Exploratory post hoc analyses of a trial comparing psilocybin-assisted therapy with escitalopram found that participants who discontinued SSRIs/SNRIs before receiving psilocybin showed reduced treatment effects on depression and wellbeing measures compared with unmedicated participants, despite no differences in the acute psychedelic experience. These hypothesis-generating results suggest pre-treatment antidepressant discontinuation might diminish response to psilocybin and indicate the need for controlled trials comparing SSRI/SNRI continuation versus discontinuation.
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Barba, T., Buehler, S., Kettner, H. et al. · BJPsych Open (2022)
Background
There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling.
Aims
Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes.
Methods
Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. Results/outcomes: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found.
Conclusion
Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.
Major depressive disorder (MDD) is a leading contributor to global disability and is commonly treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), but many patients do not respond adequately to these drugs. Psilocybin, a classic psychedelic that acts primarily at 5-HT2A receptors, has shown promise as an alternative treatment in recent trials, and acute subjective experiences during dosing are thought to help produce longer-term clinical benefits. In earlier work, including a double-blind randomised trial comparing psilocybin with escitalopram, participants who were taking serotonergic antidepressants at screening were required to taper off them before study entry because of limited safety data on co-administration and prior reports that chronic SRI treatment can attenuate psychedelic subjective effects. Erritzoe and colleagues set out to explore whether pre-trial discontinuation of SSRIs/SNRIs influenced outcomes in that psilocybin versus escitalopram trial. Using exploratory post hoc analyses, they asked whether people who had recently discontinued serotonergic medication ("discontinuers") differed from those who were unmedicated at trial entry on baseline symptom changes, antidepressant response (primary outcome QIDS-SR16 and several secondary measures), acute psychedelic experience measures, and expectation ratings, and whether any discontinuation effects differed between the two treatment arms.
Design and participants: The data derive from a double-blind randomised controlled trial that compared two oral doses of psilocybin (COMP360) plus 6 weeks of placebo to two placebo-like psilocybin doses plus 6 weeks of escitalopram in adults with moderate-to-severe unipolar MDD. Fifty-nine participants were randomised: 30 to the psilocybin condition (11 female) and 29 to escitalopram (9 female). Inclusion criteria included age 18–85, physical health and a diagnosis of unipolar MDD; key exclusions were psychotic disorder, family history of psychosis, pregnancy, substance misuse and MRI contraindications. Those taking serotonergic medication at screening were required to discontinue under GP and study psychiatrist supervision prior to baseline; tapering was typically linear over 2–4 weeks with a minimum 2-week (or ~5 half-lives) drug-free washout before baseline. Intervention and psychosocial support: Participants received approximately 20 hours of in-person therapeutic support (preparation, dosing support with reclining, eye mask and headphones, and integration) plus optional integration calls, following a standard psychedelic-therapy protocol. Psilocybin participants received two 25 mg doses separated by 3 weeks and a 6-week course of placebo; escitalopram participants received two 1 mg (placebo-like) psilocybin doses and a 6-week course of escitalopram. Outcomes: The primary outcome of the parent trial was the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16), administered weekly. Secondary and additional measures analysed here included the Beck Depression Inventory (BDI-1A, bi-weekly), clinician-rated HAM-D and MADRS (baseline and 6-week follow-up) and psychological well‑being (WEMWBS, bi-weekly). Acute subjective indices of the psychedelic experience were assessed with the Mystical Experience Questionnaire (MEQ), Ego Dissolution Inventory (EDI), Emotional Breakthrough Inventory (EBI) and Challenging Experience Questionnaire (CEQ). Expectation for treatment benefit was measured at baseline by asking participants to rate expected improvement (0–100) for 6 weeks of escitalopram and for two doses of psilocybin. Statistical approach: All analyses were exploratory and post hoc. The investigators used linear and linear mixed-effects models implemented in R (lme4, lmerTest) to test effects of Treatment (psilocybin vs escitalopram), Timepoint and Discontinuation status, and their interactions. Models compared nested specifications (referred to as M1, M2 and M3) via ANOVA or information criteria to determine whether Treatment or Discontinuation terms added significantly. Effect estimates, 95% confidence intervals and parameter effect sizes for interaction terms were reported; given the exploratory nature and high inter-correlation of measures, no correction for multiple comparisons was applied. Demographic group differences were tested with t-tests and chi-square tests. Acute-experience and expectation effects were tested with linear models and model selection using Akaike information criteria.
Psychological outcomes. For the purposes of this study, four measures of depression were analysed. Two of these measures are widely used self-report measures of depression: (1) QIDS-SR16, which acted as the primary outcome measure ofand was administered weekly for the course of the trial and (2) the Beck Depression Inventory 1A (BDI-1A;, which was administered bi-weekly for the course of the trial. The remaining two scales are clinician administered measures of depression symptomology that were administered at baseline and follow-up: (1) the Hamilton Depression Rating Scale (HAM-D)and () the Montgomery and Asberg Depression Rating Scale (MADRS). In addition to these clinical measures of depression, we also include an analysis of the Warwick-Edinburgh Mental Well-being Scales (WEMWBS;which was a key secondary outcome measure of Carhart-Harris et al. () and was measured bi-weekly for the course of the trial.
Here, we examined how pre-trial discontinuation of selective serotonin-reuptake inhibitors or serotonin noradrenaline reuptake-inhibitors affected outcomes in a 6-week double-bind randomized controlled trial comparing psilocybin with escitalopram in patients with longstanding, moderate-to-severe MDD. Our results build upon those in the response to a letter-to-the-editor byand show that SSRI/SNRI medication use may have had a substantial effect on response to treatment, even when standard withdrawal procedures prior to study commencement are followed. In the present analyses, we found that unmedicated patients had a better response to psilocybin across multiple measures, unlike those who discontinued SSRI/ SNRIs, who showed no significant difference. A larger analysis revealed that discontinuing these medications affected responses differently: discontinuers had a lesser response to psilocybin but responded better to escitalopram (Supplemental Table), suggesting that pre-treatment discontinuation of SSRI/SNRIs has contrasting impacts on treatment efficacy based on the type of medication administered. These results provide a more nuanced interpretation of the results presented in, which reported an absence of evidence for an effect of treatment condition in the primary outcome QIDS-SR-16 (despite there being betweensubjects differences in other measures of depression, possibly linked to the presence of compound imprecise items in the primary outcome). The analysis presented in this work reveals that this was the case only for discontinuers, suggesting that a discontinuation confound may have contributed to a dampening of true differences between treatment condition -that is, a superior efficacy of psilocybin. That being said, it should be emphasized that discontinuers and those unmedicated on entry were equally distributed in the two study arms, and that the further refinement introduced in the analysis presented here does not invalidate the results of, or the conventions imposed to ensure transparency in clinical trials (i.e. pre-registration of primary outcomes). Additionally, it must be stressed that the analyses presented here were exploratory and performed post hoc in response to published comments regarding. Despite these limitations, they do provide interesting insights into the potential impact of discontinuation that should be considered in psychedelic clinical trials moving forward. There are a few possible pharmacological explanations for the observed discontinuation effect. Firstly, chronic treatment with SSRI/SNRIs and related medications induce desensitization and downregulation of several serotonin receptors to maintain homeostasis). Downregulation appears to be a relatively stable phenomenon due to the time it takes for new receptors to be synthesized, rendering downregulation a possible mechanism for the current results. Particularly relevant here would be a downregulation of the 5-HT2A receptor, which is the primary receptor involved in the subjective effects of psychedelics. Previous research has identified that chronic administration of SSRI/SNRIs downregulates 5-HT2ARs in both preclinicaland clinical studies. However, this has not been found consistently. Several lines of research have highlighted the importance of the acute psychedelic experience for therapeutic effects; the intensity of which has been shown to correlate with 5HT2AR occupancy. Thus, one natural conjecture is that a downregulation of 5-HT2ARs would cause a dampening of the acute effects of psilocybin. However, here, we found no effect of discontinuation on measures of the acute experience (mystical experiences, ego dissolutions, emotional breakthroughs and challenging experiences). This is intriguing as it could imply a dissociation between the acute pharmacological action of psilocybin (and associated subjective effects) -that is not affected by SSRI/SNRI discontinuation and an antidepressant response that is affected. Indeed, preclinical work has recently hypothesized that such a dissociation between 'psychedelic' subjective effects and antidepressant psychological effects is possible. Additionally, recent research showed that psychological changes after psilocybin were not paralleled by a consistent change in neocortical 5-HT2AR binding induced by the treatment (one dose, assessed 1 week later), indicating that the relationship between 5-HT2AR downregulation and psilocybin's effects may be more complex than just receptor treatmentinduced changes in receptor density. Moreover, given the importance of extra-pharmacological factors in shaping the acute experience, the influence of the therapeutic setting in which all dosing sessions occurred for both treatment arms should not be underestimated. Such extra-pharmacological modulation is independent of 5HT2AR downregulation. It is also important that absence of evidence is not confused with evidence of absence, and that this is explored further in future studies. Another possible explanation of these results is that the shortterm discontinuation required to enter in the trial disturbed the stability previously acquired with medications, generating discontinuation symptoms. In support of this hypothesis, discontinuers showed an increase in depressive symptoms between trial screening and baseline (i.e. when withdrawal was taking place), as well as a trend towards higher depression scores at baseline compared with unmedicated patients. Tapering or cessation of SSRI/SNRIs is commonly associated with withdrawal symptoms which often resemble symptoms of depression or a worsening of depressive symptom severity. These symptoms can be distinguished from a relapse of the original disorder by rapidity of onset, the presence of somatic symptoms like nausea, shock-like feelings, dizzinessand rapid response by reintroduction of SSRI/SNRIs. While a minimum of 2 weeks of tapering is commonly considered sufficient, it may not mitigate prolonged symptoms. In fact, there is evidence suggesting that linear tapering over this period might not have additional benefit compared with abrupt discontinuation. Withdrawal symptoms were not formally assessed over the course of the trial. However, some symptoms coded as depressive could have been elevated because in part they were elevated by antidepressant discontinuation. This may have inflated antidepressant symptomology at baseline or inflated the antidepressant action in this subgroup of patients. Reintroduction of an SSRI/SNRI after discontinuation in the escitalopram group would be predicted to mitigate withdrawal symptoms, so contributing to the greater response to escitalopram in those who discontinued. There is growing interest in the role of expectation in shaping results of clinical trials, and psychedelic trials are no exception. Even though they had not responded adequately, it is conceivable that those taking SSRI/ SNRIs are more likely to hold SSRI/SNRIs in positive regard than those had presumably chosen to be unmedicated (despite being depressed). It was therefore important to assess whether individuals who were on SSRI/SNRIs at the time of the enrolment (and had to discontinue before starting trial treatment) had a different, more positive attitude towards conventional antidepressant medication, and whether this contributed to the discontinuation effect for the escitalopram arm. While we found no significant relationship between discontinuation and expectations of the efficacy of psilocybin, we found a trend for patients who discontinued to have higher expectation for escitalopram. This may be amplified by the conflation of withdrawal symptoms with depression symptoms discussed above, which may have been present for discontinuers when this expectation rating was collected. In the present paper, we have only addressed and discussed the relationship between expectation and discontinuation; however, a more focused and detailed analysis and discussion of expectancy effects will be presented in an upcoming paper. Psilocybin is now being investigated for the treatment of depression, post-traumatic stress disorder, addiction, anorexia nervosa and obsessive-compulsive disorder, conditions that are often managed with serotonergic medications (American Psychiatric Association, 2010;. From a safety point of view, there is likely little risk of combining SSRI/SNRIs with classic psychedelics like psilocybin, LSD and DMT (although this is different for psychedelics containing monoamine oxidase inhibitors, like ayahuasca, which can increase the risk of serotonin syndrome). Nevertheless, discontinuation from serotonergic ADs has become convention in the field due to both a lack of fully established evidence for safety when combining psychedelics with SSRI/SNRIs, and previous reports that SSRI/SNRIs may reduce the acute effects of psychedelics, possibly reducing their therapeutic efficacy. A recent survey study also supported these earlier reports, suggesting that concurrent use of SSRI/SNRIs may weaken psilocybin's effects acutely, despite not investigating the sub-acute antidepressants effects. A recent small open-label trial of psilocybin therapy in 19 MDD patients taking concomitant SSRI therapy delved into the matter, finding that concomitant SSRI treatment might still lead to significant antidepressant effects after psilocybin, suggesting that discontinuation might not be required. Another RCT indicated that an atypically brief period of just 15 days of pre-treatment with escitalopram had no relevant effect on positive mood effects of psilocybin. However, it significantly reduced self-rated 'bad' drug effects, physiological effects and other subjective effects like feelings of 'ineffability', 'any drug effect', 'being talkative' and 'open'. However, both these studies had small sample sizes, and the sample of the second study consisted of healthy subjects who were pre-treated with escitalopram for just 2 weeks -likely not long enough for long-term receptor downregulation effects or other homeostatic changes. However, it is known that the team behind this study are currently undertaking a trial with 6 weeks treatment with serotoninergic antidepressants (personal communication with authors), and an increasing number of ongoing psychedelic trials are not requiring discontinuation of SSRI/SNRIs prior to study enrolment anymore. In case future research on concomitant treatment with psilocybin and SSRI/SNRIs reveals an impairment of psilocybin's antidepressant effects, three speculative strategies might be adopted. The first involves a cautious tapering process, potentially over longer periods as suggested by, or employing partial tapering regimens aimed at reducing rather than completely discontinuing SSRI/SNRI doses. This could help minimize withdrawal symptoms and the influence of SSRI/SNRIs on the effects of psilocybin.note that the most substantial withdrawal symptoms occur during the final phase of tapering -from low doses to full discontinuation. However, this approach may prolong the treatment gap, increasing the risk of disease severity before psychedelic treatment. The second strategy would be to administer higher doses of psychedelics to patients currently on SSRI/SNRI treatment. This approach has not been formally researched, but a case report indicated that increasing the psilocybin dose could enable experiences akin to those with standard doses in non-SSRI/SNRI users. Given that chronic antidepressant use may lead to 5-HT2A receptor downregulation and desensitizationand considering that psychedelic experience intensity correlates with 5-HT2A receptor occupancy, investigating increased psychedelic doses in SSRI/SNRI-treated patients could be a promising research avenue. However, it is crucial to consider the potential for a ceiling effect in 5-HT2A receptor occupancy. It is important to note that these strategies are not mutually exclusive, and each presents a viable avenue for further investigation. Future research could explore these strategies to ascertain the most effective approach for enhancing psilocybin therapy outcomes. Lastly, some caution in combining psilocybin with classic SSRI/SNRIs should be mentioned in cases of QTc prolongation, which can be sometimes associated with cardiac arrhythmia. High doses of psilocybin could indeed lead to transient QTc increases up to 10 ms, and most common SSRI/SNRIs used at clinical doses are also associated with QTc prolongation. However, more research in controlled settings with chronic antidepressant users is required to better understand the interaction between SSRI/SNRIs and psychedelics before conclusions can be drawn.
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Demographics and discontinuation: There were no significant demographic differences between discontinuers and unmedicated patients in age, sex, ethnicity or employment. In total, 11 psilocybin-arm and 9 escitalopram-arm participants had discontinued SSRIs/SNRIs (venlafaxine, paroxetine, sertraline, duloxetine and citalopram) prior to the trial; a small number who had discontinued other psychiatric medications were excluded from further analyses. All discontinued participants had been off medication for at least 2 weeks before baseline. Baseline effects of discontinuation: Regression and mixed‑model analyses indicated a worsening of depressive symptoms from screening to baseline among discontinuers versus unmedicated patients. For QIDS-SR16, discontinuation predicted higher baseline scores with a mixed-model estimate of β = 2.21 (95% CI 0.21, 4.23), and for BDI the increase was β = 3.66 (95% CI 0.85, 6.48). Simple regressions on baseline scores showed trends in the same direction for QIDS-SR16, HAM-D, MADRS and BDI, but some of those CIs crossed zero in the extracted text. Primary outcome (QIDS-SR16): Analyses stratified by discontinuation status produced contrasting results. Among discontinuers, model comparison showed that Treatment (psilocybin vs escitalopram) did not significantly add to the model, indicating no consistent difference between arms. Conversely, among unmedicated patients Treatment did add significantly, with the psilocybin arm showing greater decreases from baseline at almost all timepoints except week 2. Reported additional decreases for psilocybin versus escitalopram in unmedicated patients included Week 1 β = -3.73 (95% CI -6.40, -1.06), Week 3 β = -3.21 (95% CI -5.81, -0.61), Week 4 β = -3.89 (95% CI -6.56, -1.22), Week 5 β = -4.08 (95% CI -6.73, -1.44), Week 6 β = -3.39 (95% CI -6.01, -0.76) and Follow-up β = -3.00 (95% CI -5.60, -0.40). The authors state that these amounted to an additional three to four QIDS-SR16 points in the psilocybin group, corresponding to an additional antidepressant effect of roughly 50%–120% over escitalopram in this subgroup. Other depression and well‑being measures: The pattern seen for QIDS-SR16 was mirrored on HAM-D, MADRS, BDI and WEMWBS. For discontinuers, Treatment did not significantly improve model fit for these measures. Among unmedicated participants, psilocybin produced substantially greater improvements than escitalopram: for HAM-D the additional drop was reported as 9.52 points (95% CI -12.43, -6.62), and for MADRS an additional drop of 12.08 points was reported (95% CI not fully clear in the extraction). BDI showed significant additional drops at Week 2 (β = -9.25, 95% CI -15.52, -2.99), Week 4 (β = -13.68; CI not fully reported) and Follow-up (β = -9.68; CI not fully reported). WEMWBS scores increased more with psilocybin among unmedicated patients, with added increases of about 13.4–14.2 points at several timepoints. Full-model interactions (M3): When modelling all subjects together, discontinuation moderated responses differently by treatment arm. In the escitalopram arm, discontinuers showed greater decreases in QIDS-SR16 than unmedicated patients at weekly timepoints (e.g. Week 1 β = -3.64, 95% CI -7.04, -0.24; Week 3 β = -5.91, 95% CI -9.18, -2.63). By contrast, in the psilocybin arm discontinuation was associated with a reduced antidepressant response versus unmedicated patients, with significant positive Time:Treatment:Discontinuation interactions at most timepoints (e.g. Week 2 β = 5.99, 95% CI 1.33, 10.66; Week 3 β = 6.47, 95% CI 1.91, 11.02; Week 5 β = 8.31, 95% CI 3.67, 12.94; Follow-up β = 4.79, 95% CI 0.23, 9.35), indicating that discontinuers in the psilocybin condition improved less than unmedicated participants. Acute subjective experience and expectation: Regression analyses showed that discontinuation status did not significantly predict acute experience scores on MEQ, EDI, EBI or CEQ for either dosing session (examples: MEQ dosing 1 β = 0.04, 95% CI -0.11, 0.18; CEQ dosing 1 β = 0.002, 95% CI -0.089, 0.093). By contrast, Treatment condition strongly predicted these acute measures, with clear psilocybin > escitalopram effects on MEQ, EDI and EBI. Baseline expectation analyses indicated no significant relationship between discontinuation and expected efficacy of psilocybin, though there was a trend for higher expectancy for escitalopram among discontinuers (β = 10.9, 95% CI -0.09, 21.88).
Erritzoe and colleagues interpret these exploratory post hoc findings to mean that recent discontinuation of SSRIs/SNRIs may have attenuated the antidepressant response to psilocybin in this trial, while paradoxically those who discontinued appeared to respond better to escitalopram. The investigators suggest that this discontinuation effect could have contributed to the absence of a statistically significant difference on the trial's primary outcome when analysed without accounting for discontinuation, and therefore that discontinuation status is an important potential confound to consider in psychedelic trials. Two principal mechanisms are discussed. First, chronic SSRI/SNRI treatment can induce downregulation or desensitisation of serotonin receptors, notably 5-HT2A receptors, which could in theory blunt psilocybin's efficacy; however, the present analyses found no evidence that discontinuation altered the intensity of acute subjective psychedelic experiences, which complicates a simple receptor-downregulation explanation and raises the possibility of a dissociation between acute subjective effects and antidepressant outcome. Second, the process of tapering and short-term withdrawal may have produced a discontinuation syndrome or temporary worsening of depressive symptoms: discontinuers showed increased symptom severity between screening and baseline, and withdrawal-related somatic and affective symptoms could have inflated baseline severity and interact with subsequent treatment response. Expectation effects may also have played a role, as there was a trend for discontinuers to have higher expectation for escitalopram, which could partly explain their relatively larger response in that arm. The authors emphasise that these analyses are exploratory and post hoc, with small and unequal subgroup sizes, and therefore cannot establish causation. Important limitations they acknowledge include the absence of formal measurement of withdrawal symptoms, lack of detailed taper-duration data, potential baseline differences between discontinuers and unmedicated patients (for example, greater prior treatment exposure among discontinuers), and the inability to disentangle drug effects from the considerable psychological support provided to all participants. They note that prior small studies have produced mixed findings on concomitant SSRI use and psychedelic effects, and that safety evidence for combining SSRIs/SNRIs with classic psychedelics is still limited. Finally, the researchers outline possible clinical and research implications discussed in the paper: if concomitant SSRIs/SNRIs reduce psilocybin efficacy, potential strategies for future study include longer or partial tapering regimens, investigating higher psychedelic doses for those on serotonergic medication, or formally testing continuation versus discontinuation in controlled trials. They also caution about cardiac considerations (QTc prolongation) when combining high-dose psilocybin with certain SSRIs/SNRIs and call for confirmatory research to inform clinical practice and policy.
The investigators conclude that recent discontinuation of SSRIs/SNRIs may be associated with a reduced antidepressant response to psilocybin. They recommend caution when deciding to taper serotonergic antidepressants prior to psychedelic treatment and suggest that longer or partial tapering strategies could be considered, but stress that confirmatory, prospectively designed research comparing continuation versus discontinuation is urgently needed. The authors also note that a requirement to discontinue commonly prescribed antidepressants could complicate broader implementation of psilocybin therapy, and that further work is required to determine whether discontinuation is a necessary prerequisite for effective treatment.