What this is
- This scoping review examines the safety and efficacy of using antidepressants (ADs) alongside classic psychedelics.
- It addresses concerns about serotonin syndrome and the impact of ADs on the therapeutic effects of psychedelics.
- The review includes 19 studies, highlighting the potential benefits and risks of concurrent treatment.
Essence
- Concomitant use of antidepressants and classic psychedelics appears generally safe, with no significant increase in serotonin syndrome risk. Some studies indicate improvements in depression symptoms, challenging the need for antidepressant discontinuation before psychedelic treatment.
Key takeaways
- Concomitant use of antidepressants with classic psychedelics is generally safe and tolerable, showing no robust evidence of increased serotonin toxicity.
- Some studies report significant improvements in depression and other mental health symptoms when ADs are maintained during psychedelic treatment.
- The common practice of discontinuing ADs prior to psychedelic treatment may be unnecessary and could limit patient access to these therapies.
Caveats
- The findings are based on a limited number of studies, primarily case reports and observational data, which may not provide robust evidence.
- There are significant knowledge gaps regarding specific drug interactions and the effects of different classes of antidepressants.
- Future research is needed to clarify the impact of psychological support and treatment settings on the efficacy and safety of combined treatments.
Simplified
Introduction
In the past decade, interest in the therapeutic use and potential of classic psychedelics in the treatment of various psychiatric disorders has rapidly increased (). Recent reviews have supported the promising therapeutic efficacy of psychedelics, often combined with psychological support (), with rapid and sustained improvements in a sizeable proportion of patients with major depressive disorder (MDD) (;).
In real-world environments, symptoms of MDD are typically managed with various monoaminergic antidepressants (ADs), which include selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), noradrenalin and dopamine reuptake inhibitors (NDRI), tricyclic ADs (TCAs), monoamine oxidase inhibitors (MAOIs), and atypical ADs (e.g. bupropion, mirtazapine, vortioxetine) (;;). Most of these conventional ADs seek to increase intrasynaptic levels of serotonin, which is thought to be the mechanism leading to a reduction of depressive symptoms (), either through inhibiting the reuptake of serotonin (i.e. SSRIs) and other neurotransmitters (i.e. SNRIs, NDRIs, TCAs), or by blocking the enzyme monoamine oxidase (i.e. MAOIs) that in turn prevents the breakdown of serotonin in the synaptic cleft ().
Classic psychedelics also affect serotonin neurotransmission, primarily through agonism of post-synaptic 5-HTreceptors (). Essentially, on a theoretical basis, it has been assumed that the concomitant use of ADs with classic psychedelics could synergistically increase serotonin neurotransmission and potentially cause serotonin toxicity (), which refers to a drug-induced "toxidrome" in which intrasynaptic serotonin levels are elevated as a result of drug-drug interactions (). This excess intrasynaptic serotonin agonism is responsible for serotonin syndrome that manifests with a range of clinical symptoms, such as tremor and diarrhea in mild cases, or delirium, neuromuscular rigidity, seizures, coma, and hyperthermia in more severe cases (). Furthermore, early studies indicate that the concomitant use of ADs decreases the acute subjective effects of psychedelics (;;), which are assumed to be responsible for their enduring therapeutic effects (;). Accordingly, to avoid the risk of serotonin toxicity and fully isolate the antidepressant effect of serotonergic psychedelics, patients enrolled in most contemporary clinical trials are typically required to discontinue ADs at least 2 weeks before drug administration (;;;;;).
However, the discontinuation of ADs takes time and represents a significant burden for patients, as it may lead to worsening of depressive symptomatology and increased suicidal ideation that would then occur prior to a potentially challenging psychedelic experience, either through rebound effects, AD discontinuation syndrome, or by interrupting a (partially) effective treatment (;;). Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when ADs are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HTreceptor and would also compete for serotonin binding (;;). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HTreceptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (), particularly as the 5-HTreceptor induces neuroplasticity (;;).
In this scoping review, we aim to identify sources of evidence and gaps in existing research on the concomitant use of ADs and psychedelics in humans (;). The main objective is to obtain information on safety and whether the concomitant use of ADs significantly increases serotonin toxicity risk during psychedelic treatment. We also explored the potential impact of ADs on psychedelic treatment efficacy and acute subjective effects.
Methods
We conducted a scoping review to summarize the existing literature on the concomitant use of conventional ADs and classic psychedelics. Because the extent of existing literature on this topic was initially unclear and we aimed to identify and analyse knowledge gaps (), our research team determined that a scoping review was the most appropriate methodology. This decision was further supported by the web-based "Right Review" tool (), which serves as a decision support system to confirm methodological suitability. Accordingly, we employed the methodological framework outlined by Arksey and O'Malley () and followed the most recent JBI guidelines for conducting scoping reviews ().
A comprehensive search of electronic databases was performed in MEDLINE (PubMed), EMBASE, and Scopus to retrieve relevant literature investigating the concomitant use of conventional ADs and classic psychedelics. The search string included terms relevant to "psychedelics," "antidepressants," and "concomitant use" (see). The systematic search followed PRISMA-ScR guidelines () and was conducted from inception until June 27, 2025.
Articles to be considered for this scoping review needed to focus on the concomitant use of conventional ADs and classic psychedelics. Peer-reviewed journal papers were included if they involved human participants. Quantitative, qualitative, and mixed-method studies were included in order to consider different aspects of the concomitant use of conventional ADs and classic psychedelics and their impact on safety, treatment efficacy, and acute subjective effects. There were no restrictions on language or publication date. Articles identified in all three databases were screened for eligibility by SCT. Reference lists of eligible studies were reviewed to identify additional studies (). Articles that did not fit the research question of this scoping review or with irrelevant titles and abstracts were excluded, as were studies involving animals.
Data were extracted according to a list of parameters, including the last name of the first author, year of publication, study design (e.g. randomized clinical trial, open-label, observational, case study), study population and sample size, psychedelic substance (e.g. psilocybin), dose (milligrams, micrograms, or millilitres), number of doses, psychological support, setting (e.g. environment setup), class of AD, dose of AD (if available), length of AD treatment, other concomitant psychotropic medications, safety in terms of serotonin syndrome and related (serious) adverse events, treatment efficacy, and acute subjective effects. Considering the infancy of this particular topic and limited number of studies (seeand), only SCT as first author of this article extracted data from articles and. All co-authors of the article reviewed the manuscript for correct interpretation of the data and provided input where necessary.
Results
Study flow
The search yielded 483 records, and 479 records remained after the removal of duplicates and the addition of records through reference list searching (). We screened 479 titles and abstracts, which resulted in 21 articles assessed for eligibility. Two full-text articles were excluded because one did not evaluate the concomitant use of ADs and the other assessed the impact of pre-treatment with reserpine, which is not a conventional AD. Ultimately, 19 studies were included in this scoping review. Five studies were published in the 1960s and four studies published in the 1990s, whereas the remaining 10 studies were published after 2022.
Safety
A total of 13 studies evaluated the safety of the concomitant use of ADs and psychedelics (,;;;;;;;;;;;), two randomized, double-blind placebo-controlled crossover trials (,), one double-blind placebo-controlled trial (), one placebo-controlled trial (), three case reports (;;), one retrospective survey (), and one qualitative study ().
Furthermore, the study populations taking ADs and psychedelics concomitantly within these studies consisted primarily of the general population ( = 1044) (;) followed by healthy volunteers ( = 66) (,;;), treatment-resistant depression (TRD) ( = 34) (;;), "neurotic" patients ( = 14) (), abstinent alcoholics ( = 9) (), difficult-to-treat depression ( = 1) (), and mild MDD ( = 1) ().
A total of seven studies looked at psilocybin (;;;;;;). Although two studies did not report on the dosage of psilocybin (;), three studies looked at 25 mg (;;), and only one study looked at 20 mg (). One study also included a batch of dried unknown psilocybin-containing mushrooms (3 g) and another batch of dried(1 g) mushrooms (). There were four studies that evaluated LSD (;;;) with dosages varying from 40 to 75 mcg (), 25–50–100 mcg (), 100 mcg (), and 150–500 mcg (). Only one study looked at two doses of DMT (15 and 60 mg) () and another at the DMT-containing brew, where the dosage was 100 ml ().
Only three studies included psychological support during psychedelic treatment, such as preparation, dosing supervision, and integration (;;). Two studies explicitly reported features of setting (e.g. paintings and dimmed lights) (;), whereas three studies were in ("calm") hospital rooms (,;), and four studies in uncontrolled, naturalistic settings (e.g. psychedelic retreat or ceremony) (;;;).
A total of four studies included a range of ADs (;;;), such as SSRIs, SNRIs, TCAs, MAOIs, and/or atypical ADs (e.g. vortioxetine). Five studies specifically assessed SSRIs (,;;;) and four studies did so with MAOIs (;;;). There were eight studies reporting on the length of AD treatment prior to psychedelic administration (;,;;;;;;), which varied from 2 days (), 2–5 weeks (;;;), 6 weeks (), "several" months (), or up to more than 1 year (;). Although three studies did not report the length of AD treatment (;;), there was one study that did so only for the second dose of(i.e. 2 weeks) (). Finally, there were three studies that included other concomitant psychotropic medications (;;).
Ten studies evaluating the safety of the concomitant use of ADs and classic psychedelics showed no signs of serotonin toxicity or syndrome (;,;;;;;;;). This was observed in psilocybin studies with SSRIs (;;;), SNRIs (), MAOIs (;), TCAs (), SNRIs (;), and/or atypical AD (;), as well as LSD studies with an SSRI () and MAOIs (;;). Two ascending doses of DMT (15 and 60 mg) on the same day together with the concomitant use of either an SSRI, SNRI, serotonin antagonist and reuptake inhibitor (SARI), serotonin modulator and stimulators, or atypical AD (e.g. bupropion) did not result in serotonin toxicity or syndrome (). However, one qualitative study showed that two out of 433 reports were suggestive of severe serotonin syndrome (e.g. seizure and muscle rigidity) (). In addition, one retrospective survey indicated that 2.8% ( = 55) believed they had developed serotonin syndrome, but the study authors were unable to confirm due to the absence of hospital visit reports or formal diagnoses (). Finally, one case study involving a 36-year old man who received the SSRI fluoxetine 20 mg daily for several months for his mild MDD developed symptoms of serotonin syndrome (), approximately one hour after 100 ml of(i.e. gross motor tremors, sweating, shivering, severe nausea, vomiting, as well as disorientation and confusion) but without any long-term adverse sequelae (). This was probably precipitated by MAOIs present within, which then resulted in dangerous levels of intrasynaptic serotonin ().
All 13 included studies reported on (serious) adverse events (AEs) during the concomitant use of ADs and classic psychedelics (;,;;;;;;;;;;), which primarily included headaches (;,;;;;), nausea (;,;;), and increases in blood pressure (;;;;;) . Other less frequent AEs consisted of pharyngeal discomfort and coughing (), impaired concentration and feeling dull (), vomiting (;), pupil dilation (), abdominal pain (), chest pain (), chest heaviness (), heart palpitations (), and increased heart rate (;). Psychological AEs were paranoia, memory loss, or confusion (), distress (), and "massive psychotic symptomatology" (). Furthermore, one retrospective survey showed that only 4% of their entire sample ( = 611) indicated an AE (), but it was not specified.
Notably, three studies found that the concomitant use of ADs was associated with a better safety profile compared to placebo, illustrated by (significant) decreases in systolic and diastolic blood pressure (;), heart rate (), pupil dilation (;), mean arterial pressure (), pupil dilation (), and overall (sub)acute AEs (). In addition, three studies found no significant differences compared to placebo in terms of blood pressure (), mean arterial pressure (), rate pressure product (), body temperature (), QTc interval (,), and/or other (sub)acute AEs (e.g. headaches, nausea, flashbacks, impaired concentration, feeling of weakness, abdominal bloating, lack of energy, insomnia, dry mouth, thirst) (,;). One study found no clinically meaningful changes in suicidal ideation, clinical laboratory tests, ECG, and QTc interval from baseline to 3-week follow-up (). Finally, one case study documented a hypertensive emergency and ST-elevation myocardial infarction (STEMI) in a patient following ingestion of driedmushrooms after a two-week pretreatment period with the MAOI tranylcypromine and extended-release dextroamphetamine-amphetamine, suggesting a possible interaction between both medications and the phenylethylamine found withinmushrooms ().
Treatment efficacy
Seven studies evaluated treatment efficacy following the concomitant use of ADs and psychedelics(;;;;;;). This included four case studies (;;;), two open-label trials (;), and one prospective survey ().
The study populations varied from patients with treatment-resistant depression (TRD) ( = 35) (;;;), difficult-to-treat depression ( = 1) (), mild MDD ( = 1) (), to self-reported psychiatric diagnoses ( = 131) ().
The majority of studies ( = 4) assessed psilocybin (;;;), whereas one study looked at DMT () and another at the DMT-containing brew(). One study evaluated a range of psychedelics, particularly psilocybin (71.4%), LSD (20.6%),(3.2%), and DMT/5-MeO-DMT (4.8%) (). The dosage for psilocybin was 25 mg (;;), 15 and 60 mg for DMT (), 100 ml for(), and was unknown in the study that assessed multiple psychedelic substances (). Another study included one batch of dried unknown psilocybin-containing mushrooms (3 g) and one batch of dried(1 g) mushrooms ().
There were four studies that included psychological support, such as preparation, dosing supervision, and integration (;;;). Only two studies explicitly reported the setting in which a psychedelic was administered (;), whereas three studies included an uncontrolled, naturalistic (;;), and one study a "clinical" setting ().
One open-label trial () and one case study () specifically evaluated SSRIs, whereas another case study did so with a SARI (). The remaining three studies included a range of ADs (;;;), such as SSRIs, SNRIs, SARIs, TCAs, MAOIs, serotonin modulators and stimulators, and/or atypical ADs (e.g. vortioxetine). Only three studies included the length of AD treatment prior to psychedelic administration and varied from 2 weeks (), "several" months (), and up to ~14 months (). Finally, there were three studies that included other concomitant psychotropic medications (;;). Four studies showed significant improvements in symptoms of depression following the concomitant use of ADs and classic psychedelics (;;;;). This was observed in psilocybin with SSRIs (;), SARI (), SNRIs (;), and/or atypical AD (), as well as in LSD with SSRIs and/or SNRIs (). Moreover, one study with DMT showed that decreases in depressive symptoms were greater in TRD patients with ADs compared to TRD patients without ADs, although this difference was only marginally significant (). Notably, three of studies showed full remission of depression following psilocybin (25 mg) (;) and DMT (), despite the concomitant use of ADs. This effect was sustained at the 6-month follow-up in one case study with psilocybin (). Other (significant) improvements were observed in four studies in terms of "mental health" (), anxiety (), suicidality (;), illness severity (), and well-being (). Furthermore, one case study exemplified that the experience withand the concomitant use of the SSRI fluoxetine was considered a "valuable experience" in helping a patient reconcile with his wife after being unfaithful to her, despite the aforementioned symptoms of serotonin syndrome ().
Finally, one case study indicated a worsening in symptoms of depression, anxiety, and suicidality, which was hypothesized to be the result of discontinuing the SNRI duloxetine two weeks before a second dose of psilocybin (25 mg) ().
Subjective effects
Nineteen studies evaluated the impact of concomitant AD use on the acute subjective effects of classic psychedelics (;;,;;;;;;;;;;;;;;;).
The designs of these studies varied widely and consisted of two randomized double-blind placebo-controlled crossover trial (,), one double-blind placebo-controlled trial (), one placebo-controlled trial (), five open-label trials (;;;;), five case studies (;;;;), one retrospective survey (), one prospective survey (), and three qualitative studies (;;) .
The study population was highly heterogeneous and varied from patients with MDD ( = 38) (;), treatment-resistant depression (TRD) ( = 35) (;;;), difficult-to-treat depression ( = 1) (), mild MDD ( = 1) (), anxiety disorder ( = 1) (), obsessionality ( = 1) (), dysthymia ( = 2) (;), post-traumatic stress disorder ( = 1) (), attention-deficit disorder ( = 1) (), "stress" ( = 1) (), being "neurotic" ( = 14) (), self-reported psychiatric diagnoses ( = 131) (), and abstinent alcoholics ( = 9) (). Four studies looked at healthy volunteers ( = 73) (;;;;) and two studies at the general population ( = 1,044) (;).
There were eight studies that specifically assessed psilocybin (;;;;;;;) and seven studies did so for LSD (;;;;;;). In addition, two studies looked at DMT (;) and another at the DMT-containing brew(). Finally, one study included a range of psychedelics, particularly psilocybin (71.4%), LSD (20.6%),(3.2%), and DMT/5-MeO-DMT (4.8%) (). The dosage for psilocybin was 25 mg in four studies (;;;) and 20 mg in only one study (). There was also one study that included one batch of dried unknown psilocybin-containing mushrooms (3 g) and one batch of dried(1 g) mushrooms (). Regarding LSD, the dosage varied widely from 25 mcg (), 40 mcg (), 50 mcg (), 75 mcg (;), 100 mcg (;), 150 mcg (), 400 mcg (), to 500 mcg (;). The dosage forwas 100 ml () and for DMT it was 15 mg and 60 mg () and 0.35–0.55 mg/kg and 0.65–0.84 mg/kg (). There were five studies that did not report the specific dosage for any classic psychedelic (;;;;) .
There were four studies that included psychological support, such as preparation, dosing supervision, and integration (;;;). The setting in which a psychedelic was administered was reported by only two studies, such as the use of dimmed lights and paintings in the room (;). Finally, three studies featured a (calm) hospital room (;;) and one study a "clinical" setting (). The remaining seven studies comprised uncontrolled, naturalistic settings (e.g. psychedelic retreat or ceremony) (;;;;;;).
Regarding AD class, seven studies evaluated a range of ADs (;;;;;;), including SSRIs, SNRIs, SARIs, TCAs, MAOIs, serotonin modulator and stimulators, and/or atypical ADs (e.g. bupropion or vortioxetine). Furthermore, six studies specifically assessed SSRIs (,;;;;) and another five studies looked at MAOIs (;;;;). There was only one study that evaluated a SARI (). The length of AD treatment varied widely in 12 studies and ranged from 2 days (), 4 days (), 2 weeks (;;), ~3 weeks (;;), 5 weeks (), 6 weeks (), "several" weeks (), less than 1 month (), "several" months (), ~14 months (), more than 1 year (), and up to 3 years (;). One study only reported the length of AD treatment for the second dose ofand was 2 weeks (). Finally, there were three studies that included other concomitant psychotropic medications (e.g. zolpidem) (;;).
Ten studies showed that the concomitant use of ADs (significantly) decreased the acute subjective effects of classic psychedelics (;;;;;;;;;). Specifically, this relationship was observed in four psilocybin studies with SSRIs (;;;), SNRIs (;), and/or atypical ADs (), six LSD studies with SSRIs (;;), SNRIs (), SARIs (), and/or MAOIs (;;), and one DMT study with MAOIs ().
Furthermore, six studies illustrated that the concomitant use of ADs completely eliminated the acute subjective effects of classic psychedelics (;;;;;). This was shown in two psilocybin studies with MAOIs (), TCAs (), and/or SARIs (), three LSD studies with SSRIs (), SARIs (), and/or MAOIs (;), and one DMT study with MAOIs ().
Simultaneously, eight studies show that the concomitant use of ADs does not result in (significant) changes in the acute subjective effects of classic psychedelics (;;;;;;;). This was observed in five psilocybin studies with SSRIs (;;), SNRIs (;), MAOIs (), and/or atypical ADs (;), two LSD studies involving an SSRI () or MAOI (), one DMT study involving a range of ADs (), and one study involving an SSRI and the DMT-containing brewand ().
In addition, four studies indicate an increased intensity of acute subjective effects (;;;). This was observed in two psilocybin studies concurrent with SSRIs (;), SNRIs () and/or atypical ADs (), and two LSD studies concurrent with an SSRI () and/or TCAs ().
Finally, one retrospective survey study showed that respondents ( = 128) were not sure whether their concomitant use of ADs impacted the acute subjective effects of psilocybin ().
Discussion
In this scoping review, we identified 19 studies evaluating the concomitant use of conventional ADs and classic psychedelics. The main findings indicate that this combination appears generally safe and tolerable with no robust evidence of increased risk for serotonin toxicity or syndrome. Furthermore, some studies reported significant improvements in depression and other symptoms with combined treatment. A final observation was the potential attenuation of acute subjective effects of psychedelics, although other studies did not show this. These findings appear to challenge the common practice of AD discontinuation before psychedelic treatment.
One of the most important clinical implications of this scoping review is that the concomitant use of ADs could significantly increase access to psychedelic treatment. For instance, SSRIs are the most frequently prescribed ADs for reducing depressive symptoms in patients with MDD (;). Currently, only four out of 100 registered psilocybin studies allow the use of SSRIs while 84 exclude the use of SSRIs (). Yet, findings from this scoping review suggest that this combination is not reliably associated with increased risk of serotonin toxicity (,;;;). In addition, adverse events in this scoping review were either very low (;) or similar to placebo (,;) in terms of intensity and frequency, and seem to correspond with recent psilocybin trials without concomitant AD medication (). Furthermore, combining SSRIs with psilocybin may offer a promising approach for patients with MDD who are hesitant to discontinue ADs (;), particularly due to concerns regarding relapse or withdrawal symptoms (). These concerns are well-founded as AD discontinuation symptoms can increase the risk of MDD relapse by 40% () and affect approximately 56% of patients (). Typically, symptoms following the discontinuation of SSRIs appear within the first few days and can last for several weeks, ranging from physical manifestations (e.g. headaches, malaise, insomnia, and nausea) to psychological effects (e.g. anxiety/agitation, irritability, and difficulty concentrating) (;). Notably, preliminary results indicate that AD discontinuation symptoms may negatively impact the efficacy of psilocybin (;), although most recent evidence does not support this relationship ().
This scoping review further revealed the potential of ADs to attenuate the acute subjective effects of psychedelics, which could impact the efficacy of psychedelics. In the past, some have argued that the acute subjective effects are essential for therapeutic benefit (), as it tend to be a significant predictor for positive therapeutic outcomes in several psychiatric disorders (). Conversely, it is argued that psychedelics may also exert therapeutic effects in the absence of acute subjective effects and are instead mediated by neurobiological mechanisms (,). Within this scoping review, significant improvements in mental health or depressive symptoms without any acute subjective effects was observed in two case studies involvingmushrooms (species unknown) concomitant with an MAOI and TCA (), and psilocybin concomitant with a SARI (). This therapeutic response can be explained by increases in neuroplasticity and brain-derived neurotrophic factor (BDNF) as demonstrated in rodent research involving classic psychedelics (;;;). Notably, two randomized double-blind placebo-controlled crossover trials in this scoping review show that the significant increase of BDNF following psilocybin () and LSD () is not significantly affected by concurrent use of SSRIs compared to placebo in healthy volunteers. However, one open-label trial () and another prospective survey () in this scoping review revealed significant improvements in depressive symptoms following psilocybin or LSD alongside acute psychedelic effects despite concurrent use of SSRIs and/or SNRIs. In short, regardless of whether the acute subjective effects are responsible for efficacy, findings from this scoping review indicate that the concomitant use of ADs does not appear to negatively impact psychedelic treatment outcomes. Taken together, these findings challenge the current practice of AD discontinuation before psychedelic treatment.
Findings from this scoping review must be interpreted with caution due to a paucity of randomized controlled trials, with current evidence largely derived from case reports (;;;;), qualitative studies (;;), surveys (;), and/or open-label studies lacking a control group (;;;;) with highly heterogenous study populations. Furthermore, this scoping review highlights several critical knowledge gaps and warrant further investigation. First and foremost, the complex interplay between specific dosages of ADs and classic psychedelics remains poorly understood, necessitating controlled studies to elucidate specific dose-response relationships and the distinct effects of particular AD classes. The urgent need for clearer guidance is further underscored by recent survey data, illustrating that medication interactions (e.g. ADs) with psychedelics was among the most commonly desired educational topics reported by psychiatrists (). Secondly, while psilocybin has been relatively well-studied, data for LSD is limited () and exists primarily for the concomitant use of MAOIs that is also very old (;;), albeit showing a good safety profile and no signs of serotonin syndrome. Data for DMT (;),(), and 5-MeO-DMT () is extremely limited. Further investigation is crucial to determine the precise risk of serotonin syndrome within these other classic psychedelics, particularly with specific combinations likeand SSRIs/MAOIs (;). Thirdly, robust randomized placebo-controlled trials are essential to establish the true therapeutic potential of combined treatment, focusing on different patient populations (e.g. MDD, TRD, or post-traumatic stress disorder), employing standardized clinical outcome measures, other psychotropic medications (e.g. antipsychotics), and including follow-up assessments to evaluate long-term safety and efficacy. Fourthly, the potential attenuation of acute psychedelic effects by different ADs, the duration of AD treatment, as well as the variability in individual experiences, demand further exploration through psychometric scales typically used within psychedelic research (;;). Finally, it is unclear to what extent psychological support and setting affect combined treatment due to heterogeneous and limited data (;;). Importantly, both components are implicated in safety and treatment efficacy (), and setting seems able to moderate the acute subjective effects of psychedelics (;). Future researchers should employ the Template for Intervention Description and Replication () and Reporting of Setting in Psychedelic Clinical Trials (ReSPCT) guidelines (). Respectively, this allows them to exemplify the nature and extent of psychological support and setting and how it influences safety, tolerability, and efficacy of psychedelics. Future research addressing these knowledge gaps and recommendations could significantly enhance the rigor, replicability, and generalisability of findings, ensuring the safe and effective clinical implementation of psychedelics in general as well as combined treatment with ADs.
In conclusion, findings from this scoping review indicate that the discontinuation of ADs within psychedelic research may be unnecessary and unwarranted, given the very limited evidence that ADs increase the risk of serotonin syndrome or other adverse events. Furthermore, combined treatment does not appear to impact efficacy of psychedelics. While there is some evidence that concomitant ADs may attenuate the acute subjective effects of psychedelics, it does not appear to significantly decrease therapeutic outcomes. The continuation of ADs would significantly increase accessibility for psychedelic treatment. Future research is needed to disentangle the impact of the concomitant use of ADs and psychedelics and enhance the rigor, replicability, and generalisability of findings.
Psychedelic Science