Clinical Context

There is a lot of excitement regarding the therapeutic potential of psychedelic drugs in the management of depression and anxiety, but what is the evidence for the efficacy of these treatments? Ko and colleagues performed a meta-analysis of randomized trials of psychedelic drugs to answer this question, and their results were published in the February 2023 issue of the Journal of Affective Disorders.^[1]

The meta-analysis focused on clinical trials of psychedelic drugs among patients with depression or conditions associated with depressed mood. All trials were published between 1990 and 2022. The primary study outcome was the efficacy of psychedelic drugs on symptoms of depression. The authors state that these agents are generally well-tolerated, with adverse events such as anxiety, nausea, and mild increases in heart rate and blood pressure primarily limited to time around the dosing of the medication.

Fourteen studies were included in the current analysis, including 10 randomized controlled trials and 4 open-label studies. Eight studies targeted adults with major depressive disorder, and six studies focused on adults with distress secondary to an illness beside depression. One study examined lysergic acid diethylamide (LSD). Two trials evaluated ayahuasca, and the rest focused on psilocybin.

The 1 trial of LSD focused on the efficacy of adding the drug to psychotherapy among 12 adults with anxiety related to life-threatening illness. LSD was applied in 2 doses of 200 µg and was associated with a lower score for depression symptoms vs psychotherapy alone. However, there were no tests for statistical significance in this report.

In 2 trials involving a single dose of ayahuasca, depression scores were significantly improved in the active treatment vs control groups. In 1 study of adults with treatment-resistant depression, the response rates to ayahuasca and placebo were 64% and 27%, respectively (P<0.04).

Regardless of dose, psilocybin was associated with improved depression symptom scores through 3 months. In a follow-up study of a small cohort of patients treated with psilocybin, 6 of 9 patients who responded to treatment at 5 weeks maintained treatment response at 6 months. The largest randomized trial of psilocybin involved 233 participants. Response and remission rates for a single dose of 25 mg were 36.7% and 29.1%, respectively. The respective rates for a single 10-mg dose were 18.7% and 9.3%. Another randomized trial of 59 adults comparing psilocybin and escitalopram demonstrated similar efficacy in the primary outcome, but psilocybin was superior on multiple secondary measures of depression symptoms. Finally, several small trials of psilocybin among patients with cancer have demonstrated improved anxiety scores on active treatment.

The authors of the current review note that most clinical trials of psychedelics are small and are limited by challenges with blinding patients to treatment and managing positive expectations of psychedelic therapy. The authors also note that despite positive results from clinical trials, psychedelics may be difficult to introduce in routine clinical practice because of the labor- and cost-intensive need for monitoring patients before, during, and after treatment.

Could the potential for broader application of psychedelic treatment for mood disorders be leading to an increase in the overall use of psychedelics among young people? The current study addresses this issue.

Study Synopsis and Perspective

With the exception of LSD, use of hallucinogens surged between 2018 and 2021 among adults younger than 30 years in the United States, new research shows.

In 2018, the prevalence of young adults’ past-year use of non-LSD hallucinogens was 3.4%. By 2021, it had jumped to 6.6%.

The increase in non-LSD hallucinogen use occurred while LSD use remained stable at around 4% in 2018 and 2021.

“While non-LSD hallucinogen use remains substantially less prevalent than use of substances such as alcohol and cannabis, a doubling of prevalence in just 3 years is a dramatic increase and raises possible public health concerns,” coauthor Megan Patrick, PhD, from the University of Michigan Institute for Social Research, Ann Arbor, said in a news release.

The results were published online June 7 in Addiction.^[2]

Health Concerns

The estimates are derived from the Monitoring the Future study, which includes annual assessments of adolescent and adult health in the US.

The analysis focused on 11,304 persons (52% female) aged 19 to 30 years from the US general population who were interviewed between 2018 and 2021.

Participants were asked about past 12-month use of LSD, as well as use of non-LSD hallucinogens, such as psilocybin.

From 2018 to 2021, past 12-month use of LSD remained relatively stable, at 3.7% in 2018 and 4.2% in 2021.

However, non-LSD hallucinogen use increased in prevalence from 3.4% to 6.6% from 2018 to 2021.

Across years, the odds of non-LSD use were higher among males, White people, and individuals from households with higher parental education, which is a proxy for higher socioeconomic status.

The most commonly used non-LSD hallucinogen was psilocybin.

The survey did not ask whether young adults used non-LSD hallucinogens for therapeutic or medical reasons.

“The use of psychedelic and hallucinogenic drugs for a range of therapeutic uses is increasing, given accumulating yet still preliminary data from randomized trials on clinical effectiveness,” lead author Katherine Keyes, PhD, from Columbia University Mailman School of Public Health, said in the release.

“With increased visibility for medical and therapeutic use, however, potentially comes diversion and unregulated product availability, as well as a lack of understanding among the public of potential risks,” Dr Keyes added.

“However, approved therapeutic use of psychedelics under a trained health professional’s care remains uncommon in the US, thus the trends we observe here are undoubtedly in nonmedical and nontherapeutic use,” Dr Keyes noted.

Dr Patrick said that the increased use of hallucinogens raises “concern for young adult health” and is not without risk. Although hallucinogen dependence has historically been rare in the US population, it could become more common as use increases, she noted.

The researchers will continue to track these trends to see whether the increases continue.

“We need additional research, including about the motives for hallucinogen use and how young adults are using these substances, in order to be able to mitigate the associated negative consequences,” Dr Patrick said.

The study was funded by the National Institute on Drug Abuse, part of the National Institutes of Health. Dr Keyes and Dr Patrick have disclosed no relevant financial relationships.

Addiction. Published online June 7, 2023.

Implications for the healthcare team

• A previous meta-analysis found that limited research was supportive of the use of psychedelics in the management of depression. A single dose of psilocybin was associated with remission from depression in nearly 30% of participants in 1 trial, and psilocybin was at least similar to escitalopram in another trial. There were fewer data on the application of LSD and ayahuasca in depression.
• The current study finds that the use of non-LSD psychedelics approximately doubled among young people in the US between 2018 and 2021. The use of LSD remained fairly stable during this period. Variables associated with the use of LSD and non-LSD psychedelics included male sex, White vs Black race, and having a college-educated parent.
• The healthcare team should be aware of the rising use of non–lysergic acid diethylamide psychedelics among US young people and counsel patients and families regarding the potential danger of these drugs.

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