A Psychedelic Therapy for Depression Without Hallucinations

Now that we know that low serotonin levels have nothing to do with depression and that blocking serotonin reuptake does not explain the potential benefits of popular antidepressant therapies, scientists are turning their attention to the mechanism of action of hallucinogenic drugs that produce faster positive benefits for most patients.

Major depressive disorder is one of the leading causes of disability worldwide. Conventional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), show therapeutic efficacy only after several weeks of treatment. Unfortunately, less than half of the treated patients achieve complete remission, and a third of treated patients show no improvement at all. Therefore, there is a pressing need to replace SSRIs with faster-acting treatments that produce clinical benefits for a greater percentage of depressed patients, especially for those at risk of suicide.

The first fast-acting antidepressant

Ketamine was derived from the street drug phencyclidine (PCP, angel dust) and was initially viewed as a safer anesthetic than PCP because it produced fewer hallucinations. The initial clinical trials demonstrated that ketamine was an effective and very rapid-acting antidepressant. The level of depression was reduced within 4 hours with a response rate greater than 60 percent of the patients treated. Although the benefits of ketamine were transient—the antidepressant effect of ketamine was diminished by 7 days and absent by 10 days—scientists now had a proof-of-concept that an effective and rapid antidepressant therapy was possible if they could understand how ketamine produced its anti-depressant effects. Ketamine is a potent stimulator of the NMDA glutamate receptor; however, further investigations demonstrated that this action had nothing to do with its beneficial effects on mood.

Next up: psychedelics

The use of psychedelics in treating psychiatric diseases is becoming more popular. Unfortunately, double-blind clinical studies are very difficult to conduct due to the obvious psychoactive effects on patients given the active drug. In addition, psychedelic treatments are usually administered with psychotherapy; thus, it can be difficult to determine whether benefits are due to the psychedelic or the psychotherapy.

Two psychedelic drugs, lysergic acid diethylamide (LSD) and psilocybin have been found to reduce the symptoms of depression in many clinical trials. One trial reported that a single dose (25 mg) of psilocybin could induce a rapid (within hours) reduction in depressive symptoms. Most importantly, when combined with psychological therapy, the benefits lasted from several weeks to one year. Unlike ketamine, psychedelics have fewer side effects and do not cause dependence or withdrawal symptoms.

How do psychedelics achieve this?

Most psychedelics, although not all, activate many different serotonin receptors; however, the alterations of conscious states they induce in humans are initiated primarily by binding to the serotonin receptor subtype called 5-HT2A. However, it’s important to recognize that not all chemicals that stimulate this receptor produce hallucinations. For example, the neurotransmitter serotonin stimulates this receptor, but it is certainly not a hallucinogen. (For a more detailed discussion on how hallucinations are generated, see my book Your Brain on Food: How Chemicals Control Your Thoughts & Feelings.)

A recent study investigated whether the stimulation of the 5-HT2A receptor is responsible for the fast antidepressant actions of psychedelics. The study compared the actions of psilocybin with lisuride, a nonhallucinogenic derivative that is like LSD and stimulates the 5-HT2A receptor. The study concluded that the 5-HT2A receptor is not involved in the antidepressant effects of psilocybin or lisuride. Therefore, the antidepressant activity of 5-HT2A receptor stimulators such as LSD and psilocybin is independent of their psychedelic properties.

The most important finding of this study was that a 5-HT2A receptor agonist that is devoid of psychedelic properties (i.e., lisuride) rapidly produced antidepressant effects at very low doses. Lisuride is already approved for clinical use in Europe and it has a wide margin of safety. Future clinical trials are now required to confirm these findings.

If you or someone you love is contemplating suicide, seek help immediately. For help 24/7, dial 988 for the 988 Suicide & Crisis Lifeline, or reach out to the Crisis Text Line by texting TALK to 741741. To find a therapist near you, visit the Psychology Today Therapy Directory.