Classic Psychedelics for the Treatment of Depressive Disorders: An Update for Psychiatrists in Training

The serotonergic (“classic”) psychedelics generally function through modulation of the serotonin 5-hydroxytryptamine 2_A (5-HT_2A) receptor (7). The most well-known compounds in this class are psilocybin, lysergic acid diethylamide, ayahuasca, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-DMT, and mescaline. The 5-HT_2A receptor has been proposed to underlie the “mystical effects” of psychedelics, with ongoing debate whether activity at this receptor is required for a therapeutic effect (8). However, some literature suggests that other pharmacological mechanisms may be responsible, including modulation of the default mode network, increased amygdala responsiveness, and decreased inflammatory cytokine levels (9). In contrast, “nonclassic” psychedelics, such as 3,4-methylenedioxymethamphetamine and ketamine, do not act at the 5-HT_2A receptor, and therefore, these compounds are not discussed in the present article

Trials investigating psychedelics have employed a variety of psychotherapeutic strategies to accompany dosing. A common but not standardized approach is psychedelic-assisted psychotherapy, which involves undergoing supportive, exploratory, and experience-focused preparatory therapy before dosing and integrative sessions after dosing. Although psychedelic-assisted psychotherapy may be common, there is no consensus on a standard psychotherapeutic approach for psychedelic trials.

In a 2021 randomized controlled trial, the investigators observed prompt and sustained antidepressant effects of moderate-dose (20 mg/70 kg) to high-dose (30 mg/70 kg) psilocybin for 24 patients with major depressive disorder (2). Participants in a delayed treatment control group had no statistically significant change in GRID-Hamilton Depression Rating Scale (GRID-HAM-D) scores from baseline to 1 week and 4 weeks after the session. More than 70% of participants in the psilocybin group achieved a clinically significant reduction (>50%) in GRID-HAM-D scores (lower scores indicate less severe symptoms) at week 1 and week 4, with more than 50% of participants achieving remission. A repeat study from 2022 added a 12-month follow-up and revealed comparable antidepressant effects, with a sustained response rate of 75% and remission rate of 58% with respect to GRID-HAM-D scores (10).

In 2021, a phase II double-blind randomized controlled trial compared scores on the 16-item Quick Inventory of Depressive Symptomatology (QIDS)–self-report (QIDS-SR-16) after 6 weeks between two groups (psilocybin vs. escitalopram) of patients (N=59) with major depressive disorder (4). The trial revealed no statistical difference in antidepressant effects between psilocybin and escitalopram at 6 weeks (lower QIDS-SR-16 scores indicate fewer symptoms). Although the lack of difference between treatments is notable, remission on the basis of QIDS-SR-16 scores was observed in 57% of participants in the psilocybin group at week 6 (versus 28% in the escitalopram group). Discontinuation of treatment, anxiety, anhedonia, sexual dysfunction, and dry mouth were more common in the escitalopram group. The study highlights that psilocybin may be an equal, or potentially preferable, alternative when compared with selective serotonin reuptake inhibitors. However, the effectiveness of blinding was not assessed.

A 2016 feasibility study of psilocybin’s effects on 12 patients with TRD revealed significant reductions in Beck Depression Inventory scores (lower scores indicate milder depression) (1). In 2022, a parallel-group double-blind phase II trial assessed the safety and efficacy of single-dose psilocybin in the treatment of adults with TRD with a primary endpoint assessed at 3 weeks (11). TRD was defined as having a current episode of depression after at least two failed trials of treatment with antidepressants administered at an adequate dose for an adequate duration; TRD was assessed by using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. A total of 233 patients were randomly assigned to receive a dose of 25 mg, 10 mg, or 1 mg (control group) in a 1:1:1 ratio. At 3 weeks, the 25-mg group achieved a 6.6-point least-squares mean reduction in Montgomery-Åsberg Depression Rating Scale scores (lower scores indicate fewer symptoms) compared with the 1-mg group (p<0.001). There was no difference between the 10-mg group and the 1-mg group, and differences in treatment response at a secondary endpoint of 12 weeks were not statistically significant. The study did not assess effectiveness of blinding, although participants in the 25-mg group reported more intense subjective effects. Although transient side effects during psychedelic dosing trials are common (1, 2, 4, 10, 12), all treatment groups in this 2022 study experienced severe adverse effects, including suicidal ideation, self-injury, and hospitalization (11). These adverse effects were observed at a markedly higher rate in the 25-mg (9%) and 10-mg (7%) groups compared with the 1-mg group (1%). With regard to these adverse events, it has been theorized that failing a last-resort, popular treatment may demoralize patients and contribute to thoughts of suicide (13).

In a 2023 placebo-controlled within-subject fixed-order study, the investigators assessed the effects of psilocybin among 15 patients with moderate to severe depression over a 16-week period (14). All 15 patients received placebo at week 1 followed by moderate-dose psilocybin (0.3 mg/kg) at week 4. There was no statistically significant change in GRID-HAM-D scores after psilocybin administration compared with placebo administration and no notable serious adverse events. Analysis of mystical effects and improvement in depression showed no correlation. Although the study was limited by carryover effects, lack of blinding (>78% of participants correctly guessed the administered drug), and positive expectancy bias (not qualitatively measured), the large effect sizes for psilocybin, although not statistically significant, and mood-related improvements in quality of life deserve future attention (14).

Ayahuasca is a South American herbal drink containing DMT and monoamine oxidase inhibitors. A 2016 uncontrolled open-label trial investigating ayahuasca administration to 17 participants with recurrent major depressive disorder and an average baseline mean HAM-D score of 19.24, revealed that a single dose of ayahuasca produced a statistically significant decrease in the HAM-D score to 7.56 at day 21 (lower scores indicate less severe symptoms) (15).

In a 2019 parallel-arm double-blind randomized controlled trial, the investigators assessed the efficacy of single-dose ayahuasca compared with placebo among 29 participants with TRD, excluding those with a previous history of ayahuasca use, psychotic disorders, bipolar disorders, and suicidal ideation. Changes in HAM-D scores reflected large effect sizes at 7 days after treatment in the ayahuasca group (16). Five participants misclassified placebo as ayahuasca; however, the investigators did not use a statistical means to compare blinding in the control and treatment groups.

A 2022 uncontrolled open-label fixed-order dose-escalation trial assessed the safety and efficacy of DMT among seven patients with major depressive disorder and three healthy control participants (N=10) (17). Each participant received well-tolerated doses of 0.1 mg/kg and 0.3 mg/kg of DMT at least 48 hours apart, with only two noted adverse reactions of bradycardia and hypotension. A statistically significant 4.5-point reduction in HAM-D scores relative to baseline was observed 1 day after the 0.3-mg/kg dose in the major depressive disorder group.

These few preliminary studies are promising but remain restricted by key design limitations, including small samples, insufficient blinding, and expectancy bias. Although sample sizes were large enough to detect statistical differences, larger sample sizes are needed for greater generalizability and ability to monitor side effects. Inherent difficulties exist in blinding due to the powerful subjective effects of psychedelics, as well as in expectancy bias from “trip-seeking” individuals (11, 14, 18). There is ongoing debate on whether the issue of blinding can be resolved. The use of an active placebo, a decrease in the promotion of psychedelics in research communities and among the general public, and the use of well-trained raters may help mitigate concerns of blinding and bias (19). The heterogeneity in psychedelic-assisted therapy is another genuine limitation that may affect trial reproducibility and clinical implementation.

Recent reviews from the Canadian Network for Mood and Anxiety Treatments (CANMAT) task force and the American Psychiatric Association (APA) Task Force on Novel Biomarkers and Treatments (a division of the APA Council of Research) discussed evidence for the treatment of depression with serotonergic psychedelics, with psilocybin having the most promise (5, 20). However, the CANMAT report rates the available evidence as low (level 3 to 4) due to the low number of double-blind randomized controlled trials relative to the number of pilot studies or other uncontrolled studies (5). The next stage of psychedelic research involves addressing these gaps with more randomized double-blinded trials that involve larger, diverse populations.

Increasing our understanding of the risks and contraindications of psychedelics is paramount. Many of these early studies excluded persons with personal or family histories of suicidal ideation, bipolar disorder, or schizophrenia, which limits generalizability. As noted above, emergent suicidality appears to be a possible concern for participants in some populations who are administered psilocybin (11). Furthermore, discussions about the implementation of psychedelics in clinical practice, accessibility issues, and the role of standardized psychedelic-assisted therapy should be considered.

Psychedelics have emerged as a promising modality to treat depressive disorders. However, there are significant limitations in the available studies. Larger double-blinded clinical trials should reveal severe adverse effects and continue to explore the efficacy of psychedelics.