at home. Every emergency room doctor and psychiatrist in the country can tell you a horror story of something awful that happened after the use of hallucinogens, from death from vital sign instability (hyperthermia) after using synthetic MDMA to a patient of mine who became psychotic for 8 months straight (through 6 hospitalizations!) after a few days' use of mushrooms. Any agent with powerful effects can have powerful side effects as well, and should be utilized with knowledge of the risks and benefits and appropriate care.

copyright Emily Deans MD