This article was authored by Tommaso Barba, a PhD candidate at the Centre for Psychedelic Research at Imperial College London.

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Introduction

Psilocybin, a classic psychedelic compound, has emerged as a potential breakthrough treatment for mental health conditions such as treatment-resistant depression (TRD), anxiety, and PTSD (Davis et al., 2021). Clinical trials have shown promising results, with rapid and sustained improvements in mood and overall well-being following psilocybin-assisted therapy. However, given the widespread use of serotonergic antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), a critical question arises: Can psilocybin be safely and effectively administered to individuals already on these medications? Understanding this interaction is essential for both clinical research and future therapeutic applications. The implications extend to accessibility, safety protocols, and treatment outcomes for a large population already dependent on these medications.

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What are SSRIs and SNRIs and how do they work?

SSRIs and SNRIs are two of the most commonly prescribed classes of antidepressants. SSRIs, such as fluoxetine, sertraline, and escitalopram, work by selectively inhibiting the reuptake of serotonin (5-HT) at the synapse, thereby increasing its availability and enhancing mood regulation. SNRIs, like venlafaxine and duloxetine, function similarly but also inhibit the reuptake of norepinephrine, offering a dual mechanism of action that can provide additional benefits for some patients. These medications are considered the cornerstone of modern antidepressant therapy due to their relatively favourable side effect profiles and effectiveness in treating symptoms of major depressive disorder (MDD), generalized anxiety, PTSD, and obsessive-compulsive disorder (OCD).

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Both SSRIs and SNRIs contribute to improved stress tolerance and emotional resilience by modulating serotonin receptor pathways, particularly the 5-HT1A receptor, which fosters emotional stability and stress adaptation (Carhart-Harris & Nutt, 2017). Despite their therapeutic benefits, some evidence suggests that chronic administration of SSRIs/SNRIs can desensitize or down-regulate 5-HT receptors, including the 5-HT2A receptors (Meyer et al., 2001). This downregulation is significant because 5-HT2A receptor simulation is considered central to psilocybin’s mechanism of action. The receptor's reduced sensitivity raises concerns about whether SSRIs/SNRIs might dampen psilocybin’s effects or interfere with its ability to produce therapeutic breakthroughs. Understanding this potential interaction is crucial for ensuring safe and effective integration of psilocybin into psychiatric treatment plans.

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Do SSRIs alter psychedelic experiences? A closer look

‍Summary: SRIs might dampen the intensity of the psychedelic experience, especially in regards of challenging emotional components. However, the research mostly come from observational studies not conducted in controlled settings, limiting the validity of the results. More research is needed before stronger conclusions can be made.

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‍Evidence suggests that individuals on SSRIs/SNRIs may experience reduced intensity of psilocybin’s acute psychedelic effects. A recent prospective survey study by Barbut-Siva, Barba et al. (2024) compared the experiences of individuals on serotonergic reuptake inhibitors (SRIs) with those not taking any psychiatric medications.

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• Key Findings:
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  • Participants on serotoninergic antidepressants (referred to as SRIs) reported significantly less intense mystical experiences (18.2% lower), emotional breakthroughs (31.9% lower), and challenging experiences (50.9% lower) compared to non-SRI users.
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  • Interestingly, visual effects were not significantly diminished, suggesting that SRI-induced downregulation primarily affects the emotional and introspective components of the psychedelic experience (Figure 1).

Further complicating this picture, a large retrospective survey by Gukasyan et al. (2023) explored both concurrent use of psilocybin with antidepressants and post-discontinuation effects. The study found that nearly half of individuals taking SSRIs (47%) and a majority on SNRIs (55%) reported weaker-than-expected psilocybin effects when compared to their prior experiences or to others taking the same dose. Intriguingly, this dampening effect did not resolve immediately after stopping antidepressants; instead, it persisted for a significant period, with 30% of participants still reporting reduced psilocybin effects up to 3–6 months after discontinuation (figure 2).

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The study also noted that the likelihood of diminished effects was lower when compared to non-serotonergic antidepressants, such as bupropion, which showed a weaker impact (29%). This difference underscores the role of serotonergic pathways in mediating psilocybin’s effects. Notably, removing fluoxetine from the analysis, an SSRI with a particularly long half-life, did not significantly alter these findings, suggesting that the dampening effect is not exclusive to any single medication but may be a class-wide phenomenon.

The reduction in acute subjective effects may stem from SRI-induced desensitization of 5-HT2A receptors, which are critical for the subjective effects of psilocybin. Chronic exposure to SSRIs/SNRIs can lead to receptor downregulation, reducing their responsiveness. Additionally, emotional blunting, a commonly reported side effect of SRIs (Opbroek et al., 2002) may further dampen the range of emotions experienced during a psychedelic session. This blunting can mute both positive and negative facets of the experience, potentially limiting the transformative breakthroughs associated with psychedelic therapy.

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Adding nuance to this evidence, Becker et al. (2022) conducted a randomized, double-blind, placebo-controlled crossover study examining the effects of psilocybin after short-term escitalopram pretreatment. In contrast to Barbut-Siva, Barba et al. (2024) and Gukasyan et al. (2023) findings, Becker et al. reported that while escitalopram pretreatment significantly reduced negative drug effects, such as anxiety, adverse cardiovascular responses, and other physical side effects, it had no significant impact on psilocybin's positive mood effects. The study also found no changes in the pharmacokinetics of psilocin, the active metabolite of psilocybin, or in gene expression of the 5-HT2A receptor.

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• Key differences with Barbut-Siva, Barba et al. (2024):‍
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  • Becker et al. utilized a short-term pretreatment period (14 days), compared to the chronic SRI exposure likely present in Siva et al.'s naturalistic survey participants.
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  • Becker's study involved healthy subjects, while Siva focused on individuals with psychiatric conditions. Differences in receptor expression and baseline neurobiology could influence the observed results.
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  • Escitalopram's specific pharmacological profile may differ from other SSRIs and SNRIs, limiting generalizability.
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  • However, the controlled nature of this study makes these findings potentially stronger from a scientific point of view, highlighting the need for controlled research on the topic of chronic SSRI users.

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While Becker's findings provide encouraging preliminary evidence for the safety of combining short-term escitalopram with psilocybin, they highlight the need for further research in clinical populations with chronic antidepressant exposure. Taken together, these studies suggest that while SRIs may dampen some aspects of the subjective psychedelic experience, they may also mitigate negative responses, raising questions about the trade-offs between subjective intensity and patient comfort during psychedelic therapy.

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Antidepressant effects remain comparable

‍Summary: While subjective effects may be diminished, the strongest and most controlled study on the topic to date found that participants continuing SSRIs during psilocybin therapy exhibited comparable improvements in core depressive symptoms, including mood, anhedonia, and emotional regulation.

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‍Despite the reduced subjective effects, Barbut-Siva, Barba et al. (2024) found no significant differences in antidepressant outcomes between participants on SRIs and those not on medication. Both groups exhibited similar improvements in well-being and depressive symptoms following the psychedelic experience. These findings suggest that the antidepressant benefits of psilocybin may not be entirely dependent on the intensity of the acute subjective effects. While a strong mystical experience is often linked to therapeutic outcomes (Griffiths et al., 2006), it is not always a prerequisite for benefit. This suggests that psilocybin's therapeutic efficacy may be mediated by broader neurobiological mechanisms, such as enhanced neuroplasticity, functional brain network reorganization, and downstream signalling processes, which are not solely dependent on subjective intensity (Yu et al., 2022). Therefore, while the acute experience can be profound, its muted intensity in the presence of SSRIs does not necessarily undermine the long-term therapeutic potential of psilocybin.

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In confirmation of these findings, Goodwin et al. (2023) conducted a phase II clinical trial exploring the safety and efficacy of psilocybin administered alongside ongoing SSRI treatment in patients with treatment-resistant depression.

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• Key Findings:
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  • Participants received a single 25 mg dose of psilocybin with psychological support while continuing their SSRI regimen.
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  • At three weeks post-treatment, participants showed significant reductions in depressive symptoms, with response and remission rates (42%) comparable to previous studies where participants had discontinued antidepressants prior to psilocybin therapy.
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  • Importantly, no serious adverse events (TEAEs) were reported, and most side effects were mild and transient.

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These results challenge the long-held assumption that SSRIs must be discontinued before psilocybin therapy. While subjective effects may be reduced, the overall therapeutic outcomes in terms of depression relief appear to remain intact (Figure 3).

Potential mechanisms of interaction

The interaction between psilocybin and SSRIs/SNRIs likely arises from changes in serotonin receptor sensitivity and downstream signaling pathways:

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• Downregulation and desensitization of 5-HT2A receptors: Chronic SSRI/SNRI use might reduce the availability and sensitivity of 5-HT2A receptors, possibly diminishing psilocybin’s capacity to induce profound emotional and mystical experiences. However, these changes may not block psilocybin’s therapeutic mechanisms.

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• Emotional blunting: SRIs often reduce emotional responsivity, potentially reducing the challenging yet transformative emotional breakthroughs associated with psilocybin therapy. However, these reductions might not be strong enough to impede the therapeutic effects. 

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• Compensatory mechanisms: Some evidence suggests that downstream signalling pathways, neuroplasticity, and functional changes in brain connectivity may still occur despite receptor downregulation. These processes might explain why therapeutic benefits persist even when acute subjective effects are diminished.

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Goodwin et al. (2023), with the strongest and most controlled study on the topic to date, found that participants continuing SSRIs during psilocybin therapy exhibited comparable improvements in core depressive symptoms, including mood, anhedonia, and emotional regulation. This finding highlights an ongoing debate: Is it better to discontinue serotonergic antidepressants before psilocybin therapy, or can patients safely remain on them? While discontinuing antidepressants may theoretically enhance the acute psychedelic effects, it comes with risks such as withdrawal symptoms, treatment gaps, and potential diminished treatment effects.

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A recent post hoc analysis by Erritzoe et al. (2024) found that discontinuing SSRIs/SNRIs prior to psilocybin therapy resulted in reduced treatment outcomes compared to unmedicated patients. While no significant effects on the acute psychedelic experience were observed, the overall therapeutic response appeared weaker in those who had recently stopped antidepressants. This raises the possibility that abrupt discontinuation may negatively impact psilocybin's efficacy, further complicating decisions about whether to taper or continue these medications. relapse. On the other hand, remaining on SSRIs may blunt the subjective experience but does not appear to significantly compromise therapeutic outcomes, particularly for individuals with treatment-resistant depression. This question remains unresolved and underscores the need for further research on this issue.

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Conclusion

‍The interaction between psilocybin and serotonergic antidepressants (SSRIs/SNRIs) presents a nuanced and complex picture. Some evidence indicates that individuals on SSRIs may experience reduced acute psychedelic effects, particularly in emotional and mystical domains, likely due to receptor desensitization and emotional blunting. Visual effects appear to be less affected, underscoring the specificity of these changes. Other research did not detect such changes. However, despite the potential reduced intensity of the acute experience, therapeutic outcomes in terms of depressive symptom relief appear comparable to those seen in individuals not taking SRIs. This suggests that the antidepressant benefits of psilocybin may not rely solely on the intensity of the acute experience but may involve additional mechanisms such as neuroplasticity and brain network reorganization.

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‍Key considerations:
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1. Safety: Preliminary findings (Goodwin et al., 2023) suggest that combining psilocybin with SSRIs is generally safe and well-tolerated, with no significant adverse events reported. However, further vigilance is necessary for identifying rare or idiosyncratic reactions.
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2. Efficacy: While subjective effects may be diminished, antidepressant benefits remain significant, particularly in treatment-resistant populations.
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3. Practical Implications: Discontinuing SSRIs before psilocybin therapy can be challenging due to withdrawal symptoms, treatment gaps, and risks of relapse. Studies exploring gradual tapering or partial dose reduction may offer more patient-friendly alternatives. However, tapering antidepressants comes with its own challenges, including the risk of withdrawal symptoms such as anxiety, insomnia, and mood destabilization. Additionally, abrupt or poorly managed dose reductions may exacerbate underlying conditions, potentially leaving patients vulnerable during the transition. Clinicians must carefully balance these risks with the potential benefits of enhanced psychedelic effects, tailoring the approach to individual needs and circumstances.
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‍Future directions

‍Further large-scale, controlled clinical trials are essential to:
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• Confirm the safety, efficacy, and long-term outcomes of combining psilocybin with ongoing SRI treatment.
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• Identify optimal strategies for tapering antidepressants where necessary, balancing safety and efficacy.
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• Explore the role of neuroplasticity and brain connectivity changes in psilocybin’s therapeutic mechanisms beyond the acute psychedelic effects.
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In conclusion, while questions remain, current evidence supports the cautious and informed use of psilocybin alongside SSRIs. This approach could pave the way for broader accessibility to this promising treatment option for depression and related conditions, offering hope to individuals for whom conventional therapies have proven insufficient.

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Read next: Psilocybin Therapy for Depression

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References

• Barbut Siva, J., Barba, T., Kettner, H., Kuc, J., Nutt, D. J., Carhart-Harris, R., & Erritzoe, D. (2024). Interactions between classic psychedelics and serotonergic antidepressants: Effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study. Journal of psychopharmacology (Oxford, England), 38(2), 145–155. https://doi.org/10.1177/02698811231224217.
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• Becker AM, Holze F, Grandinetti T, et al. (2022) Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clinical Pharmacology and Therapy 111: 886–895.
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• Carhart-Harris, R. L., & Nutt, D. J. (2017). Serotonin and brain function: a tale of two receptors. Journal of psychopharmacology (Oxford, England), 31(9), 1091–1120. https://doi.org/10.1177/0269881117725915
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• Davis, A.K.; Barrett, F.S.; May, D.G.; Cosimano, M.P.; Sepeda, N.D.; Johnson, M.W.; Finan, P.H.; Griffiths, R.R. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry 2021, 78, 481–489
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• Erritzoe, D., Barba, T., Spriggs, M. J., Rosas, F. E., Nutt, D. J., & Carhart-Harris, R. (2024). Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression. Journal of psychopharmacology (Oxford, England), 38(5), 458–470.
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• Gukasyan N, Griffiths RR, Yaden DB, et al. (2023) Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use. Journal of Psychopharmacology 37: 707–716.
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• Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187, 268-283.
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• Goodwin GM, Croal M, Feifel D, et al. (2023) Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology 48: 1492–1499.
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• Meyer JH, Kapur S, Eisfeld B, et al. (2001) The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. American Journal of Psychiatry 158: 78–85.
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• Opbroek A, Delgado PL, Laukes C, et al. (2002) Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? International Journal of Neuropsychopharmacology 5: 147–151.
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• Yu, C. L., Liang, C. S., Yang, F. C., Tu, Y. K., Hsu, C. W., Carvalho, A. F., ... & Su, K. P. (2022). Trajectory of antidepressant effects after single-or two-dose administration of psilocybin: A systematic review and multivariate meta-analysis. Journal of clinical medicine, 11(4), 9