Are Psychedelics the Next Wave for Treating Depression?

Several times in the past year, my patients have asked if micro-dosing is a viable treatment option for depression. I had to admit it was not my area of expertise, but it was being studied at local clinical research centers. Since Matthew Perry’s unfortunate death, this topic has again been brought to my attention. Perry, a former castmate of Friends, was found dead at his home in October. The autopsy report indicated his death was due to the combined effects of ketamine, drowning, and Buprenorphine, an opioid-like drug used in the treatment of opioid addiction.

Last week, the MAPS Public Benefit Corporation announced it submitted a New Drug Application to the FDA investigating MDMA-assisted therapy for individuals with post-traumatic stress disorder. If approved, MDMA-assisted therapy would be the first psychedelic-assisted therapy in the U.S. since the 1950s, when LSD became widely used by psychologists and psychiatrists in research and clinical practice for over 15 years.

Perry was public about his struggles with opioid addiction and, more recently, had been treated with ketamine infusions under supervision for his co-existing depression. However, the ketamine found in his digestive tract at autopsy indicated he was also taking it orally, which is only used recreationally. MDMA, also called molly or ecstasy, is known as a party drug. Due to its psychoactive effects, drugs like MDMA are often taken at raves, clubs, or music festivals, where participants use these substances to amplify their experience.

Why are so-called party drugs making their way into practice for treating challenging psychiatric diagnoses?

History of Psychedelic Drugs in Culture

Throughout history, many pre-Columbian cultures used hallucinogenic substances in magical, therapeutic, and religious rituals. However, it was not until 1938 that Swiss chemist Albert Hofmann synthesized the first synthetic hallucinogen, lysergic acid diethylamide (LSD) while working at Sandoz. Years later, Sandoz marketed LSD under the trade name Delysid as an agent for studying psychoses and as an adjunct to traditional psychotherapy.

The Department of Psychology at Harvard University was once home to two of the leading figures in the 1960s counterculture of psychedelic drugs. In 1960, Timothy Leary and Richard Alpert began exploring the effects of psychotropic substances on the human mind. They argued the field had a “legitimate interest in learning how cognition, perception, and emotion are affected by mind-altering substances.” The possible dangers of researching such substances were not as well-known at that time.

What Is Currently Available?

In early 2020, the American Psychiatric Association issued a review of psychedelic therapies indicating that “despite insufficient research to support U.S. Food and Drug Administration (FDA) approval of any psychedelics at that point, continued study of the efficacy of psychedelics for mental disorders was warranted.”

In May 2019, Denver passed a city ordinance to de-criminalize mushrooms containing psilocybin.

A 2022 study published in the New England Journal of Medicine describes outcome measures of a phase two trial of single-dose psilocybin for treating resistant depression. They concluded that “psilocybin at a single dose of 25 milligrams, but not 10 milligrams, reduced depression scores significantly more than a 1-milligram dose over three weeks but was associated with adverse effects including headache, nausea, dizziness, suicidal ideation or behavior, or self-injury. “They concluded the adverse effects outweighed this study group's benefits.

A prescription version of ketamine, called esketamine, given through a nasal spray, was approved by the FDA in 2019 for patients with treatment-resistant depression. However, according to the guidelines, it is only to be used "under the supervision of a health care provider in a certified doctor's office or clinic."

Esketamine isn't a first-line treatment for depression. It is generally used only when other, more longstanding treatments haven't been effective. It is not thought to be curative; rather, it improves symptoms for a certain amount of time. Independent, outpatient ketamine clinics are becoming more prevalent. It is estimated that there are currently hundreds to thousands of these clinics — almost all of which were established in 2019 when ketamine was approved for treatment-resistant depression. These clinics are for-profit enterprises that operate on a fee-for-service arrangement, as insurance rarely covers this treatment. In the Washington metro area where I practice, the ketamine infusions cost about $500 each, and a course of six infusions, along with a clinical re-evaluation, is typically recommended.

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How Does It Work?

A 2018 study published in the Harvard Review of Psychiatry looked at neuroimaging of patients who suffered from treatment-resistant depression before and after ketamine treatment. Although the study size was small, they found actual brain changes as the result of treatment, including reduced brain activation in regions associated with self-monitoring and increased activity in regions associated with emotional blunting. Overall, ketamine’s effects were most notably found in several areas of the brain called the hippocampus. These areas overlap with the growing body of neuroimaging literature that implicates abnormalities of certain brain networks in the pathophysiology of depression.

Previously, it was thought that depression was caused by an imbalance in the brain’s level of a chemical called serotonin. The development of a class of antidepressants called serotonin reuptake inhibitors (SSRIs) was developed in response to this. However, it became clear that the serotonin hypothesis didn’t fully explain depression. Not only were SSRIs of limited help to more than one-third of people given them for depression, but growing research showed that the neurotransmitters these drugs target (like serotonin) account for less than 20 percent of the neurotransmitters in a person’s brain. The other 80 percent are neurotransmitters called GABA and glutamate. Ketamine triggers glutamate production, prompting your brain to form new neural connections in complex events. The result makes your brain more adaptable and able to create new pathways to develop more positive thoughts and behaviors.

The effects of ketamine are not long-lasting, which is why, currently, it is best used in conjunction with a more comprehensive plan to treat depression, including therapy and antidepressants. However, the use of ketamine may rapidly improve severe depressive symptoms while waiting for traditional antidepressants to take full effect.

As more research into the effects of MDMA and other psychedelics, such as psilocybin, becomes available, they, too, may prove to be an asset in treating patients with TRD.