Psychedelics can have a pharmacological antidepressant effect, even though the field often pushes towards psychotherapy.

The way psychedelics are discussed often suggests that the substance is primarily a tool to enhance psychotherapy. That perception is understandable, but scientifically not yet entirely fair. In fact, evidence is accumulating that serotonergic psychedelics themselves—that is, as a pharmacological intervention—can already have a clear antidepressant effect. At the same time, modern literature remains heavily colored by the model of psychedelic-assisted psychotherapy, partly because many studies are designed, conducted, and interpreted by psychiatrists, psychologists, and psychotherapists. This does not automatically mean that their conclusions are incorrect, but it does mean that a structural bias towards therapy as a preferred explanation can emerge. 

Why that bias towards psychotherapy is logical

The current field of psychedelics is largely built upon psychiatry and psychology. This is reflected in the research teams, the study models, and the language used to describe results. A recent methodological paper explicitly states that psychedelic-assisted therapy should be viewed as a complex intervention and also discusses issues such as blinding bias and allegiance bias. Allegiance bias refers to the fact that researchers or treatment centers are often already implicitly or explicitly attached to a particular therapeutic model, which can influence the design, execution, and interpretation of studies. Additionally, a meta-analysis from 2026 showed that more preparatory psychological therapy was associated with a stronger reduction in depressive symptoms, but the same publication also notes that many studies carry a high risk of bias, partly due to difficult blinding. This makes it possible for therapy to sometimes genuinely help, but also for the importance of therapy to be exaggerated relatively quickly in this literature.

The strongest recent argument for a pharmacological effect

The most direct clinical indication comes from the new JAMA Psychiatry study with inhaled GH001, a formulation of 5-MeO-DMT, in treatment-resistant depression. In that study, starting or modifying psychotherapy during the trial was prohibited. Moreover, the researchers explicitly state that while there was psychological support according to standard care, there was no planned psychotherapeutic intervention before, during, or after dosing. Nevertheless, the antidepressant effect was substantial: depression scores decreased significantly more than with placebo, and remission on day 8 was 57.5 percent in the GH001 group compared to 0 percent in the placebo group. This is not easily compatible with the idea that psychotherapy alone works. This study actually shows that a serotonergic psychedelic itself can make a substantial antidepressant contribution, even without a detailed therapy protocol as an active treatment component.JAMA Network)

The earlier phase 1/2 study with GH001 also pointed in that direction. In that study, the authors wrote that the short duration of action of GH001 facilitates administration without specific psychotherapeutic interventions, and that preparation and support in their program were part of standard medical care, not of an integrated psychotherapeutic treatment. Rapid and powerful antidepressant effects were also observed in that small study.PMC)

Ayahuasca also shows that the substance itself matters.

Ayahuasca is often mentioned in the same breath as ceremony, ritual, and guidance, leading people to quickly assume that the effect is primarily contextual or psychotherapeutic. However, in the randomized placebo-controlled study of treatment-resistant depression, there was no extensive psychotherapy protocol like in many modern psilocybin studies. The session took place in a quiet, controlled environment; participants received explanations regarding potential effects and support if needed, but the design did not revolve around a multi-day therapeutic treatment. Despite this more austere framework, rapid antidepressant effects were still found compared to placebo. 

There is another important point to consider. In a biomarker analysis of the same ayahuasca trial, higher serum BDNF levels were found in the ayahuasca group than in the placebo group 48 hours after the session, and higher BDNF was associated with lower depression symptoms. This points to a biological effect that goes beyond merely “a meaningful experience.” It suggests that ayahuasca also triggers something via neurotrophic and neuroplastic pathways.PMC)

DMT and 5-MeO-DMT fit well within a pharmacological model.

DMT and 5-MeO-DMT are particularly interesting because of their short duration of action. Precisely because of this, they are less dependent on hours of supervision than, for example, LSD or psilocybin. In natural or semi-natural settings, associations have long been observed with 5-MeO-DMT and improvements in depression and anxiety without the involvement of formal psychotherapy. This is not hard evidence like a large double-blind trial, but it does fit the idea that these substances can induce therapeutically relevant changes on their own.

With DMT, the picture is more mixed. The new phase IIa study with intravenous DMT for depression did use psychotherapeutic support; this study cannot be considered pure evidence of efficacy without therapy. Nevertheless, there are also prospective and placebo-controlled data in healthy volunteers in which significant improvements in depression scores were observed 1 to 2 weeks after DMT. These are not depression treatments in the clinical sense, but they do support the hypothesis that DMT itself can induce rapid changes in mood.

BDNF is one of the clearest biological pathways

One of the most discussed pharmacological mechanisms is the increase in neuroplasticity. BDNF plays a central role in this. The ayahuasca study already provided a human signal that BDNF can rise within 48 hours in people with depression. In addition, recent reviews describe that psychedelics stimulate neuroplastic processes and that BDNF is likely an important part of this. This helps explain why some effects occur so quickly and can persist longer afterwards than one would expect based on the acute trip alone.

Reducing inflammation is likely more than a side effect.

In some people, depression also has an inflammatory component. Therefore, it is relevant that recent reviews describe that psychedelics can reduce neuroinflammation, primarily via 5-HT2A-mediated pathways and influence on, among others, NF-κB, PI3K/Akt, and mTOR. Furthermore, a systematic review from 2025 concluded that classical psychedelics can alleviate existing inflammatory activity, although the findings were not uniform in every context. Preclinical DMT research also shows anti-inflammatory effects, including inhibition of pro-inflammatory cytokines and chemokines. All of this does not yet prove that the antidepressant effect is entirely due to inflammation reduction, but it does support a serious pharmacological model. 

Neurogenesis and broader neuroplasticity make the story biologically plausible.

In addition to BDNF, neurogenesis is also frequently mentioned. It is important to remain precise on this point. In humans, neurogenesis is difficult to measure directly, so much of the evidence is indirect or preclinical. Nevertheless, the direction is consistent. Reviews from 2024 and 2025 describe that psychedelics promote changes in neural plasticity, neurite growth, spinogenesis, and possibly neurogenesis. Furthermore, an animal study in Neuropsychopharmacology showed that 5-HT2A agonists could produce antidepressant-like effects that did not appear to be entirely dependent on classic hallucinogenic properties. This is conceptually important because it suggests that antidepressant activity may be at least partially decoupled from psychological experience as the sole explanation.

Telomeres and telomerase are interesting, but more research is needed.

In the field of aging and cell biology, the situation is even more speculative. For psilocybin, however, there has been experimental evidence since 2025 that psilocin can extend cellular lifespan in human fibroblasts and that psilocybin improved survival in old mice. In that research, preservation of telomere length, reduced oxidative stress, and improved DNA damage responses were also observed. This is interesting because it aligns with ideas about cellular resilience and repair.

But telomerase is another story. For classic psychedelics, there is currently no solid clinical evidence that telomerase activity is reliably increased in humans. Hypotheses and theoretical papers exist regarding psilocybin and telomeres, but this is not yet a hard-proven human outcome. The strongest recent data therefore concern telomere length preservation and markers of DNA stability in cells and animals, not convincingly proven telomerase activation in patients. So whether Psychedelics can help with depression via the DNA route. remains to be seen.

The push towards psychotherapy is therefore partly substantive and partly cultural.

Psychotherapy is not useless in the field of psychedelics. Guidance can be very valuable for preparation, safety, integration, and behavioral change. Moreover, meta-analyses suggest that more therapy hours may be associated with better outcomes. However, this does not automatically imply that pharmacology is secondary. The short-acting DMT and 5-MeO-DMT lineage actually demonstrates that the substance itself can have a rapid and substantial effect, even when formal psychotherapy is minimal or does not form an integral part of the intervention.

This creates a field of tension. On the one hand, it is logical for clinicians to package psychedelics within a psychotherapeutic model, because it is safer, better known, and easier to regulate. On the other hand, that model can narrow the perspective, leading to insufficient recognition that serotonergic psychedelics may also simply be powerful, fast-acting biological antidepressants. This risk is particularly real in a field heavily staffed by psychotherapists and psychiatrists with therapeutic frameworks. The literature itself now acknowledges that blinding, expectation, and allegiance bias are significant methodological problems.

Conclusion

The fairest conclusion, therefore, is not that psychotherapy is unimportant, but that the current discourse too often acts as if psychedelics only work by deepening therapy. The evidence has by now become too strong to maintain that position. Ayahuasca, DMT, and especially 5-MeO-DMT demonstrate that serotonergic psychedelics can produce rapid antidepressant effects even without an extensive psychotherapy protocol. Biologically, this is plausible due to mechanisms of action such as BDNF elevation, neuroplasticity, possible neurogenesis, and likely also inflammation modulation. The signal is interesting for telomere and aging mechanisms, but much remains to be confirmed in this area, certainly regarding telomerase.

In the coming years, the most important question will likely not be whether psychotherapy can play a role, but rather how much of the effect of psychedelics is truly pharmacological, how much contextual, and how much arises from the interaction between the two. So far, the evidence points clearly in one direction: these substances are likely not only psychotherapeutic catalysts but also pharmacologically active antidepressants. This also raises the question of whether psychedelic sessions can be just as effective when supervised by trip sitters or therapists other than psychotherapists, as also discussed in the article: Psychedelics without psychotherapy