The mushrooming of the psychedelic renaissance: A scoping review identifying trends in ongoing clinical trials

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John Winhusen, Davide Amato This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8544354/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aims: The investigation of psychedelics as potential therapies has expanded dramatically in the past decade, leading to their study in a wide range of conditions. Here, we characterize all ongoing clinical trials utilizing a psychedelic intervention with the goals of identifying trends in experimental design and application and discuss how findings from individual, ongoing clinical trials may address current unanswered questions or recommendations from the field. Methods: A scoping review approach was used to identify registered clinical trials at ClinicalTrials.gov that listed a classic psychedelic as intervention criteria. All ongoing clinical trials were characterized by their study criteria, experimental design, and clinical trial status. When available, specific psychedelic analogs are included with their representative trial. Results: We identified 165 ongoing clinical trials that utilize a treatment intervention with a classic psychedelic. Most clinical trials were early phase, actively recruiting trials based in the United States for depression. Comparisons of experimental design criteria revealed that psychedelics are mostly administered a single time and use either an open-label, single-arm design, or a parallel-assignment, quadruple-blinded, active-placebo design. In our search, we found that only six trials explicitly report blinding effectiveness as a trial outcome and that 33 different placebos are being used as a control across psychedelic trials. Conclusion and Implications: Multiple clinical trials have been initiated that have the potential to shed insight on common critiques and unanswered questions in the field. Despite this, some areas warranting clarity remain, such as identifying a proper placebo or improving participant masking rates. We hope that insights from this review will help inform the reader of the status for clinical psychedelic research and inspire initiation of new clinical trials that may address the shortcomings discussed herein. Clinical Pharmacology Psychiatry psychedelics psilocybin depression psychiatric disorders clinical trials Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Between 1990 and 2019, prevalence of mental disorders including depressive, anxiety, eating, and bipolar disorders has risen nearly 150% (654.8 million to 970.1 million) with most notable increases in depressive (163%; 170.8 million to 279.6 million) and anxiety (154%; 194.9 million to 301.4 million) disorders ( 1 ). These increases were further exacerbated following the COVID-19 pandemic where prevalence of depression and anxiety has been estimated to have raised 25–30% ( 2 , 3 ). Perhaps the largest concern for addressing these alarming trends is the high rate of treatment resistance. Although estimates vary, antidepressant treatment-resistance occurs in approximately 30% ( 4 ) of individuals with estimates as high as 55% ( 5 ) and antipsychotic treatment resistance occurs in about 23% of individuals with 84% being resistant at illness onset ( 6 ). In pursuit of more efficacious treatments for psychiatric and mental illnesses, there has been a resurgence of interest in classic psychedelics for their ability to induce mystical experiences that are accompanied by rapid and lasting changes in depressive symptoms and neuroplasticity ( 7 – 10 ). Classic psychedelics include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline; however, most attention in clinical trials has been given to psilocybin. This class of drugs has widespread effects in the brain primarily through serotonin 2A (5-HT 2A ) receptor agonism causing downstream activation of glutamatergic, brain derived neurotrophic factor (BDNF), dopaminergic, GABAergic, and anti-inflammatory systems, which are believed to underlie the subjective effects, neuroplasticity, and antidepressant effects of the drugs ( 10 – 12 ). Recently, COMP360 ( 13 ), CYB003 ( 14 ) and synthesized psilocybin ( 15 ), which are derivatives of natural-occurring psilocybin or its active metabolite psilocin, were granted ‘Breakthrough Therapy’ designation by the Food and Drug Administration (FDA) for major depressive disorder (MDD) or treatment-resistant depression (TRD) indicating these compounds offer new benefits over existing standard of care. Following promising results in early phase clinical trials indicated for depression, psychedelics are now being tested for other mental and psychiatric conditions that lack efficacious treatments. We recently characterized all registered clinical trials applying psychedelics to substance use disorders (SUDs) to capture the status of clinical investigations ( 12 ). Here, we expand our characterization of ongoing registered clinical trials to all applications of classic psychedelics with the goal of capturing these new clinical applications, identifying trends in psychedelic clinical trials, and assessing the research outlook for psychedelics. Last, we highlight key clinical trials that may address unanswered questions or limitations in the field and provide a discussion of how the generalizability of psychedelics fit into current theoretical models. Methods This scoping review protocol was not registered allowing for flexibility in our search approach. We sought all registered clinical trials that are reported by ClinicalTrials.gov that utilized classic psychedelics as a treatment intervention. To limit the possibility of missing clinical trials through advanced search terminology and techniques, basic searches were carried out with condition criteria for Depressive Disorders, Anxiety Disorders, Post Traumatic Stress Disorder, or Psychiatric Disorders and interventions for either psilocybin, LSD, DMT, and mescaline. No inputs for “Other Terms” were used except for Post-Traumatic Stress Disorder searches and Psychiatric Disorders, which were “PTSD” and “Psychotic Disorders”, respectively. Grey searches were conducted for each condition with the intervention criterion listed as “psychedelic”. Additionally, a grey search was conducted for each individual classic psychedelic intervention with no condition or other term inputs. An example search is provided in supplementary material. Data was exported for each search to obtain NCT Number, Study Title, Study Status, Conditions, Interventions, Primary Outcome Measures, Secondary Outcome Measures, Sponsor, Sex, Phases, Enrollment, Study Type, Study Design, Start Date, and Completion Date. The last search occurred on May 18th, 2025, and there were no restrictions for the year uploaded. Figure 1: Systematic Review Methodology Flowchart schematic of systematic search for ongoing clinical trials in the clinicaltrials.gov database. Clinical trials were then manually characterized and verified by L.W. and D.A. independently. Exclusion criteria for our characterization involved lacking relevance, a classic psychedelic, or psychedelic intervention. Thus, observational and retrospective study designs were excluded. Additionally, two clinical trials were excluded due to reporting inconsistencies, and one clinical trial utilized a psilocybin as a control/comparator group to characterize the acute subjective effects of 4-bromo-2,5-dimethoxyphenethylamine (2-CB) (NCT05523401). Trends and characteristics were then identified across all clinical trials using Microsoft Excel and visualized using GraphPad Prism 10 software. All clinical trials were then sorted by their relevant condition and input into condition-specific tables using Microsoft Excel. Condition sorting was done through comparing the target population or condition, listed goal and purpose of the experiment, and primary outcomes resulting in some similar clinical trials to be separated, but not repeated, across tables. For example, clinical trials measuring depressive symptoms in populations diagnosed with life-threatening illnesses are characterized with other clinical trials focused on individuals with life-threatening illnesses independent of those focused on major depressive disorder for simplification. Some data using completed clinical trials are included in the supplemental information; however, because completed clinical trials are outside the scope of this review, full characterization of completed clinical trials is not shown but are available upon request from the authors. Results A total of 1446 clinical trials were identified ( Fig. 1 ). Following the removal of duplicates (n = 740) and exclusions (n = 416), there were 290 total clinical trials. Of these, 101 clinical trials were completed, 24 had either withdrawn, suspended, terminated, or unknown status; and 165 were ongoing clinical trials. Most ongoing clinical trials are taking place in the United States (n = 96), Canada (n = 25), Switzerland (n = 11), or United Kingdom (n = 8) ( Fig. 2A ). Nearly all clinical trials are early phase clinical trials, particularly phase I (n = 60), II (n = 72), I/II (n = 9) ( Fig. 2B) . Additionally, there are twelve phase III clinical trials, one phase IV clinical trial, one phase II/III clinical trial, and ten clinical trials that did not fall under a specific phase, such as pilot studies where the trial manager specified “N/A” under Phase criterion. Status varied across all groups with most clinical trials either actively recruiting (n = 92) or not yet recruiting (n = 47) ( Fig. 2C ). Twenty-three clinical trials were active, but not recruiting, and three clinical trials were enrolling by invitation only. Despite most clinical trials still in early stages in investigation, more than 75% of clinical trials have expected study completion dates in the next few years (2025 n = 55; 2026 n = 41; 2027 n = 33) (Fig. 2D ). Clinical trial protocols can be registered under specific purpose designations, which include treatment, prevention, supportive care, screening, diagnostic, health services research, basic science, device feasibility, or other. The most common purpose detected in ongoing clinical trials was treatment (n = 111) indicating a psychedelic intervention being tested to treat a diagnosis or condition ( Fig. 2E ). Basic science indication was the second most common category (n = 25), which are protocols designed to investigate components of a psychedelic intervention such as mechanism of action, neural activity or plasticity changes, biomarkers, or feasibility of a new psychedelic protocol/application. Additionally, seven clinical trials were indicated for supportive care, three trials for health services research, two for prevention, and 17 indicated as other. Both sexes were included for all clinical trials except for three, which only included females ( Fig. 2F ). These clinical trials are testing the efficacy of psilocybin interventions for sexual assault-related PTSD (NCT06902974), fear of ovarian or breast cancer recurrence (NCT06430541), and chronic pain in fibromyalgia (NCT05068791), all of which are conditions with higher prevalence in females ( 16 – 18 ). Figure 2: Characteristics of ongoing clinical trials using psychedelic interventions Clinical trial characteristics of unique hits reported by trial managers including study location (A), trial phase (B), status (C), estimated completion year (D), reported purpose (E), and included sex (F). Trials that lacked a study location were organized based on Sponsor criteria for visualization. Across all ongoing clinical trials, the most common experimental design was a parallel assignment (n = 80) where a psychedelic intervention is compared to a placebo or active comparator group ( Fig. 3A ). Although it was more common that clinical trials implemented a placebo or comparator group ( Fig. 3B inset ), there is a large variety of placebos and comparators being used resulting in no placebo being the most consistent approach across clinical trials (n = 59). Active placebos, the most common placebo type utilized ( Fig. 3B ) are compounds comparator groups receive that are either the same drug as the experimental group at a lower, often inactive dose, or a different compound that has therapeutic effects independent of the tested condition, like niacin. Thirty-seven of the fifty clinical trials that utilized an active placebo gave individuals either a lower dose of the same psychedelic compound or the same dose with an experimental manipulation. Inactive placebos refer to a wide range of placebos that are known to not have a pharmacotherapeutic effects for the tested condition. The most common inactive placebos detected was microcrystalline cellulose (n = 6). For both design manipulation and comparator drug groups, there were no more than two clinical trials that utilized the same comparator group treatment. Some of these included, sham vagus nerve stimulation, treatment as usual, waitlist control; and ketamine, cannabis, and MDMA. Unfortunately, twenty-six clinical trials stated they are using a placebo, but did not specify what placebo or treatment these individuals are receiving ( Fig. 3B ). Due to the prominence of single assignment, placebo-lacking clinical trial designs, the most common blinding type was open-label (n = 72) approaches indicating participants, clinicians, researchers, and outcomes assessor were fully aware of the treatments all participants were receiving ( Fig. 3C ). The second most common blinding approach was a quadruple (n = 47) blinding where all parties remain blinded through the duration of the study. Triple blinding typically involved the blinding of participants, investigators, and outcomes assessor. One clinical trial (NCT05259943) utilizes triple blinding of the participant, clinician, and researcher, but has an optional open-label crossover after participants complete the trial. Clinical Trials by Psychedelic Drug We were able to identify clinical trials that utilize every classic psychedelic. The most prominently studied classic psychedelic is psilocybin (n = 144) ( Fig. 3D ), which also had the largest number of specific compounds (n = 11) ( Fig. 3E ). Specified psilocybin compounds include: APEX002-02 (n = 1), COMP360 (n = 7), CY-39 (n = 1), CYB003 (n = 4), ELE-101 (n = 1), MLS101 (n = 1), PEX010 (n = 18), PEX020 (n = 1), PEX030, TRP-8802 (n = 1), and psilocybin cubensis (n = 3). Analysis of individual dose and dosing schedule utilized revealed that psilocybin is most often administered at a fixed 25mg dose (n = 92) in a single administration (n = 78). However, a wide range of doses for psilocybin are being tested, which vary between 0.15mg to 50mg. Because many clinical trials that administer psilocybin more than twice are testing efficacy of doses reflective of microdose use patterns, these doses are often administered daily. DMT was the second most common psychedelic being tested in clinical trials ( Fig. 3D ) with doses ranging from 0.75-40mg. However, most total doses were unable to be calculated or compared due to DMT doses often being reported as infusions rates (mg/min) without a total infusion time. There are three unique compounds being studied including GH001 (n = 2), CYB004 (n = 1), and SM-001 (n = 1). Investigations into the efficacy of DMT appear to be in an early stage as over half (7/13) trials are testing healthy volunteers. Thus, most trials utilize either a single administration (n = 5), often for safety, or multiple administrations (n = 4) with a dose-escalation design, often for pharmacokinetic profiling. The other six clinical trials are early phase clinical trials testing MDD, TRD, Alcohol Use Disorder, Generalized Anxiety Disorder (GAD), and grief. Figure 3: Trial design of ongoing psychedelic clinical trials Group assignments methodologies being employed in trial design (A). Types of placebo used (B), number of trials using a placebo (B insert panel). Experimenter blinding design (C). Open-label refers to unblinded trials; ‘Single (outcomes)’ refers to an open-label trail where only the outcomes analyst is blinded to treatment groups. Representation of classic psychedelic used (D), specific compound or analog (E), and number of administrations (F). There are eleven clinical trials that are using an LSD treatment intervention and only one unique compound (MM-120; n = 3) was identified. Unlike clinical trials using DMT, only two LSD clinical trials are testing in healthy volunteers. One of these trials (NCT05964647) is a feasibility study investigating the ability of ketanserin, olanzapine, and lorazepam to shorten or attenuate the subjective effects following an administration of LSD. The other trial (NCT05953038) is investigating the plasma concentration and 5-HT 2A receptor occupancy as quantified by the radiolabel [11C]CIMBI-36 in Positron Emission Tomography (PET). Other conditions being investigated using LSD include cluster headaches, alcohol use disorder, MDD, GAD, and end of life distress. Dose scheduling of LSD in these trials are mostly single administration (n = 5) with dosages ranging from 25ug-250ug and 100ug LSD being the most common (n = 5). Only one clinical trial utilizing mescaline was identified in our searches (NCT05933213), which compares the use of mescaline sodium enteric-coated tablets and morte-mescaline as adjunctive treatments to glucocorticoids for individuals diagnosed with Lupus Nephritis. Conditions, Outcome Measures, and Endpoints: Currently, psychedelics are being applied to a wide range of conditions, which often overlap or exist as comorbidities. For simplicity, we have categorized these conditions as Depression, Substance Use Disorder (SUD), Quality-of -Life, Pain, Trauma, Anxiety, Healthy Volunteers, and Other ( Fig. 4A ). When clinical trials were registered for more than one condition or were treating a specific symptom in a condition, the primary condition was used and was validated by the primary outcome measure. Clinical trials categorized as depression were most prevalent (n = 40) and consisted of those involving a formal diagnosis of depression ( Supp. Table 1 ). The most common diagnoses were MDD (n = 23) and TRD (n = 14). There are three clinical trials for MDD that measure populations with comorbid diagnoses including alcohol use disorder (NCT04620759), borderline personality disorder (NCT05399498), and PTSD (NCT06141876). There are two clinical trials that include individuals with either MDD or TRD (NCT05259943, NCT06303739), and two clinical trials that are measuring TRD in individuals diagnosed with either autism spectrum disorder (NCT06731621) or bipolar II disorder (NCT06943573). Twenty-seven clinical trials were categorized as SUD ( Fig. 4A ), and are testing alcohol, cannabis, cocaine, methamphetamine, and opioid use disorder ( Supp. Table 2 ), many which we characterized previously ( 12 ). Only one clinical trial is using DMT (NCT06070649) or LSD (NCT05474989) with all others using psilocybin ( Fig. 4C-E). Quality of life clinical trials (n = 25; Fig. 4A ) were those that utilized psychedelics to treat distress, anxiety, depression without a formal MDD or TRD diagnosis, demoralization, grief, cognitive decline, or burnout ( Supp. Table 3 ). These were often in individuals diagnosed with a life-threatening condition, such as amyotrophic lateral sclerosis (NCT06656702), or had an experimental outcome testing for quality of life, suicidality, or depression. Only one clinical trial is utilizing DMT or LSD ( Fig. 4C-E) , which are for grief (NCT06150859) and end of life distress (NCT05883540) respectively. Figure 4: Ongoing clinical trial categorization Clinical trials were organized by their disease indication (A), primary outcome endpoint (B), and by psychedelic compound (C-E). We identified twelve clinical trials that use classic psychedelics to treat pain symptomology in various conditions. Psilocybin is being investigated to treat pain in individuals diagnosed with chronic pain, migraines, pain in fibromyalgia, persistent post-concussive symptoms, and phantom limb pain ( Supp. Table 4 ). Interestingly, LSD is being investigated to alleviate cluster headaches in two clinical trials (NCT03781128, NCT05477459), which is the only psychedelic being tested for this indication. Clinical investigations using classic psychedelics to treat PTSD appear to be in very early stages as only nine clinical trials are testing psilocybin for individuals with PTSD ( Supp. Table 5 ) and only three trials (NCT06407635, NCT06885996, NCT06853912) have a comparator or placebo group. One clinical trial (NCT05042466) is testing the feasibility of using microdoses of psilocybin (0.15–1.5mg) to treat trauma. Healthy volunteer was tied with SUD for second most prominent ‘condition’ type with 27 trials each ( Fig. 4A ). Further, healthy volunteer was the most common application for LSD ( Fig. 4D ) and DMT (Fig. 4E ) clinical trials. As expected, many of these clinical trials are establishing pharmacokinetic profiling, such as plasma concentrations and elimination half-life, safety, and tolerability for novel analogs or dosing regiments ( Supp. Table 6 ). Additionally, this category includes exploratory clinical trials that can establish preliminary evidence before going into further clinical trial stages for other indications, identify novel applications of psychedelics, or probe the molecular basis or changes in brain activity that may underlie the therapeutic benefits of psychedelics. Any clinical trials that did not meet the criteria for any of these established groups were then categorized as ‘Other’. While there are some conditions with more than one relevant clinical trial, like obsessive compulsive disorder (OCD) (n = 4), generalized anxiety disorder (n = 3), or irritable bowel syndrome (n = 2), most conditions in this category only had one clinical trial actively investigating the application of psychedelics ( Supp. Table 7 ). Some of these conditions include anorexia nervosa, lupus nephritis, psychogenic nonepileptic seizures, and self-harm. Interestingly, for the three clinical trials investigating generalized anxiety disorder, none were using psilocybin. This was the only condition in our search that was investigating both LSD and DMT, but not psilocybin. Figure 5: Primary endpoint timeline for the 10 most common outcomes The top ten reported outcomes across all trials are reported for Psilocybin (yellow), DMT (red), and LSD (blue) studies. Substance use disorder measures were separated for drug use and craving to distinguish between distinct behavioral measures. Neuroimaging, including PET, fMRI or MRI, and EEG were included for its relevance for neurobiological innovations. When comparing the primary endpoints across all ongoing clinical trials, we found that the most common endpoint measurement was three months ( Fig. 4B ). However, there were no primary endpoints that predominated with a good balance of measurements being taken across one week, one month, two months, three months, six months, and one year. There was a clear gap in primary endpoints and measurements between six months and one year with only one clinical trial measuring at seven (NCT05227612) and eight (NCT06407635) months each. No trials are using nine months as an end point, which is a potential area for improvement to generate data that can help predict long-term efficacy and identify potential time-to-redose strategies. This may be a potential area for new clinical trials to target to detect any deficits in efficacy that may occur between the six- and twelve-month time points. It is important to note that some clinical trials may measure at these time points as we only report primary endpoints, and, for short term clinical trials, follow-up measurements after trial completion may occur in this gap. After filtering out outcome measurements for safety, feasibility, and tolerability (like adverse events, vital measurements, recruitment rate, and retention rate), we then charted the time points being collected for the ten most common outcome measurements ( Fig. 5 ). We then separated measurements of drug use and drug craving for clarity. Additionally, we charted the time points in which neuroimaging outcomes were being taken, which included EEG, fMRI, MRI, and PET imaging. As expected, psilocybin is the most studied psychedelic across all outcome measurement types, which is due to greater representation in trial design. Clinical trials using DMT and LSD were most prominent at the one week or less time point, which is reflective of their current application for establishing safety and tolerability. Only two outcomes (depression and PTSD symptomology) are being measured beyond the one week or less time point for DMT. LSD is being tested for up to three months for depression, anxiety, and quality of life. One notable shortfall of ongoing clinical trials is the lack of neuroimaging for DMT or LSD. It would be useful if future clinical trials investigate lasting brain changes induced by DMT or LSD and compare them to psilocybin-induced changes at timepoints extending beyond 1 week. Discussion Although great progress has been made in unveiling potential therapeutic applications of psychedelics to various conditions that currently lack efficacious treatment options or are difficult to treat, there are multiple overarching questions that remain unanswered by current literature. Results from this systematic review are limited in its ability to answer these questions directly due to the scope of capturing ongoing clinical trials, thus lacking results. Rather, using our findings, we can understand how clinical trials are addressing these concerns and highlight key clinical trials that will be crucial for resolving lingering questions of the field in the coming years. Can psychedelics be safely co-administered with SSRIs/SNRIs One critique facing psychedelic clinical trials is that participants are often required to discontinue prescribed medication, namely antidepressants in trials indicated for MDD or TRD, prior to the initiation of psychedelic assisted psychotherapies. Antidepressant tapering is often implemented in trial protocols for two key reasons. First, antidepressants and psychedelics exert their effects through serotonin modulation and are metabolized in a similar manner. Psychedelics including psilocybin ( 19 ), DMT and 5-MeO-DMT ( 20 , 21 ), and LSD ( 22 ) are metabolized through CYP2D6, which 85% of antidepressants are a substrate for ( 23 ), suggesting potential competition or inhibition. Additionally, it is likely that initial trial protocols acted in precaution to avoid potential serotonin syndrome, which is associated with antidepressant use and is of greater risk when combinational pharmacology targeting serotonin neurotransmission is utilized ( 24 ). However, the risk of psychedelic-induced serotonin syndrome is rare and is believed to be related to the inability of classic psychedelics to increase intrasynaptic serotonin, a hypothesized predictor for serotonin syndrome ( 24 ). Indeed, there has been a case where serotonin toxicity was observed following psilocybin use alongside antidepressants ( 25 ). However, the individual was taking unknown microdoses recreationally while prescribed multiple serotonin modulators including and SNRI (venlafaxine) and 5-HT2A antagonist (trazodone) that could have increased serotonin toxicity risk of psilocybin. This is likely the case as a recent meta-analysis of thirty psychedelic trials, including four indicated for major depressive disorder, found only nine reported serious adverse events across 1072 psychedelic administrations ( 26 ), four of which were suicidal ideation from one clinical trial in the post-acute phase (three weeks following psychedelic administration) ( 27 ). No cases of serotonin syndrome were observed ( 26 ), which may support the notion that the observed case of serotonin syndrome was likely due to other prescribed medications and recreational use of illicit psilocybin. However, it is important to note all psilocybin trials captured by the authors utilized synthetic psilocybin, which may not fully reflect the case of serotonin syndrome observed ( 25 ) warranting further research into the safety of natural-occurring psilocybin with antidepressants and other compounds that modulate serotonin. Second, chronic administration of antidepressants is known to blunt the acute subjective effects of psychedelics ( 28 – 30 ), a strong predictor of long-term antidepressant and mental wellbeing outcomes ( 31 , 32 ). Because of these relationships, antidepressants should, in theory, disrupt the long-term efficacy of psychedelics and would thus support antidepressant discontinuation prior to psychedelic administration. However, recent accumulating data suggest that this phenomenon is not observed and may support maintaining antidepressant regimens through trial participation. For example, in a phase 2 exploratory trial determining preliminary safety and efficacy data of adjunctive 25mg COMP360 with ongoing antidepressants found no serious adverse events with a 42% depression remission rate up to three weeks after psychedelic administration ( 33 ). A recent scoping review of psychedelic trials found that concomitant antidepressant and psychedelics were safe and tolerable and had no risk of serotonin syndrome ( 34 ). Tap and colleagues found four clinical trials where depression symptoms significantly improved and three clinical trials where full remission was observed. Further, post-hoc analysis of Goodwin et al., 2022 ( 27 ) (n = 233; NCT03775200) for COMP360 (1, 10, 25mg) showed antidepressant drug discontinuation did not contribute to worsening depression symptoms before administration and psilocybin efficacy and experience was unaltered ( 35 ). Finally, an open-label trial in healthy subjects were pretreated with escitalopram for two weeks prior to psilocybin administration found no effect of escitalopram on positive mood, HRT2A or SLC6A4 gene expression, and plasma-BDNF levels induced by psilocybin or psilocybin’s half-life ( 36 ). Additionally, escitalopram pretreatment attenuated bad drug effects, anxiety, and adverse events of psilocybin suggesting a better safety profile. Further studies in depressed participants exposed to antidepressants for longer periods of time is warranted to confirm these findings and measure depression outcomes. Together, while acute subjective effects may be blunted, it appears that concomitant antidepressant use does not vastly attenuate psychedelic depression outcomes. Our search captured five clinical trials that will be testing psychedelic safety and efficacy with continuing antidepressant prescription. All trials are studying psilocybin either with psilocybe cubensis mushroom (NCT06898606; NCT06746441) or CYB003 (NCT06793397; NCT06564818; NCT06605105), a synthetic deuterated psilocybin derivative also known as HLP003. The COGUNILA trial (NCT06898606) is investigating the safety of concurrent 20mg/kg fluoxetine with 3g psilocybe cubensis assisted psychotherapy for individuals diagnosed with TRD and measuring changes in acute psychedelic effects, adverse events, and changes in MADRS after one month. The other trial (NCT06746441) was completed in July 2025, but no results have been posted or published at the time of writing. This trial administered a supratherapeutic dose (5-6g) psilocybe cubensis twice, with or without cognitive behavioral therapy, for individuals diagnosed with MDD and continued antidepressant treatment. Changes in depression, anxiety, serum BDNF, EEG, and other biomarkers were measured at baseline and after each administration session. All trials using CYB003 are phase 3 trials that include EMBRACE (NCT06793397), APPROACH (NCT06564818), and EXTEND (NCT06605105). Both EMBRACE and APPROACH trials will be measuring depression, illness severity, anxiety, and QoL at baseline through end of treatment. EMBRACE is administering placebo, 8mg CYB003, or 16mg CYB003; and APPROACH is only administering placebo or 16mg CYB003. The EXTEND trial is a long-term extension where non-responders or individuals with depression relapse can participate in to receive up to 3 more 16mg CYB003 doses, two three-weeks apart and one additional if participants relapse again. Depression scores will be measured up to 301 days after baseline. Because the extent of detailed reporting in the clinicaltrials.gov database is at the discretion of the clinical trial manager, sponsor, and trial uploader, this is likely an underestimate of ongoing trials investigating the safety of concomitant antidepressant and psychedelic use. Nonetheless, these trials will remain pivotal for understanding of psychedelic-antidepressant interactions, optimizing psychedelic assisted therapy protocols, and support FDA approvals for psychedelics, namely psilocybin, as an adjunctive therapy to partial or non-response to ongoing antidepressant therapies. Is the ‘psychedelic experience’ necessary for therapeutic benefits? Several barriers to the use of psychedelics as therapeutics are specifically related to the associated ‘psychedelic experience.’ For example, one potential barrier to FDA approval of psychedelic therapies lies in the difficulty in disentangling the impact of the medication from the psychedelic-specific therapy dedicated to preparation for, and integration of, the psychedelic experience. In the absence of the psychedelic experience, “psychedelics” could be offered with or without therapy, similar to the clinical use of antidepressant medications. The ‘psychedelic experience’ also makes blinding and controlling for expectancy effects in clinical trials very challenging. Should psychedelics be approved for clinical use, the psychedelic experience would result in significant healthcare costs given the need to have facilitator(s) present during the treatment session to help patients navigate potentially challenging experiences; this will be particularly costly for psychedelics with longer-lasting effects. At present, it is unknown whether the ‘psychedelic experience’ is needed for the therapeutic effects or if the therapeutic effects are driven strictly by the neurobiological consequences, such as brain changes induced by serotonin and BDNF signaling cascades. It is important to acknowledge that this question is not whether the subjective effects contribute to the psychedelic-induced neuroplasticity, but rather if the two could be separated, as described previously ( 37 ). It has been argued that subjective effects are a necessary component to achieve the full and lasting therapeutic effects of psychedelics, which is rooted in clinical findings that the psychedelic experience is often reported as one of the most meaningful events in the participant’s life and is predictive of therapeutic outcomes ( 38 ). On the other hand, some have argued that the lack of causality may indicate that the subjective effects may be involved, but not necessary for observing notable therapeutic effects and may serve as a predictor for 5-HT 2A agonism ( 39 ). Although most of the data supporting this point of view stems from preclinical evidence, a recently reported case study of an individual with TRD and receiving psilocybin-assisted psychotherapy who had used trazadone, a 5-HT 2A antagonist, the night before had lasting anti-depressant effects in absence of subjective effects ( 40 ). Due to a lack of clinical evidence separating subjective and therapeutic effects, it is difficult to decipher how much of the lasting therapeutic effects of psychedelics are dictated by subjective/mystical experiences or distinct neurobiological changes induced by psychedelic-induced signaling. There has been a prior suggestion that clinical trials should investigate blocking subjective effects by administering psychedelics under sedation, as demonstrated in clinical trials for ketamine ( 39 ). No clinical trials were captured that utilized this approach, but we captured six clinical trials that are investigating the ability to block the subjective effects induced by psychedelic while maintaining therapeutic efficacy. Although testing healthy volunteers, one clinical trial (NCT06796361) appears to directly address a prior recommendation to use a 5-HT 2A antagonist pre-treatment to test the molecular basis of therapeutic efficacy ( 41 ) by using ketanserin to block psilocybin with measures for subjective effects, mood, personality, cognition, sleep, and pharmacokinetic parameters. Three other clinical trials are testing the feasibility of antipsychotics to block the subjective effects caused by psilocybin. Two trials are using 1mg risperidone to block the subjective effects of psilocybin in individuals with TRD and are measuring depressive symptoms (NCT05710237, NCT06512220) or utilizing brain imaging techniques to detect changes in prefrontal cortex function, hippocampus function, and plasticity (NCT06512220) after one week. The third clinical trial is using 34 mg pimavanserin and testing depressive symptoms up to five weeks later (NCT06592833). Apart from antipsychotics, one clinical trial is sedating participants with MDD using propofol during a DMT administration session and will be measuring depression and plasma BDNF levels after 2 weeks (NCT06927076). Another clinical trial (NCT06692192) is a follow-up to a prior clinical trial (NCT04842045) that induces amnesia of the subjective effects induced by psilocybin with midazolam. NCT04842045 measured the feasibility of the amnesia protocol, which is completed but has not reported results yet. The ongoing clinical trial is utilizing the same approach and is measuring changes in brain activity via MRI and TMS-EEG one month after psychedelic administration. Results from these clinical trials could help determine the role, or lack thereof, of the ‘psychedelic experience’ in the therapeutic potential of these drugs. Additionally, one clinical trial (NCT05964647) tests the feasibility of administering either ketanserin (40mg), olanzapine (10mg), or lorazepam (2mg) after LSD administration to shorten or attenuate LSD-induced subjective effects. Although ketanserin is known to block the effects of psilocybin ( 42 ) and LSD ( 43 , 44 ) in humans already, findings from this clinical trial can give greater understanding for how clinicians can control the subjective effects caused by psychedelics. More importantly, being able to safely control when subjective effects end could shorten the length of treatment sessions and the high healthcare costs associated with psychedelic-assisted psychotherapy treatment regiments. Capturing neuroplasticity in humans It has been well-understood that psychedelics are capable of inducing neuroplasticity through activation of BDNF, which has been recently described well ( 9 , 10 ) and characterized through systematic review ( 8 ). However, most of this evidence stems from findings using animal models. Because of the invasiveness of retrieving brain levels of BDNF in human populations, these findings have not yet been confirmed. The best efforts thus far have been measurements of serum BDNF, but findings so far have been inconclusive ( 10 ). Through our search, we identified six ongoing clinical trials that are measuring plasma BDNF in their participants. Two clinical trials are measuring BDNF one day (NCT05559931) or two weeks (NCT06927076) after DMT administration. All other clinical trials are measuring BDNF one week (NCT04718792), one month (NCT06768944), five weeks (NCT06072898), and three months (NCT05416229) after psilocybin administration. Across these six clinical trials, BDNF will be measured in participants that are diagnosed with MDD or alcohol use disorder or are healthy volunteers. One possible explanation for why serum BDNF is not being measured frequently could be that more novel approaches have been recommended. For example, PET imaging to detect synaptic vesicle protein 2A (SV2A) could be leveraged to better measure of neuroplasticity in humans ( 45 ), detect changes in various conditions relevant to psychedelic research, confirm findings derived from animal models ( 46 ). In line with this, we found that 53 of 165 ongoing clinical trials captured in our searches are utilizing a neuroimaging technique including PET, fMRI, MRI, or EEG (data not shown). Only three trials with a neuroimaging technique utilize a psychedelic other than psilocybin with one clinical trial having an endpoint longer than one day after psychedelic administration ( Fig. 5 ). Thus, there is a great need for more clinical trials that utilize neuroimaging techniques at longer endpoints to better understand psychedelic-induced changes in brain functioning. Functional unblinding and the placebo problem Many critiques and unanswered questions in the field of psychedelics are rooted in the experimental design of clinical trials. Although randomized controlled trials (RCTs) are considered the gold standard of clinical trials ( 47 ), this is only the case when researcher staff and clinicians are blinded to group assignments and participants are masked to the treatment intervention they received. Great efforts have been made to improve masking and attempt avoiding the functional unblinding of participants following a psychedelic administration; however, a recent systematic review of completed clinical trials found that over 75% of psychedelic clinical trials had poor masking success ( 48 ). Despite this concern, we were only able to detect six ongoing clinical trials that are measuring experimental blinding effectiveness of participants (NCT06671977, NCT03781128, NCT05477459, NCT05474989, NCT06341426, NCT06455293). Some suggestions have been made, such as systematically investigating the specific contextual components of how psychedelics are administered (commonly referred to as ‘set and setting’) that contribute to outcomes ( 49 ), administering psychedelics under anesthesia ( 39 ), and including analysis of individual factors such as therapeutic alliance, expectancy, and credibility effects ( 50 ). Because participant blinding is a relatively simple measure to carry out, often requiring a single questionnaire like the Credibility and Expectancy Questionnaire ( 51 ), clinical trials going forward should implement and report blinding effectiveness data. Additionally, a new computational model to evaluate activated expectancy bias (a combination of weak blinding and treatment expectancy) and a counteracting statistical test to estimate outcomes and detect false positives has been developed that could be adopted ( 52 ). Implementation of these recommendations would aid in understanding the validity of different experimental designs, create a standard protocol with proven blinding effectiveness, and detect experimental or participant biases that may influence trial outcomes. One major factor contributing to functional unblinding in psychedelic trials is the absence of a standardized placebo that has comparable effects to moderate or high doses of psychedelics. This is especially concerning due to large effect sizes that have been observed in 60% of active placebo trials and 75% of inactive placebo trials ( 48 ). Similar drugs (MDMA and ketamine) that have also lacked an adequate placebo or had notable functional unblinding have faced setbacks by the FDA as summarized previously ( 53 ). Further, a recent systematic review of 50 completed studies revealed that no individuals that received a psychedelic incorrectly guessed they were in the placebo group, and the only studies that blinding was successful were for those with an active placebo ( 54 ). Prior to 2020, most psychedelic clinical trials that utilized a placebo group chose an inert placebo (61.2%) and only 20% of clinical trials used an active comparator ( 55 ). Of the 165 ongoing clinical trials discussed here, the most common placebo was a low dose of the experimental drug (n = 39) that made up most of the active placebo group (Fig. 3B). When accounting for 59 clinical trials that did not use a placebo and 26 clinical trials did not specify their placebo, this means that 33 different placebos or comparators were used across the remaining 42 clinical trials. Although it appears ongoing experimental designs have now opted for an active placebo, the need for a more appropriate placebo that can maintain integrity of participant blinding remains. To address this issue, a novel, well-thought out set of recommendations that has been proposed for a multitude of psychedelic administration types, which include salvinorin A for vaped DMT, dextromethorphan and THC for oral LSD or psilocybin; and diphenhydramine or a stimulant for low dose oral LSD or psilocybin ( 53 ). An additional recommendation of high dose THC has been proposed as a placebo for its ability to induce a similar experience to that of a psychedelic while being unlikely to induce neuroplasticity ( 37 ). In our search, we identified five clinical trials that meet these recommendations including THC as a comparator (NCT06464367, NCT06671977), and diphenhydramine (NCT06070649) or dextromethorphan (NCT06731335, NCT05068791) as a placebo. Importantly, one of the clinical trials that is using THC as a comparator to DMT to test efficacy for MDD is also reporting blinding and expectancy effects (NCT06671977). While limited to one clinical trial and one psychedelic tested, findings from this study can demonstrate the feasibility of THC as an active placebo that keeps participant blinding intact for psychedelic clinical trials. Other recommendations to increase scientific rigor have been made regarding recruitment and enrollment, preparation and integration sessions for psychedelic administration, and statistical analysis ( 56 ). However, our search was only able to capture study design and dosing information. Therefore, to capture trends in clinical research that would address these recommendations, it would be more appropriate to look at published results of newly completed clinical trials that would provide more methodological detail. Psychedelics and the Default Mode Network Following promising results of using psychedelics as treatments in MDD, TRD, and SUD, the field is rapidly investigating the feasibility of psychedelics for a multitude of other diagnoses. We captured this trend in our characterization of ongoing clinical trials where a psychedelic intervention is being tested to treat symptoms related to depression, anxiety, substance use, trauma, demoralization, self-harm, pain, eating disorders, quality-of-life in life threatening illness, OCD, seizures, irritable bowel syndrome, and others ( Supp. Tables 1–6 ). Despite psychedelics having great therapeutic promise, it is unlikely a single biological mechanism or pathway could be responsible for the generalizability of psychedelics across this wide range of diagnoses i.e. depressive disorders, substance use disorders, eating disorders, and others, as the neurobiology of these conditions vary greatly. Therefore, it is more likely the generalizable therapeutic effects of psychedelics are more reflective of widespread alterations of brain functioning, which could ‘override’ or ‘rewire’ maladaptive neurocircuitry. In an effort to capture this, many active clinical trials are utilizing neuroimaging techniques, namely fMRI and PET imaging, to capture functional connectivity and changes in brain network activity with particular interest in the default mode network (DMN). The DMN can be understood as the ‘off’ mode of the brain where processes such as reflection, mind-wandering, and resting are promoted through activity of the medial prefrontal, lateral parietal, and posterior cingulate cortices. DMN dysfunction has been observed in various psychiatric illnesses, mood disorders, and mental disorders and has been described in depth elsewhere (see Buckner et al., 2008 ( 57 ); Doucet et al., 2020 ( 58 ), Mohan et al., 2016 ( 59 )). Briefly, DMN hyperconnectivity is observed in MDD ( 60 , 61 ), OCD ( 62 ), and schizophrenia ( 63 ) while hypoconnectivity is observed in cognitive disorders, like Alzheimer’s disease and Parkinson’s disease. DMN hypoconnectivity is also observed in mild cognitive impairment, however, a systematic review has found notable inconsistencies across studies ( 64 ). Additionally, SUD and behavioral addictions cause widespread changes across multiple brain networks including hyperconnectivity between DMN and the frontoparietal, salience, and affective networks ( 65 ). Authors also found SUD-specific functional connectivity changes involving the DMN and frontoparietal network, which authors suggest may be attributed specifically to the administration of an addictive drug ( 65 ). In other cases, DMN dysfunction can rise from alterations in the suppression or promotion of DMN activity, as is the case for individuals with attention deficit hyperactivity disorder (ADHD) (see Mohan et al ( 59 ). This could explain mixed results found in a systematic review of autism spectrum disorder (ASD) fMRI studies, as authors note there are significant clinical and genetic overlap and notable comorbidity ( 66 ). Another potential explanation for variable results is differences between seed- and network-based approaches, which has been suggested to underly variable DMN findings in eating disorders ( 67 ). A comprehensive analysis of 14,027 patients diagnosed with either ADHD, anxiety disorders, ASD, bipolar disorder, depressive disorder, OCD, PTSD, or schizophrenia revealed hypoconnectivity within DMN, between DMN and ventral salience network and hyperconnectivity between DMN and ventral salience network and dorsal salience network compared to healthy controls ( 68 ). Additionally, these changes in brain network function and connectivity were associated with network-specific grey matter loss and suggest that common brain network adaptations may underlie the presentation of symptoms, like cognitive deficits, across a wide range of psychiatric illnesses, many which we show are being investigated in psychedelic clinical trials ( Fig. 5 ). Although DMN dysfunction is a common maladaptation across psychiatric illnesses, these changes do not appear to be direction- or region-specific. Thus, how psychedelics, often after a single administration, may be therapeutic in both hypoconnective and hyperconnective DMN states remains elusive. There are currently three leading models that could describe these effects, all which are well-summarized by Doss and colleagues ( 69 ). It is important to note that these models do not necessarily negate one another and likely co-exist through shared mechanisms of serotonergic modulation of neurotransmission, overlapping neurobiology, and alterations in thalamic gating of information. One idea is the relaxed beliefs under psychedelics (REBUS) model where administration of a psychedelic reduces DMN top-down activity and disrupts predictive coding, particularly involving the sensory cortex, posterior parietal cortex, prefrontal cortex, and hippocampus ( 69 , 70 ). This reduction of activity allows the maladaptive connections to be disassembled, new connections to form, and greater involvement of cortical regions resulting in a less constrained and greater interconnected brain ( 71 ). These changes can also be understood as mechanisms to increase entropy, the measure of disorder in a neural system. In line with this, the entropic brain hypothesis explains the therapeutic effects of psychedelics in the context of a U-shaped relationship between entropy and cognition ( 72 ). In this relationship, high levels of entropy are reflective of high disorder and flexible cognition, such as infant consciousness, early psychosis, near death experiences, and creativity. In contrast, low entropy is characteristic of low disorder and rigid, reduced consciousness. Low entropy could be reflective of unconscious thought states, such as comas, anesthesia, or deep sleep but also describe diagnoses of rigid thoughts or behaviors observed in MDD, OCD, and SUDs. A healthy individual is understood as relatively equally between high and low entropy states with a slight skew toward low entropy. Carhart-Harris and colleagues explain that when an individual is administered a psychedelic, the individual enters a high-entropy state as a result of neurobiological (5-HT2A and pyramidal neuron stimulation), network (desynchronized cortical activity, replacement of rigid connectivity with new motifs), and metastability changes ( 72 ). Importantly, one consideration this hypothesis seems to indirectly support is the notion that psychedelics may not be appropriate treatments for any psychiatric illness that has altered DMN functioning described above. For example, there are biological and DMN-related rationales for why psychedelics may be relevant for treating individuals with schizophrenia ( 73 ). In fact, Sapienza and colleagues describe early LSD and mescaline studies that reported promising results for treating schizophrenia symptoms prior to prohibition ( 73 ). However, there is great concern that psychedelic experiences may exacerbate positive symptoms of schizophrenia. Positive symptoms of schizophrenia, like hallucinations, delusions, and psychosis would be representative of high entropy under the entropic brain hypothesis ( 72 ). Although psychedelics may be therapeutic for negative symptoms of schizophrenia, which reflect states closer to MDD, the risk of worsening positive symptoms is a current rationale for not testing psychedelics as schizophrenia treatment. Interestingly, results from clinical trials investigating the feasibility of antipsychotic pretreatment to block the psychedelic experience but spare neuroplastic and antidepressant effects could prove pivotal for this area of research. If successful, these trials may provide the basis for new clinical trials that aim to treat negative and cognitive symptoms while minimizing the risk exacerbating positive symptoms in individuals diagnosed with schizophrenia that respond to antipsychotics. Another proposed model is the cortico-striatal thalamo-cortical loop (CSTC) model, where psychedelics disrupt bottom-up sensory input, top-down information processing, and thalamic gating by stimulating cortico-striatal and thalamo-cortical glutamatergic afferents and modulating neurotransmission via serotonergic efferents of the dorsal raphe ( 69 , 74 ). Vollenweider and Preller propose that the reduction of thalamic filtering of information would decrease integrative processing through decreased connectivity of the association cortices while increased sensory processing would arise from increased connectivity of sensory cortices ( 75 ). While this model accounts for the involvement of other neurotransmitters, such as dopamine, GABA, and glutamate ( 74 ), the proposed model only accounts for 5-HT signaling from the dorsal raphe. Thus, neuromodulation and transmission that are facilitated by localized serotonergic tone in other cortical and subcortical areas are unaccounted for. More recently, Doss and colleagues have resolved this point with the cortico-claustro-cortical model, where communication between prefrontal, posterior parietal, and sensory cortices are modulated by the claustrum ( 69 ). In this model, the claustrum, which is rich in serotonergic receptors, creates a circuit through glutamatergic afferents from the prefrontal cortex and glutamatergic efferents to the prefrontal, posterior parietal, and sensory cortices allowing for the modulation of synchronicity between networks. Additionally, the claustrum is extensively linked with cortical and subcortical regions ( 76 ). In brain imaging studies, it has been shown that the claustrum is functionally connected to the DMN and task positive network, activates when a cognitive task is presented, and is active when DMN activity is suppressed ( 77 , 78 ), an effect that can be modulated by psilocybin ( 79 ). While not depicted by Doss and colleagues in their proposed model schematic ( 69 ), preclinical findings in feline ( 80 ) and primate ( 81 ) models shown the claustrum receives serotonergic inputs, which have been suggested to originate from the dorsal raphe ( 76 ). Studies into the role of claustrum in potentially mediating states consciousness have been limited by its size, shape, and location, however theories have been postulated as early as 2005 ( 82 ) and have been summarized elsewhere ( 83 ). Alongside these models, it is possible that the underlying generalized mechanism of psychedelics is driven through unlocking a window of neuroplasticity. Indeed, it has been shown that psychedelics such as psilocybin, LSD, ibogaine, and MDMA can open critical periods of social learning ( 84 ). This, alongside neurobiological mechanisms such as psychedelic-mediated or BDNF-induced neuroplasticity ( 12 ), could provide a temporary critical period for the brain to transform affected neurotransmission under the guidance of clinician-led psychotherapy, which could facilitate the cognitive flexibility of a participant in a clinical trial setting. Thus far, it is unclear if these mechanisms and proposed models are neurobiologically connected or act as independent therapeutic mechanisms following administration of a psychedelic to produce notable, long-lasting improvement for participants in clinical trials. By further elucidating the neurobiological changes brought about by psychedelic interventions through functional imaging accompanied by clinical behavioral scales between healthy and affected participants, these mechanisms may become clearer. Limitations: Our systematic search has several limitations that should be considered when interpreting our findings. First, we only utilized the clinicaltrial.gov database to capture registered, ongoing clinical trials, which may have resulted in missed potential hits that are registered in other clinical trial databases. For the clinical trials detected, multiple reporting errors or missing information existed across trials, such as the dose of the psychedelic being administered, how often the dose was given, listing outcomes in the trial description but not the outcomes and endpoints sections, and, in some cases, endpoints or experimental groups that did not match the trial description. Although we resolved these issues manually in most cases by either identifying the information in a different section or not including that measure in analysis, there were two clinical trials that had to be excluded for reporting issues that could not be resolved by the authors. Lastly, for our visualization of clinical trial endpoints, it is possible that measures may be taken more often than just the primary endpoints, including long-term follow-up studies that could extend efficacy and neuroimaging measures beyond what is depicted ( Fig. 5 ). Conclusion Through our scoping review approach, we captured 165 ongoing registered clinical trials with a treatment intervention using a classic psychedelic and tracked trial characteristics and methodological approaches to better understand trends in experimental design, identify possible gaps in research, and identify specific clinical trials that are addressing current critiques or unanswered questions in the field. Most clinical trials were early phase, actively recruiting, administering psilocybin, measuring depressive symptoms, and are expected to be completed in the next two years. Additionally, we identified 15 unique psychedelic analogues that are being tested for market approval. From this, we hope this scoping review can serve as a snapshot to describe the current state of clinical psychedelic research, and the trends and recommendations discussed herein could be used to increase scientific rigor and trial-to-trial continuity to aid in advancing the field. Declarations Acknowledgments The authors would like to thank Dr. Anna Kruyer and Nathan Koorndyk for reading the manuscript and providing constructive feedback. Declaration of Interest: The authors report no conflicts of interest linked with any content of this manuscript. Funding: The authors have no funding to declare that supported this work. References Collaborators GBDMD (2022) Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. 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J Alzheimers Dis 70(1):107–120 Zeng X, Han X, Zheng D, Jiang P, Yuan Z (2024) Similarity and difference in large-scale functional network alternations between the behavioral addictions and substance use disorder: A comparative meta-analysis - CORRIGENDUM. Psychol Med. :1 Harikumar A, Evans DW, Dougherty CC, Carpenter KLH, Michael AM (2021) A Review of the Default Mode Network in Autism Spectrum Disorders and Attention Deficit Hyperactivity Disorder. Brain Connect 11(4):253–263 Steward T, Menchon JM, Jimenez-Murcia S, Soriano-Mas C, Fernandez-Aranda F (2018) Neural Network Alterations Across Eating Disorders: A Narrative Review of fMRI Studies. Curr Neuropharmacol 16(8):1150–1163 Sha Z, Wager TD, Mechelli A, He Y (2019) Common Dysfunction of Large-Scale Neurocognitive Networks Across Psychiatric Disorders. Biol Psychiatry 85(5):379–388 Doss MK, Madden MB, Gaddis A, Nebel MB, Griffiths RR, Mathur BN et al (2022) Models of psychedelic drug action: modulation of cortical-subcortical circuits. Brain 145(2):441–456 Carhart-Harris RL, Friston KJ (2019) REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacol Rev 71(3):316–344 Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ et al (2014) Homological scaffolds of brain functional networks. J R Soc Interface 11(101):20140873 Carhart-Harris RL, Leech R, Hellyer PJ, Shanahan M, Feilding A, Tagliazucchi E et al (2014) The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci 8:20 Sapienza J, Martini F, Comai S, Cavallaro R, Spangaro M, De Gregorio D et al (2025) Psychedelics and schizophrenia: a double-edged sword. Mol Psychiatry 30(2):679–692 Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull 56(5):495–507 Vollenweider FX, Preller KH (2020) Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci 21(11):611–624 Mathur BN (2014) The claustrum in review. Front Syst Neurosci 8:48 Huang CHL, Stewart BW, Liu CY, Phylactou P, Mathur BN, Seminowicz DA (2025) The Human Claustrum Activates Across Multiple Cognitive Control Tasks. Eur J Neurosci 62(9):e70318 Krimmel SR, White MG, Panicker MH, Barrett FS, Mathur BN, Seminowicz DA (2019) Resting state functional connectivity and cognitive task-related activation of the human claustrum. NeuroImage 196:59–67 Barrett FS, Krimmel SR, Griffiths RR, Seminowicz DA, Mathur BN (2020) Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention. NeuroImage 218:116980 Rahman FE, Baizer JS (2007) Neurochemically defined cell types in the claustrum of the cat. Brain Res 1159:94–111 Baizer JS (2001) Serotonergic innervation of the primate claustrum. Brain Res Bull 55(3):431–434 Crick FC, Koch C (2005) What is the function of the claustrum? Philos Trans R Soc Lond B Biol Sci 360(1458):1271–1279 Nichols DE, Psychedelics (2016) Pharmacol Rev 68(2):264–355 Nardou R, Sawyer E, Song YJ, Wilkinson M, Padovan-Hernandez Y, de Deus JL et al (2023) Psychedelics reopen the social reward learning critical period. Nature 618(7966):790–798 Additional Declarations The authors declare no competing interests. Supplementary Files PsychedelicsGeneralizedPRISMA.pdf PRISMA Checklist SuppTable1DepressionTrials.pdf Supp. Table 1: Depression Trials SuppTable2SUDTrials.pdf Supp. Table 2: SUD Trials SuppTable3QoLTrials.pdf Supp. Table 3: Quality of Life Trials SuppTable4PainTrials.pdf Supp. Table 4: Pain Trials SuppTable5TraumaTrials.pdf Supp. Table 5: Trauma Trials SuppTable6HealthyVolunteerTrials.pdf Supp. Table 6: Healthy Volunteer Trials SuppTable7OtherTrials.pdf Supp. Table 7: Other Trials SupplementaryMaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8544354","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":571034864,"identity":"82e08d1c-c0d8-4867-bfc6-a7f3be4eec35","order_by":0,"name":"Lucas Wittenkeller","email":"","orcid":"","institution":"University of Cincinnati, College of Pharmacy, Division of Pharmaceutical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Lucas","middleName":"","lastName":"Wittenkeller","suffix":""},{"id":571034865,"identity":"065d6bb6-73f0-43c5-b08c-52a160bcbc13","order_by":1,"name":"Gary Gudelsky","email":"","orcid":"","institution":"University of Cincinnati, College of Pharmacy, Division of Pharmaceutical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Gary","middleName":"","lastName":"Gudelsky","suffix":""},{"id":571034866,"identity":"c4a4decf-6ba6-4194-8c54-e7b509b08a71","order_by":2,"name":"T. John Winhusen","email":"","orcid":"","institution":"University of Cincinnati, College of Medicine, Department of Psychiatry and Behavioral Neuroscience","correspondingAuthor":false,"prefix":"","firstName":"T.","middleName":"John","lastName":"Winhusen","suffix":""},{"id":571034867,"identity":"c6d4b594-406a-4bf8-8e3b-b33824d41bd2","order_by":3,"name":"Davide Amato","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYDCCA0DEA+N8AJMJRGthZmCcQawWBpgWZh5itPAdP2N44E0Fg7xu+/mDj23b7Bj42XMM8GqRPJNjcHDOGQbDbWeSmY1z25IZJHve4NdicCAt4TBvGwPjtgPJbNK5bQcYDG4QsMXg/DOgln8M9tvOP2aTtgRqsSeo5UbygcO8DQyJ224AbWEE2SJByC83Hh84OOeYRPK2G4+NDXvOJfNInHlWgFcL3/nE5g9vamxst51PfPjgR5mdHH978ga8WqBAAs7iwaNqFIyCUTAKRgGxAADi10r9gqHJPgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Cincinnati, College of Pharmacy, Division of Pharmaceutical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Davide","middleName":"","lastName":"Amato","suffix":""}],"badges":[],"createdAt":"2026-01-07 18:06:28","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8544354/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8544354/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100362102,"identity":"e95e17ce-e00a-4356-aa28-8f2fee95a4db","added_by":"auto","created_at":"2026-01-16 07:46:11","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":215699,"visible":true,"origin":"","legend":"","description":"","filename":"01082026ClinicalTrialsofPsychedelics.docx","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/2fbc5ecefe1cd01511ebba06.docx"},{"id":100018153,"identity":"ecca03f7-4789-40b7-9a70-ab850182d71d","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs8544354.json","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/e4d50cf407b624f868c49c77.json"},{"id":100362555,"identity":"cddc579f-b0d8-4a9b-b117-3e2a3cdd3a23","added_by":"auto","created_at":"2026-01-16 07:47:01","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":178058,"visible":true,"origin":"","legend":"","description":"","filename":"rs85443540enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/1bb1dfe5ed6aa0fcfe1147c8.xml"},{"id":100018159,"identity":"5076b0f7-2cdf-404d-a160-d216a7b9050b","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":175329,"visible":true,"origin":"","legend":"","description":"","filename":"rs85443540structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/6553f1eee3d846c08b014529.xml"},{"id":100362741,"identity":"8ff4ec0d-4974-4110-9bf3-a2b11aadbceb","added_by":"auto","created_at":"2026-01-16 07:48:00","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":189360,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/974a3134b066ab318c2f9e03.html"},{"id":100362749,"identity":"880a390c-cd0e-448c-bbac-4e20c42ac238","added_by":"auto","created_at":"2026-01-16 07:48:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1112593,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSystematic Review Methodology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFlowchart schematic of systematic search for ongoing clinical trials in the clinicaltrials.gov database.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"F1ClinicalTrialMethods.png","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/6ee5bd034cf63a0fba3d9f55.png"},{"id":100018154,"identity":"81ac762d-dd92-4d7f-8eba-195bd8770180","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1727321,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCharacteristics of ongoing clinical trials using psychedelic interventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical trial characteristics of unique hits reported by trial managers including study location (A), trial phase (B), status (C), estimated completion year (D), reported purpose (E), and included sex (F). Trials that lacked a study location were organized based on Sponsor criteria for visualization.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"F2TrialCharacteristics.png","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/a2105138c7ee39fbaf34c203.png"},{"id":100361546,"identity":"0f979e00-4a3e-42e1-81d9-36e05eb6f93d","added_by":"auto","created_at":"2026-01-16 07:45:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2019703,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eTrial design of ongoing psychedelic clinical trials\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGroup assignments methodologies being employed in trial design (A). Types of placebo used (B), number of trials using a placebo (B insert panel). Experimenter blinding design (C). Open-label refers to unblinded trials; ‘Single (outcomes)’ refers to an open-label trail where only the outcomes analyst is blinded to treatment groups. Representation of classic psychedelic used (D), specific compound or analog (E), and number of administrations (F).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"F3TrialExperimentalMethods.png","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/0b6dbe217b6a0c2369d7c912.png"},{"id":100362181,"identity":"ae540a93-53b6-4b6a-bf06-e455ea7bb8d0","added_by":"auto","created_at":"2026-01-16 07:46:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1768379,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOngoing clinical trial categorization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical trials were organized by their disease indication (A), primary outcome endpoint (B), and by psychedelic compound (C-E).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"F4TrialsByPsychedelic.png","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/ba885ca5fd5893ba830fd957.png"},{"id":100018167,"identity":"fd8e0c12-e76a-46f4-bbf0-5a91520dfbe7","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":320252,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePrimary endpoint timeline for the 10 most common outcomes\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe top ten reported outcomes across all trials are reported for Psilocybin (yellow), DMT (red), and LSD (blue) studies. Substance use disorder measures were separated for drug use and craving to distinguish between distinct behavioral measures. Neuroimaging, including PET, fMRI or MRI, and EEG were included for its relevance for neurobiological innovations.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"F5ClinicalTrialEndPoints.png","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/85d5dc9a19d25ec8409273a7.png"},{"id":100443954,"identity":"777e4f12-b56f-473b-b7a0-ae59cd9faeb9","added_by":"auto","created_at":"2026-01-16 17:29:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8572749,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/349c41d9-ac94-4030-820e-8ea1115ed429.pdf"},{"id":100018151,"identity":"14a8282b-72b5-4867-811d-8b8b3a3fb1e3","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":97864,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA Checklist\u003c/p\u003e","description":"","filename":"PsychedelicsGeneralizedPRISMA.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/54f6cbdf4714e7646c82f326.pdf"},{"id":100362752,"identity":"c230a39e-e8b4-44ae-87f8-9b39cd646112","added_by":"auto","created_at":"2026-01-16 07:48:01","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":167344,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 1: Depression Trials\u003c/p\u003e","description":"","filename":"SuppTable1DepressionTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/8aa9addf37789417f0237208.pdf"},{"id":100362313,"identity":"e61d84e2-4a07-48b7-99a6-f2ae95f6a934","added_by":"auto","created_at":"2026-01-16 07:46:33","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":141122,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 2: SUD Trials\u003c/p\u003e","description":"","filename":"SuppTable2SUDTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/53ed7da7b6012db11ec0c99d.pdf"},{"id":100018162,"identity":"43799543-8f12-4037-88ad-d2135841f198","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":151416,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 3: Quality of Life Trials\u003c/p\u003e","description":"","filename":"SuppTable3QoLTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/c318deb391012e68101a0ab4.pdf"},{"id":100362786,"identity":"b24bb4bf-bb3f-47c7-9e39-da7adf441861","added_by":"auto","created_at":"2026-01-16 07:48:05","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":115851,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 4: Pain Trials\u003c/p\u003e","description":"","filename":"SuppTable4PainTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/fed4cb33d0a7afec0f940361.pdf"},{"id":100018170,"identity":"97e645a4-2545-46fd-8fe9-9f329bf7beab","added_by":"auto","created_at":"2026-01-12 07:13:54","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":107962,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 5: Trauma Trials\u003c/p\u003e","description":"","filename":"SuppTable5TraumaTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/2f434b937ccebf1acc598f87.pdf"},{"id":100362619,"identity":"d79ffee9-f000-4fde-9886-daefe9169522","added_by":"auto","created_at":"2026-01-16 07:47:39","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":151398,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 6: Healthy Volunteer Trials\u003c/p\u003e","description":"","filename":"SuppTable6HealthyVolunteerTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/e73c9f5518af374a950694f3.pdf"},{"id":100362226,"identity":"d404dc48-8ae1-4706-b84b-f99cb6303ae5","added_by":"auto","created_at":"2026-01-16 07:46:23","extension":"pdf","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":128925,"visible":true,"origin":"","legend":"\u003cp\u003eSupp. Table 7: Other Trials\u003c/p\u003e","description":"","filename":"SuppTable7OtherTrials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/55a1567199125b2b039787d0.pdf"},{"id":100361965,"identity":"3430fcfc-6386-4db9-8cde-ddf56a79f3f0","added_by":"auto","created_at":"2026-01-16 07:45:59","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":17231,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8544354/v1/37f485da7f6a2a1180a81645.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eThe mushrooming of the psychedelic renaissance: A scoping review identifying trends in ongoing clinical trials\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBetween 1990 and 2019, prevalence of mental disorders including depressive, anxiety, eating, and bipolar disorders has risen nearly 150% (654.8\u0026nbsp;million to 970.1\u0026nbsp;million) with most notable increases in depressive (163%; 170.8\u0026nbsp;million to 279.6\u0026nbsp;million) and anxiety (154%; 194.9\u0026nbsp;million to 301.4\u0026nbsp;million) disorders (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These increases were further exacerbated following the COVID-19 pandemic where prevalence of depression and anxiety has been estimated to have raised 25\u0026ndash;30% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Perhaps the largest concern for addressing these alarming trends is the high rate of treatment resistance. Although estimates vary, antidepressant treatment-resistance occurs in approximately 30% (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) of individuals with estimates as high as 55% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and antipsychotic treatment resistance occurs in about 23% of individuals with 84% being resistant at illness onset (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In pursuit of more efficacious treatments for psychiatric and mental illnesses, there has been a resurgence of interest in classic psychedelics for their ability to induce mystical experiences that are accompanied by rapid and lasting changes in depressive symptoms and neuroplasticity (\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Classic psychedelics include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline; however, most attention in clinical trials has been given to psilocybin. This class of drugs has widespread effects in the brain primarily through serotonin 2A (5-HT\u003csub\u003e2A\u003c/sub\u003e) receptor agonism causing downstream activation of glutamatergic, brain derived neurotrophic factor (BDNF), dopaminergic, GABAergic, and anti-inflammatory systems, which are believed to underlie the subjective effects, neuroplasticity, and antidepressant effects of the drugs (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecently, COMP360 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), CYB003 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and synthesized psilocybin (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), which are derivatives of natural-occurring psilocybin or its active metabolite psilocin, were granted \u0026lsquo;Breakthrough Therapy\u0026rsquo; designation by the Food and Drug Administration (FDA) for major depressive disorder (MDD) or treatment-resistant depression (TRD) indicating these compounds offer new benefits over existing standard of care. Following promising results in early phase clinical trials indicated for depression, psychedelics are now being tested for other mental and psychiatric conditions that lack efficacious treatments. We recently characterized all registered clinical trials applying psychedelics to substance use disorders (SUDs) to capture the status of clinical investigations (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Here, we expand our characterization of ongoing registered clinical trials to all applications of classic psychedelics with the goal of capturing these new clinical applications, identifying trends in psychedelic clinical trials, and assessing the research outlook for psychedelics. Last, we highlight key clinical trials that may address unanswered questions or limitations in the field and provide a discussion of how the generalizability of psychedelics fit into current theoretical models.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis scoping review protocol was not registered allowing for flexibility in our search approach. We sought all registered clinical trials that are reported by ClinicalTrials.gov that utilized classic psychedelics as a treatment intervention. To limit the possibility of missing clinical trials through advanced search terminology and techniques, basic searches were carried out with condition criteria for Depressive Disorders, Anxiety Disorders, Post Traumatic Stress Disorder, or Psychiatric Disorders and interventions for either psilocybin, LSD, DMT, and mescaline. No inputs for \u0026ldquo;Other Terms\u0026rdquo; were used except for Post-Traumatic Stress Disorder searches and Psychiatric Disorders, which were \u0026ldquo;PTSD\u0026rdquo; and \u0026ldquo;Psychotic Disorders\u0026rdquo;, respectively. Grey searches were conducted for each condition with the intervention criterion listed as \u0026ldquo;psychedelic\u0026rdquo;. Additionally, a grey search was conducted for each individual classic psychedelic intervention with no condition or other term inputs. An example search is provided in supplementary material. Data was exported for each search to obtain NCT Number, Study Title, Study Status, Conditions, Interventions, Primary Outcome Measures, Secondary Outcome Measures, Sponsor, Sex, Phases, Enrollment, Study Type, Study Design, Start Date, and Completion Date. The last search occurred on May 18th, 2025, and there were no restrictions for the year uploaded.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 1: Systematic Review Methodology\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eFlowchart schematic of systematic search for ongoing clinical trials in the clinicaltrials.gov database.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eClinical trials were then manually characterized and verified by L.W. and D.A. independently. Exclusion criteria for our characterization involved lacking relevance, a classic psychedelic, or psychedelic intervention. Thus, observational and retrospective study designs were excluded. Additionally, two clinical trials were excluded due to reporting inconsistencies, and one clinical trial utilized a psilocybin as a control/comparator group to characterize the acute subjective effects of 4-bromo-2,5-dimethoxyphenethylamine (2-CB) (NCT05523401). Trends and characteristics were then identified across all clinical trials using Microsoft Excel and visualized using GraphPad Prism 10 software. All clinical trials were then sorted by their relevant condition and input into condition-specific tables using Microsoft Excel. Condition sorting was done through comparing the target population or condition, listed goal and purpose of the experiment, and primary outcomes resulting in some similar clinical trials to be separated, but not repeated, across tables. For example, clinical trials measuring depressive symptoms in populations diagnosed with life-threatening illnesses are characterized with other clinical trials focused on individuals with life-threatening illnesses independent of those focused on major depressive disorder for simplification. Some data using completed clinical trials are included in the supplemental information; however, because completed clinical trials are outside the scope of this review, full characterization of completed clinical trials is not shown but are available upon request from the authors.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 1446 clinical trials were identified (\u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e). Following the removal of duplicates (n\u0026thinsp;=\u0026thinsp;740) and exclusions (n\u0026thinsp;=\u0026thinsp;416), there were 290 total clinical trials. Of these, 101 clinical trials were completed, 24 had either withdrawn, suspended, terminated, or unknown status; and 165 were ongoing clinical trials. Most ongoing clinical trials are taking place in the United States (n\u0026thinsp;=\u0026thinsp;96), Canada (n\u0026thinsp;=\u0026thinsp;25), Switzerland (n\u0026thinsp;=\u0026thinsp;11), or United Kingdom (n\u0026thinsp;=\u0026thinsp;8) (\u003cb\u003eFig.\u0026nbsp;2A\u003c/b\u003e). Nearly all clinical trials are early phase clinical trials, particularly phase I (n\u0026thinsp;=\u0026thinsp;60), II (n\u0026thinsp;=\u0026thinsp;72), I/II (n\u0026thinsp;=\u0026thinsp;9) (\u003cb\u003eFig.\u0026nbsp;2B)\u003c/b\u003e. Additionally, there are twelve phase III clinical trials, one phase IV clinical trial, one phase II/III clinical trial, and ten clinical trials that did not fall under a specific phase, such as pilot studies where the trial manager specified \u0026ldquo;N/A\u0026rdquo; under Phase criterion. Status varied across all groups with most clinical trials either actively recruiting (n\u0026thinsp;=\u0026thinsp;92) or not yet recruiting (n\u0026thinsp;=\u0026thinsp;47) (\u003cb\u003eFig.\u0026nbsp;2C\u003c/b\u003e). Twenty-three clinical trials were active, but not recruiting, and three clinical trials were enrolling by invitation only. Despite most clinical trials still in early stages in investigation, more than 75% of clinical trials have expected study completion dates in the next few years (2025 n\u0026thinsp;=\u0026thinsp;55; 2026 n\u0026thinsp;=\u0026thinsp;41; 2027 n\u0026thinsp;=\u0026thinsp;33) \u003cb\u003e(Fig.\u0026nbsp;2D\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eClinical trial protocols can be registered under specific purpose designations, which include treatment, prevention, supportive care, screening, diagnostic, health services research, basic science, device feasibility, or other. The most common purpose detected in ongoing clinical trials was treatment (n\u0026thinsp;=\u0026thinsp;111) indicating a psychedelic intervention being tested to treat a diagnosis or condition (\u003cb\u003eFig.\u0026nbsp;2E\u003c/b\u003e). Basic science indication was the second most common category (n\u0026thinsp;=\u0026thinsp;25), which are protocols designed to investigate components of a psychedelic intervention such as mechanism of action, neural activity or plasticity changes, biomarkers, or feasibility of a new psychedelic protocol/application. Additionally, seven clinical trials were indicated for supportive care, three trials for health services research, two for prevention, and 17 indicated as other. Both sexes were included for all clinical trials except for three, which only included females (\u003cb\u003eFig.\u0026nbsp;2F\u003c/b\u003e). These clinical trials are testing the efficacy of psilocybin interventions for sexual assault-related PTSD (NCT06902974), fear of ovarian or breast cancer recurrence (NCT06430541), and chronic pain in fibromyalgia (NCT05068791), all of which are conditions with higher prevalence in females (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 2: Characteristics of ongoing clinical trials using psychedelic interventions\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eClinical trial characteristics of unique hits reported by trial managers including study location (A), trial phase (B), status (C), estimated completion year (D), reported purpose (E), and included sex (F). Trials that lacked a study location were organized based on Sponsor criteria for visualization.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eAcross all ongoing clinical trials, the most common experimental design was a parallel assignment (n\u0026thinsp;=\u0026thinsp;80) where a psychedelic intervention is compared to a placebo or active comparator group (\u003cb\u003eFig.\u0026nbsp;3A\u003c/b\u003e). Although it was more common that clinical trials implemented a placebo or comparator group (\u003cb\u003eFig.\u0026nbsp;3B inset\u003c/b\u003e), there is a large variety of placebos and comparators being used resulting in no placebo being the most consistent approach across clinical trials (n\u0026thinsp;=\u0026thinsp;59). Active placebos, the most common placebo type utilized (\u003cb\u003eFig.\u0026nbsp;3B\u003c/b\u003e) are compounds comparator groups receive that are either the same drug as the experimental group at a lower, often inactive dose, or a different compound that has therapeutic effects independent of the tested condition, like niacin. Thirty-seven of the fifty clinical trials that utilized an active placebo gave individuals either a lower dose of the same psychedelic compound or the same dose with an experimental manipulation. Inactive placebos refer to a wide range of placebos that are known to not have a pharmacotherapeutic effects for the tested condition. The most common inactive placebos detected was microcrystalline cellulose (n\u0026thinsp;=\u0026thinsp;6). For both design manipulation and comparator drug groups, there were no more than two clinical trials that utilized the same comparator group treatment. Some of these included, sham vagus nerve stimulation, treatment as usual, waitlist control; and ketamine, cannabis, and MDMA. Unfortunately, twenty-six clinical trials stated they are using a placebo, but did not specify what placebo or treatment these individuals are receiving (\u003cb\u003eFig.\u0026nbsp;3B\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eDue to the prominence of single assignment, placebo-lacking clinical trial designs, the most common blinding type was open-label (n\u0026thinsp;=\u0026thinsp;72) approaches indicating participants, clinicians, researchers, and outcomes assessor were fully aware of the treatments all participants were receiving (\u003cb\u003eFig.\u0026nbsp;3C\u003c/b\u003e). The second most common blinding approach was a quadruple (n\u0026thinsp;=\u0026thinsp;47) blinding where all parties remain blinded through the duration of the study. Triple blinding typically involved the blinding of participants, investigators, and outcomes assessor. One clinical trial (NCT05259943) utilizes triple blinding of the participant, clinician, and researcher, but has an optional open-label crossover after participants complete the trial.\u003c/p\u003e\n\u003ch3\u003eClinical Trials by Psychedelic Drug\u003c/h3\u003e\n\u003cp\u003eWe were able to identify clinical trials that utilize every classic psychedelic. The most prominently studied classic psychedelic is psilocybin (n\u0026thinsp;=\u0026thinsp;144) (\u003cb\u003eFig.\u0026nbsp;3D\u003c/b\u003e), which also had the largest number of specific compounds (n\u0026thinsp;=\u0026thinsp;11) (\u003cb\u003eFig.\u0026nbsp;3E\u003c/b\u003e). Specified psilocybin compounds include: APEX002-02 (n\u0026thinsp;=\u0026thinsp;1), COMP360 (n\u0026thinsp;=\u0026thinsp;7), CY-39 (n\u0026thinsp;=\u0026thinsp;1), CYB003 (n\u0026thinsp;=\u0026thinsp;4), ELE-101 (n\u0026thinsp;=\u0026thinsp;1), MLS101 (n\u0026thinsp;=\u0026thinsp;1), PEX010 (n\u0026thinsp;=\u0026thinsp;18), PEX020 (n\u0026thinsp;=\u0026thinsp;1), PEX030, TRP-8802 (n\u0026thinsp;=\u0026thinsp;1), and psilocybin cubensis (n\u0026thinsp;=\u0026thinsp;3). Analysis of individual dose and dosing schedule utilized revealed that psilocybin is most often administered at a fixed 25mg dose (n\u0026thinsp;=\u0026thinsp;92) in a single administration (n\u0026thinsp;=\u0026thinsp;78). However, a wide range of doses for psilocybin are being tested, which vary between 0.15mg to 50mg. Because many clinical trials that administer psilocybin more than twice are testing efficacy of doses reflective of microdose use patterns, these doses are often administered daily.\u003c/p\u003e \u003cp\u003eDMT was the second most common psychedelic being tested in clinical trials (\u003cb\u003eFig.\u0026nbsp;3D\u003c/b\u003e) with doses ranging from 0.75-40mg. However, most total doses were unable to be calculated or compared due to DMT doses often being reported as infusions rates (mg/min) without a total infusion time. There are three unique compounds being studied including GH001 (n\u0026thinsp;=\u0026thinsp;2), CYB004 (n\u0026thinsp;=\u0026thinsp;1), and SM-001 (n\u0026thinsp;=\u0026thinsp;1). Investigations into the efficacy of DMT appear to be in an early stage as over half (7/13) trials are testing healthy volunteers. Thus, most trials utilize either a single administration (n\u0026thinsp;=\u0026thinsp;5), often for safety, or multiple administrations (n\u0026thinsp;=\u0026thinsp;4) with a dose-escalation design, often for pharmacokinetic profiling. The other six clinical trials are early phase clinical trials testing MDD, TRD, Alcohol Use Disorder, Generalized Anxiety Disorder (GAD), and grief.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 3: Trial design of ongoing psychedelic clinical trials\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eGroup assignments methodologies being employed in trial design (A). Types of placebo used (B), number of trials using a placebo (B insert panel). Experimenter blinding design (C). Open-label refers to unblinded trials; \u0026lsquo;Single (outcomes)\u0026rsquo; refers to an open-label trail where only the outcomes analyst is blinded to treatment groups. Representation of classic psychedelic used (D), specific compound or analog (E), and number of administrations (F).\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThere are eleven clinical trials that are using an LSD treatment intervention and only one unique compound (MM-120; n\u0026thinsp;=\u0026thinsp;3) was identified. Unlike clinical trials using DMT, only two LSD clinical trials are testing in healthy volunteers. One of these trials (NCT05964647) is a feasibility study investigating the ability of ketanserin, olanzapine, and lorazepam to shorten or attenuate the subjective effects following an administration of LSD. The other trial (NCT05953038) is investigating the plasma concentration and 5-HT\u003csub\u003e2A\u003c/sub\u003e receptor occupancy as quantified by the radiolabel [11C]CIMBI-36 in Positron Emission Tomography (PET). Other conditions being investigated using LSD include cluster headaches, alcohol use disorder, MDD, GAD, and end of life distress. Dose scheduling of LSD in these trials are mostly single administration (n\u0026thinsp;=\u0026thinsp;5) with dosages ranging from 25ug-250ug and 100ug LSD being the most common (n\u0026thinsp;=\u0026thinsp;5).\u003c/p\u003e \u003cp\u003eOnly one clinical trial utilizing mescaline was identified in our searches (NCT05933213), which compares the use of mescaline sodium enteric-coated tablets and morte-mescaline as adjunctive treatments to glucocorticoids for individuals diagnosed with Lupus Nephritis.\u003c/p\u003e\n\u003ch3\u003eConditions, Outcome Measures, and Endpoints:\u003c/h3\u003e\n\u003cp\u003eCurrently, psychedelics are being applied to a wide range of conditions, which often overlap or exist as comorbidities. For simplicity, we have categorized these conditions as Depression, Substance Use Disorder (SUD), Quality-of -Life, Pain, Trauma, Anxiety, Healthy Volunteers, and Other (\u003cb\u003eFig.\u0026nbsp;4A\u003c/b\u003e). When clinical trials were registered for more than one condition or were treating a specific symptom in a condition, the primary condition was used and was validated by the primary outcome measure. Clinical trials categorized as depression were most prevalent (n\u0026thinsp;=\u0026thinsp;40) and consisted of those involving a formal diagnosis of depression (\u003cb\u003eSupp. Table\u0026nbsp;1\u003c/b\u003e). The most common diagnoses were MDD (n\u0026thinsp;=\u0026thinsp;23) and TRD (n\u0026thinsp;=\u0026thinsp;14). There are three clinical trials for MDD that measure populations with comorbid diagnoses including alcohol use disorder (NCT04620759), borderline personality disorder (NCT05399498), and PTSD (NCT06141876). There are two clinical trials that include individuals with either MDD or TRD (NCT05259943, NCT06303739), and two clinical trials that are measuring TRD in individuals diagnosed with either autism spectrum disorder (NCT06731621) or bipolar II disorder (NCT06943573).\u003c/p\u003e \u003cp\u003eTwenty-seven clinical trials were categorized as SUD (\u003cb\u003eFig.\u0026nbsp;4A\u003c/b\u003e), and are testing alcohol, cannabis, cocaine, methamphetamine, and opioid use disorder (\u003cb\u003eSupp. Table\u0026nbsp;2\u003c/b\u003e), many which we characterized previously (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Only one clinical trial is using DMT (NCT06070649) or LSD (NCT05474989) with all others using psilocybin (\u003cb\u003eFig.\u0026nbsp;4C-E).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eQuality of life clinical trials (n\u0026thinsp;=\u0026thinsp;25; \u003cb\u003eFig.\u0026nbsp;4A\u003c/b\u003e) were those that utilized psychedelics to treat distress, anxiety, depression without a formal MDD or TRD diagnosis, demoralization, grief, cognitive decline, or burnout (\u003cb\u003eSupp. Table\u0026nbsp;3\u003c/b\u003e). These were often in individuals diagnosed with a life-threatening condition, such as amyotrophic lateral sclerosis (NCT06656702), or had an experimental outcome testing for quality of life, suicidality, or depression. Only one clinical trial is utilizing DMT or LSD (\u003cb\u003eFig.\u0026nbsp;4C-E)\u003c/b\u003e, which are for grief (NCT06150859) and end of life distress (NCT05883540) respectively.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 4: Ongoing clinical trial categorization\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eClinical trials were organized by their disease indication (A), primary outcome endpoint (B), and by psychedelic compound (C-E).\u003c/em\u003e \u003c/p\u003e \u003cp\u003eWe identified twelve clinical trials that use classic psychedelics to treat pain symptomology in various conditions. Psilocybin is being investigated to treat pain in individuals diagnosed with chronic pain, migraines, pain in fibromyalgia, persistent post-concussive symptoms, and phantom limb pain (\u003cb\u003eSupp. Table\u0026nbsp;4\u003c/b\u003e). Interestingly, LSD is being investigated to alleviate cluster headaches in two clinical trials (NCT03781128, NCT05477459), which is the only psychedelic being tested for this indication.\u003c/p\u003e \u003cp\u003eClinical investigations using classic psychedelics to treat PTSD appear to be in very early stages as only nine clinical trials are testing psilocybin for individuals with PTSD (\u003cb\u003eSupp. Table\u0026nbsp;5\u003c/b\u003e) and only three trials (NCT06407635, NCT06885996, NCT06853912) have a comparator or placebo group. One clinical trial (NCT05042466) is testing the feasibility of using microdoses of psilocybin (0.15\u0026ndash;1.5mg) to treat trauma.\u003c/p\u003e \u003cp\u003eHealthy volunteer was tied with SUD for second most prominent \u0026lsquo;condition\u0026rsquo; type with 27 trials each (\u003cb\u003eFig.\u0026nbsp;4A\u003c/b\u003e). Further, healthy volunteer was the most common application for LSD (\u003cb\u003eFig.\u0026nbsp;4D\u003c/b\u003e) and DMT \u003cb\u003e(Fig.\u0026nbsp;4E\u003c/b\u003e) clinical trials. As expected, many of these clinical trials are establishing pharmacokinetic profiling, such as plasma concentrations and elimination half-life, safety, and tolerability for novel analogs or dosing regiments (\u003cb\u003eSupp. Table\u0026nbsp;6\u003c/b\u003e). Additionally, this category includes exploratory clinical trials that can establish preliminary evidence before going into further clinical trial stages for other indications, identify novel applications of psychedelics, or probe the molecular basis or changes in brain activity that may underlie the therapeutic benefits of psychedelics.\u003c/p\u003e \u003cp\u003eAny clinical trials that did not meet the criteria for any of these established groups were then categorized as \u0026lsquo;Other\u0026rsquo;. While there are some conditions with more than one relevant clinical trial, like obsessive compulsive disorder (OCD) (n\u0026thinsp;=\u0026thinsp;4), generalized anxiety disorder (n\u0026thinsp;=\u0026thinsp;3), or irritable bowel syndrome (n\u0026thinsp;=\u0026thinsp;2), most conditions in this category only had one clinical trial actively investigating the application of psychedelics (\u003cb\u003eSupp. Table\u0026nbsp;7\u003c/b\u003e). Some of these conditions include anorexia nervosa, lupus nephritis, psychogenic nonepileptic seizures, and self-harm. Interestingly, for the three clinical trials investigating generalized anxiety disorder, none were using psilocybin. This was the only condition in our search that was investigating both LSD and DMT, but not psilocybin.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure 5: Primary endpoint timeline for the 10 most common outcomes\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eThe top ten reported outcomes across all trials are reported for Psilocybin (yellow), DMT (red), and LSD (blue) studies. Substance use disorder measures were separated for drug use and craving to distinguish between distinct behavioral measures. Neuroimaging, including PET, fMRI or MRI, and EEG were included for its relevance for neurobiological innovations.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eWhen comparing the primary endpoints across all ongoing clinical trials, we found that the most common endpoint measurement was three months (\u003cb\u003eFig.\u0026nbsp;4B\u003c/b\u003e). However, there were no primary endpoints that predominated with a good balance of measurements being taken across one week, one month, two months, three months, six months, and one year. There was a clear gap in primary endpoints and measurements between six months and one year with only one clinical trial measuring at seven (NCT05227612) and eight (NCT06407635) months each. No trials are using nine months as an end point, which is a potential area for improvement to generate data that can help predict long-term efficacy and identify potential time-to-redose strategies. This may be a potential area for new clinical trials to target to detect any deficits in efficacy that may occur between the six- and twelve-month time points. It is important to note that some clinical trials may measure at these time points as we only report primary endpoints, and, for short term clinical trials, follow-up measurements after trial completion may occur in this gap.\u003c/p\u003e \u003cp\u003eAfter filtering out outcome measurements for safety, feasibility, and tolerability (like adverse events, vital measurements, recruitment rate, and retention rate), we then charted the time points being collected for the ten most common outcome measurements (\u003cb\u003eFig.\u0026nbsp;5\u003c/b\u003e). We then separated measurements of drug use and drug craving for clarity. Additionally, we charted the time points in which neuroimaging outcomes were being taken, which included EEG, fMRI, MRI, and PET imaging. As expected, psilocybin is the most studied psychedelic across all outcome measurement types, which is due to greater representation in trial design. Clinical trials using DMT and LSD were most prominent at the one week or less time point, which is reflective of their current application for establishing safety and tolerability. Only two outcomes (depression and PTSD symptomology) are being measured beyond the one week or less time point for DMT. LSD is being tested for up to three months for depression, anxiety, and quality of life. One notable shortfall of ongoing clinical trials is the lack of neuroimaging for DMT or LSD. It would be useful if future clinical trials investigate lasting brain changes induced by DMT or LSD and compare them to psilocybin-induced changes at timepoints extending beyond 1 week.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough great progress has been made in unveiling potential therapeutic applications of psychedelics to various conditions that currently lack efficacious treatment options or are difficult to treat, there are multiple overarching questions that remain unanswered by current literature. Results from this systematic review are limited in its ability to answer these questions directly due to the scope of capturing ongoing clinical trials, thus lacking results. Rather, using our findings, we can understand how clinical trials are addressing these concerns and highlight key clinical trials that will be crucial for resolving lingering questions of the field in the coming years.\u003c/p\u003e\n\u003ch3\u003eCan psychedelics be safely co-administered with SSRIs/SNRIs\u003c/h3\u003e\n\u003cp\u003eOne critique facing psychedelic clinical trials is that participants are often required to discontinue prescribed medication, namely antidepressants in trials indicated for MDD or TRD, prior to the initiation of psychedelic assisted psychotherapies. Antidepressant tapering is often implemented in trial protocols for two key reasons. First, antidepressants and psychedelics exert their effects through serotonin modulation and are metabolized in a similar manner. Psychedelics including psilocybin (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), DMT and 5-MeO-DMT (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), and LSD (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) are metabolized through CYP2D6, which 85% of antidepressants are a substrate for (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), suggesting potential competition or inhibition. Additionally, it is likely that initial trial protocols acted in precaution to avoid potential serotonin syndrome, which is associated with antidepressant use and is of greater risk when combinational pharmacology targeting serotonin neurotransmission is utilized (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). However, the risk of psychedelic-induced serotonin syndrome is rare and is believed to be related to the inability of classic psychedelics to increase intrasynaptic serotonin, a hypothesized predictor for serotonin syndrome (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Indeed, there has been a case where serotonin toxicity was observed following psilocybin use alongside antidepressants (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). However, the individual was taking unknown microdoses recreationally while prescribed multiple serotonin modulators including and SNRI (venlafaxine) and 5-HT2A antagonist (trazodone) that could have increased serotonin toxicity risk of psilocybin. This is likely the case as a recent meta-analysis of thirty psychedelic trials, including four indicated for major depressive disorder, found only nine reported serious adverse events across 1072 psychedelic administrations (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), four of which were suicidal ideation from one clinical trial in the post-acute phase (three weeks following psychedelic administration) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). No cases of serotonin syndrome were observed (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), which may support the notion that the observed case of serotonin syndrome was likely due to other prescribed medications and recreational use of illicit psilocybin. However, it is important to note all psilocybin trials captured by the authors utilized synthetic psilocybin, which may not fully reflect the case of serotonin syndrome observed (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) warranting further research into the safety of natural-occurring psilocybin with antidepressants and other compounds that modulate serotonin.\u003c/p\u003e \u003cp\u003eSecond, chronic administration of antidepressants is known to blunt the acute subjective effects of psychedelics (\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), a strong predictor of long-term antidepressant and mental wellbeing outcomes (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Because of these relationships, antidepressants should, in theory, disrupt the long-term efficacy of psychedelics and would thus support antidepressant discontinuation prior to psychedelic administration. However, recent accumulating data suggest that this phenomenon is not observed and may support maintaining antidepressant regimens through trial participation. For example, in a phase 2 exploratory trial determining preliminary safety and efficacy data of adjunctive 25mg COMP360 with ongoing antidepressants found no serious adverse events with a 42% depression remission rate up to three weeks after psychedelic administration (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). A recent scoping review of psychedelic trials found that concomitant antidepressant and psychedelics were safe and tolerable and had no risk of serotonin syndrome (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Tap and colleagues found four clinical trials where depression symptoms significantly improved and three clinical trials where full remission was observed. Further, post-hoc analysis of Goodwin et al., 2022 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;233; NCT03775200) for COMP360 (1, 10, 25mg) showed antidepressant drug discontinuation did not contribute to worsening depression symptoms before administration and psilocybin efficacy and experience was unaltered (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Finally, an open-label trial in healthy subjects were pretreated with escitalopram for two weeks prior to psilocybin administration found no effect of escitalopram on positive mood, \u003cem\u003eHRT2A\u003c/em\u003e or \u003cem\u003eSLC6A4\u003c/em\u003e gene expression, and plasma-BDNF levels induced by psilocybin or psilocybin\u0026rsquo;s half-life (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Additionally, escitalopram pretreatment attenuated bad drug effects, anxiety, and adverse events of psilocybin suggesting a better safety profile. Further studies in depressed participants exposed to antidepressants for longer periods of time is warranted to confirm these findings and measure depression outcomes. Together, while acute subjective effects may be blunted, it appears that concomitant antidepressant use does not vastly attenuate psychedelic depression outcomes.\u003c/p\u003e \u003cp\u003eOur search captured five clinical trials that will be testing psychedelic safety and efficacy with continuing antidepressant prescription. All trials are studying psilocybin either with \u003cem\u003epsilocybe cubensis\u003c/em\u003e mushroom (NCT06898606; NCT06746441) or CYB003 (NCT06793397; NCT06564818; NCT06605105), a synthetic deuterated psilocybin derivative also known as HLP003. The COGUNILA trial (NCT06898606) is investigating the safety of concurrent 20mg/kg fluoxetine with 3g \u003cem\u003epsilocybe cubensis\u003c/em\u003e assisted psychotherapy for individuals diagnosed with TRD and measuring changes in acute psychedelic effects, adverse events, and changes in MADRS after one month. The other trial (NCT06746441) was completed in July 2025, but no results have been posted or published at the time of writing. This trial administered a supratherapeutic dose (5-6g) \u003cem\u003epsilocybe cubensis\u003c/em\u003e twice, with or without cognitive behavioral therapy, for individuals diagnosed with MDD and continued antidepressant treatment. Changes in depression, anxiety, serum BDNF, EEG, and other biomarkers were measured at baseline and after each administration session. All trials using CYB003 are phase 3 trials that include EMBRACE (NCT06793397), APPROACH (NCT06564818), and EXTEND (NCT06605105). Both EMBRACE and APPROACH trials will be measuring depression, illness severity, anxiety, and QoL at baseline through end of treatment. EMBRACE is administering placebo, 8mg CYB003, or 16mg CYB003; and APPROACH is only administering placebo or 16mg CYB003. The EXTEND trial is a long-term extension where non-responders or individuals with depression relapse can participate in to receive up to 3 more 16mg CYB003 doses, two three-weeks apart and one additional if participants relapse again. Depression scores will be measured up to 301 days after baseline.\u003c/p\u003e \u003cp\u003eBecause the extent of detailed reporting in the clinicaltrials.gov database is at the discretion of the clinical trial manager, sponsor, and trial uploader, this is likely an underestimate of ongoing trials investigating the safety of concomitant antidepressant and psychedelic use. Nonetheless, these trials will remain pivotal for understanding of psychedelic-antidepressant interactions, optimizing psychedelic assisted therapy protocols, and support FDA approvals for psychedelics, namely psilocybin, as an adjunctive therapy to partial or non-response to ongoing antidepressant therapies.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIs the \u0026lsquo;psychedelic experience\u0026rsquo; necessary for therapeutic benefits?\u003c/h2\u003e \u003cp\u003eSeveral barriers to the use of psychedelics as therapeutics are specifically related to the associated \u0026lsquo;psychedelic experience.\u0026rsquo; For example, one potential barrier to FDA approval of psychedelic therapies lies in the difficulty in disentangling the impact of the medication from the psychedelic-specific therapy dedicated to preparation for, and integration of, the psychedelic experience. In the absence of the psychedelic experience, \u0026ldquo;psychedelics\u0026rdquo; could be offered with or without therapy, similar to the clinical use of antidepressant medications. The \u0026lsquo;psychedelic experience\u0026rsquo; also makes blinding and controlling for expectancy effects in clinical trials very challenging. Should psychedelics be approved for clinical use, the psychedelic experience would result in significant healthcare costs given the need to have facilitator(s) present during the treatment session to help patients navigate potentially challenging experiences; this will be particularly costly for psychedelics with longer-lasting effects. At present, it is unknown whether the \u0026lsquo;psychedelic experience\u0026rsquo; is needed for the therapeutic effects or if the therapeutic effects are driven strictly by the neurobiological consequences, such as brain changes induced by serotonin and BDNF signaling cascades. It is important to acknowledge that this question is not whether the subjective effects contribute to the psychedelic-induced neuroplasticity, but rather if the two could be separated, as described previously (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). It has been argued that subjective effects are a necessary component to achieve the full and lasting therapeutic effects of psychedelics, which is rooted in clinical findings that the psychedelic experience is often reported as one of the most meaningful events in the participant\u0026rsquo;s life and is predictive of therapeutic outcomes (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). On the other hand, some have argued that the lack of causality may indicate that the subjective effects may be involved, but not necessary for observing notable therapeutic effects and may serve as a predictor for 5-HT\u003csub\u003e2A\u003c/sub\u003e agonism (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Although most of the data supporting this point of view stems from preclinical evidence, a recently reported case study of an individual with TRD and receiving psilocybin-assisted psychotherapy who had used trazadone, a 5-HT\u003csub\u003e2A\u003c/sub\u003e antagonist, the night before had lasting anti-depressant effects in absence of subjective effects (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDue to a lack of clinical evidence separating subjective and therapeutic effects, it is difficult to decipher how much of the lasting therapeutic effects of psychedelics are dictated by subjective/mystical experiences or distinct neurobiological changes induced by psychedelic-induced signaling. There has been a prior suggestion that clinical trials should investigate blocking subjective effects by administering psychedelics under sedation, as demonstrated in clinical trials for ketamine (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). No clinical trials were captured that utilized this approach, but we captured six clinical trials that are investigating the ability to block the subjective effects induced by psychedelic while maintaining therapeutic efficacy. Although testing healthy volunteers, one clinical trial (NCT06796361) appears to directly address a prior recommendation to use a 5-HT\u003csub\u003e2A\u003c/sub\u003e antagonist pre-treatment to test the molecular basis of therapeutic efficacy (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) by using ketanserin to block psilocybin with measures for subjective effects, mood, personality, cognition, sleep, and pharmacokinetic parameters. Three other clinical trials are testing the feasibility of antipsychotics to block the subjective effects caused by psilocybin. Two trials are using 1mg risperidone to block the subjective effects of psilocybin in individuals with TRD and are measuring depressive symptoms (NCT05710237, NCT06512220) or utilizing brain imaging techniques to detect changes in prefrontal cortex function, hippocampus function, and plasticity (NCT06512220) after one week. The third clinical trial is using 34 mg pimavanserin and testing depressive symptoms up to five weeks later (NCT06592833). Apart from antipsychotics, one clinical trial is sedating participants with MDD using propofol during a DMT administration session and will be measuring depression and plasma BDNF levels after 2 weeks (NCT06927076). Another clinical trial (NCT06692192) is a follow-up to a prior clinical trial (NCT04842045) that induces amnesia of the subjective effects induced by psilocybin with midazolam. NCT04842045 measured the feasibility of the amnesia protocol, which is completed but has not reported results yet. The ongoing clinical trial is utilizing the same approach and is measuring changes in brain activity via MRI and TMS-EEG one month after psychedelic administration. Results from these clinical trials could help determine the role, or lack thereof, of the \u0026lsquo;psychedelic experience\u0026rsquo; in the therapeutic potential of these drugs.\u003c/p\u003e \u003cp\u003eAdditionally, one clinical trial (NCT05964647) tests the feasibility of administering either ketanserin (40mg), olanzapine (10mg), or lorazepam (2mg) after LSD administration to shorten or attenuate LSD-induced subjective effects. Although ketanserin is known to block the effects of psilocybin (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) and LSD (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) in humans already, findings from this clinical trial can give greater understanding for how clinicians can control the subjective effects caused by psychedelics. More importantly, being able to safely control when subjective effects end could shorten the length of treatment sessions and the high healthcare costs associated with psychedelic-assisted psychotherapy treatment regiments.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCapturing neuroplasticity in humans\u003c/h3\u003e\n\u003cp\u003eIt has been well-understood that psychedelics are capable of inducing neuroplasticity through activation of BDNF, which has been recently described well (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and characterized through systematic review (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, most of this evidence stems from findings using animal models. Because of the invasiveness of retrieving brain levels of BDNF in human populations, these findings have not yet been confirmed. The best efforts thus far have been measurements of serum BDNF, but findings so far have been inconclusive (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Through our search, we identified six ongoing clinical trials that are measuring plasma BDNF in their participants. Two clinical trials are measuring BDNF one day (NCT05559931) or two weeks (NCT06927076) after DMT administration. All other clinical trials are measuring BDNF one week (NCT04718792), one month (NCT06768944), five weeks (NCT06072898), and three months (NCT05416229) after psilocybin administration. Across these six clinical trials, BDNF will be measured in participants that are diagnosed with MDD or alcohol use disorder or are healthy volunteers.\u003c/p\u003e \u003cp\u003eOne possible explanation for why serum BDNF is not being measured frequently could be that more novel approaches have been recommended. For example, PET imaging to detect synaptic vesicle protein 2A (SV2A) could be leveraged to better measure of neuroplasticity in humans (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), detect changes in various conditions relevant to psychedelic research, confirm findings derived from animal models (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). In line with this, we found that 53 of 165 ongoing clinical trials captured in our searches are utilizing a neuroimaging technique including PET, fMRI, MRI, or EEG (data not shown). Only three trials with a neuroimaging technique utilize a psychedelic other than psilocybin with one clinical trial having an endpoint longer than one day after psychedelic administration (\u003cb\u003eFig.\u0026nbsp;5\u003c/b\u003e). Thus, there is a great need for more clinical trials that utilize neuroimaging techniques at longer endpoints to better understand psychedelic-induced changes in brain functioning.\u003c/p\u003e\n\u003ch3\u003eFunctional unblinding and the placebo problem\u003c/h3\u003e\n\u003cp\u003eMany critiques and unanswered questions in the field of psychedelics are rooted in the experimental design of clinical trials. Although randomized controlled trials (RCTs) are considered the gold standard of clinical trials (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), this is only the case when researcher staff and clinicians are blinded to group assignments and participants are masked to the treatment intervention they received. Great efforts have been made to improve masking and attempt avoiding the functional unblinding of participants following a psychedelic administration; however, a recent systematic review of completed clinical trials found that over 75% of psychedelic clinical trials had poor masking success (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). Despite this concern, we were only able to detect six ongoing clinical trials that are measuring experimental blinding effectiveness of participants (NCT06671977, NCT03781128, NCT05477459, NCT05474989, NCT06341426, NCT06455293). Some suggestions have been made, such as systematically investigating the specific contextual components of how psychedelics are administered (commonly referred to as \u0026lsquo;set and setting\u0026rsquo;) that contribute to outcomes (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e), administering psychedelics under anesthesia (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), and including analysis of individual factors such as therapeutic alliance, expectancy, and credibility effects (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). Because participant blinding is a relatively simple measure to carry out, often requiring a single questionnaire like the Credibility and Expectancy Questionnaire (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e), clinical trials going forward should implement and report blinding effectiveness data. Additionally, a new computational model to evaluate activated expectancy bias (a combination of weak blinding and treatment expectancy) and a counteracting statistical test to estimate outcomes and detect false positives has been developed that could be adopted (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Implementation of these recommendations would aid in understanding the validity of different experimental designs, create a standard protocol with proven blinding effectiveness, and detect experimental or participant biases that may influence trial outcomes.\u003c/p\u003e \u003cp\u003eOne major factor contributing to functional unblinding in psychedelic trials is the absence of a standardized placebo that has comparable effects to moderate or high doses of psychedelics. This is especially concerning due to large effect sizes that have been observed in 60% of active placebo trials and 75% of inactive placebo trials (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). Similar drugs (MDMA and ketamine) that have also lacked an adequate placebo or had notable functional unblinding have faced setbacks by the FDA as summarized previously (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). Further, a recent systematic review of 50 completed studies revealed that no individuals that received a psychedelic incorrectly guessed they were in the placebo group, and the only studies that blinding was successful were for those with an active placebo (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Prior to 2020, most psychedelic clinical trials that utilized a placebo group chose an inert placebo (61.2%) and only 20% of clinical trials used an active comparator (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e). Of the 165 ongoing clinical trials discussed here, the most common placebo was a low dose of the experimental drug (n\u0026thinsp;=\u0026thinsp;39) that made up most of the active placebo group (Fig.\u0026nbsp;3B). When accounting for 59 clinical trials that did not use a placebo and 26 clinical trials did not specify their placebo, this means that 33 different placebos or comparators were used across the remaining 42 clinical trials. Although it appears ongoing experimental designs have now opted for an active placebo, the need for a more appropriate placebo that can maintain integrity of participant blinding remains.\u003c/p\u003e \u003cp\u003eTo address this issue, a novel, well-thought out set of recommendations that has been proposed for a multitude of psychedelic administration types, which include salvinorin A for vaped DMT, dextromethorphan and THC for oral LSD or psilocybin; and diphenhydramine or a stimulant for low dose oral LSD or psilocybin (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e). An additional recommendation of high dose THC has been proposed as a placebo for its ability to induce a similar experience to that of a psychedelic while being unlikely to induce neuroplasticity (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). In our search, we identified five clinical trials that meet these recommendations including THC as a comparator (NCT06464367, NCT06671977), and diphenhydramine (NCT06070649) or dextromethorphan (NCT06731335, NCT05068791) as a placebo. Importantly, one of the clinical trials that is using THC as a comparator to DMT to test efficacy for MDD is also reporting blinding and expectancy effects (NCT06671977). While limited to one clinical trial and one psychedelic tested, findings from this study can demonstrate the feasibility of THC as an active placebo that keeps participant blinding intact for psychedelic clinical trials.\u003c/p\u003e \u003cp\u003eOther recommendations to increase scientific rigor have been made regarding recruitment and enrollment, preparation and integration sessions for psychedelic administration, and statistical analysis (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). However, our search was only able to capture study design and dosing information. Therefore, to capture trends in clinical research that would address these recommendations, it would be more appropriate to look at published results of newly completed clinical trials that would provide more methodological detail.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePsychedelics and the Default Mode Network\u003c/h2\u003e \u003cp\u003eFollowing promising results of using psychedelics as treatments in MDD, TRD, and SUD, the field is rapidly investigating the feasibility of psychedelics for a multitude of other diagnoses. We captured this trend in our characterization of ongoing clinical trials where a psychedelic intervention is being tested to treat symptoms related to depression, anxiety, substance use, trauma, demoralization, self-harm, pain, eating disorders, quality-of-life in life threatening illness, OCD, seizures, irritable bowel syndrome, and others (\u003cb\u003eSupp. Tables\u0026nbsp;1\u0026ndash;6\u003c/b\u003e). Despite psychedelics having great therapeutic promise, it is unlikely a single biological mechanism or pathway could be responsible for the generalizability of psychedelics across this wide range of diagnoses i.e. depressive disorders, substance use disorders, eating disorders, and others, as the neurobiology of these conditions vary greatly. Therefore, it is more likely the generalizable therapeutic effects of psychedelics are more reflective of widespread alterations of brain functioning, which could \u0026lsquo;override\u0026rsquo; or \u0026lsquo;rewire\u0026rsquo; maladaptive neurocircuitry. In an effort to capture this, many active clinical trials are utilizing neuroimaging techniques, namely fMRI and PET imaging, to capture functional connectivity and changes in brain network activity with particular interest in the default mode network (DMN).\u003c/p\u003e \u003cp\u003eThe DMN can be understood as the \u0026lsquo;off\u0026rsquo; mode of the brain where processes such as reflection, mind-wandering, and resting are promoted through activity of the medial prefrontal, lateral parietal, and posterior cingulate cortices. DMN dysfunction has been observed in various psychiatric illnesses, mood disorders, and mental disorders and has been described in depth elsewhere (see Buckner et al., 2008 (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e); Doucet et al., 2020 (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e), Mohan et al., 2016 (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e)). Briefly, DMN hyperconnectivity is observed in MDD (\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e), OCD (\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e), and schizophrenia (\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e) while hypoconnectivity is observed in cognitive disorders, like Alzheimer\u0026rsquo;s disease and Parkinson\u0026rsquo;s disease. DMN hypoconnectivity is also observed in mild cognitive impairment, however, a systematic review has found notable inconsistencies across studies (\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e). Additionally, SUD and behavioral addictions cause widespread changes across multiple brain networks including hyperconnectivity between DMN and the frontoparietal, salience, and affective networks (\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e). Authors also found SUD-specific functional connectivity changes involving the DMN and frontoparietal network, which authors suggest may be attributed specifically to the administration of an addictive drug (\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn other cases, DMN dysfunction can rise from alterations in the suppression or promotion of DMN activity, as is the case for individuals with attention deficit hyperactivity disorder (ADHD) (see Mohan et al (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e). This could explain mixed results found in a systematic review of autism spectrum disorder (ASD) fMRI studies, as authors note there are significant clinical and genetic overlap and notable comorbidity (\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e). Another potential explanation for variable results is differences between seed- and network-based approaches, which has been suggested to underly variable DMN findings in eating disorders (\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA comprehensive analysis of 14,027 patients diagnosed with either ADHD, anxiety disorders, ASD, bipolar disorder, depressive disorder, OCD, PTSD, or schizophrenia revealed hypoconnectivity within DMN, between DMN and ventral salience network and hyperconnectivity between DMN and ventral salience network and dorsal salience network compared to healthy controls (\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e). Additionally, these changes in brain network function and connectivity were associated with network-specific grey matter loss and suggest that common brain network adaptations may underlie the presentation of symptoms, like cognitive deficits, across a wide range of psychiatric illnesses, many which we show are being investigated in psychedelic clinical trials (\u003cb\u003eFig.\u0026nbsp;5\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eAlthough DMN dysfunction is a common maladaptation across psychiatric illnesses, these changes do not appear to be direction- or region-specific. Thus, how psychedelics, often after a single administration, may be therapeutic in both hypoconnective and hyperconnective DMN states remains elusive. There are currently three leading models that could describe these effects, all which are well-summarized by Doss and colleagues (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e). It is important to note that these models do not necessarily negate one another and likely co-exist through shared mechanisms of serotonergic modulation of neurotransmission, overlapping neurobiology, and alterations in thalamic gating of information.\u003c/p\u003e \u003cp\u003eOne idea is the relaxed beliefs under psychedelics (REBUS) model where administration of a psychedelic reduces DMN top-down activity and disrupts predictive coding, particularly involving the sensory cortex, posterior parietal cortex, prefrontal cortex, and hippocampus (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e). This reduction of activity allows the maladaptive connections to be disassembled, new connections to form, and greater involvement of cortical regions resulting in a less constrained and greater interconnected brain (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e). These changes can also be understood as mechanisms to increase entropy, the measure of disorder in a neural system.\u003c/p\u003e \u003cp\u003eIn line with this, the entropic brain hypothesis explains the therapeutic effects of psychedelics in the context of a U-shaped relationship between entropy and cognition (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e). In this relationship, high levels of entropy are reflective of high disorder and flexible cognition, such as infant consciousness, early psychosis, near death experiences, and creativity. In contrast, low entropy is characteristic of low disorder and rigid, reduced consciousness. Low entropy could be reflective of unconscious thought states, such as comas, anesthesia, or deep sleep but also describe diagnoses of rigid thoughts or behaviors observed in MDD, OCD, and SUDs. A healthy individual is understood as relatively equally between high and low entropy states with a slight skew toward low entropy. Carhart-Harris and colleagues explain that when an individual is administered a psychedelic, the individual enters a high-entropy state as a result of neurobiological (5-HT2A and pyramidal neuron stimulation), network (desynchronized cortical activity, replacement of rigid connectivity with new motifs), and metastability changes (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eImportantly, one consideration this hypothesis seems to indirectly support is the notion that psychedelics may not be appropriate treatments for any psychiatric illness that has altered DMN functioning described above. For example, there are biological and DMN-related rationales for why psychedelics may be relevant for treating individuals with schizophrenia (\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e). In fact, Sapienza and colleagues describe early LSD and mescaline studies that reported promising results for treating schizophrenia symptoms prior to prohibition (\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e). However, there is great concern that psychedelic experiences may exacerbate positive symptoms of schizophrenia. Positive symptoms of schizophrenia, like hallucinations, delusions, and psychosis would be representative of high entropy under the entropic brain hypothesis (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e). Although psychedelics may be therapeutic for negative symptoms of schizophrenia, which reflect states closer to MDD, the risk of worsening positive symptoms is a current rationale for not testing psychedelics as schizophrenia treatment. Interestingly, results from clinical trials investigating the feasibility of antipsychotic pretreatment to block the psychedelic experience but spare neuroplastic and antidepressant effects could prove pivotal for this area of research. If successful, these trials may provide the basis for new clinical trials that aim to treat negative and cognitive symptoms while minimizing the risk exacerbating positive symptoms in individuals diagnosed with schizophrenia that respond to antipsychotics.\u003c/p\u003e \u003cp\u003eAnother proposed model is the cortico-striatal thalamo-cortical loop (CSTC) model, where psychedelics disrupt bottom-up sensory input, top-down information processing, and thalamic gating by stimulating cortico-striatal and thalamo-cortical glutamatergic afferents and modulating neurotransmission via serotonergic efferents of the dorsal raphe (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e). Vollenweider and Preller propose that the reduction of thalamic filtering of information would decrease integrative processing through decreased connectivity of the association cortices while increased sensory processing would arise from increased connectivity of sensory cortices (\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e). While this model accounts for the involvement of other neurotransmitters, such as dopamine, GABA, and glutamate (\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e), the proposed model only accounts for 5-HT signaling from the dorsal raphe. Thus, neuromodulation and transmission that are facilitated by localized serotonergic tone in other cortical and subcortical areas are unaccounted for.\u003c/p\u003e \u003cp\u003eMore recently, Doss and colleagues have resolved this point with the cortico-claustro-cortical model, where communication between prefrontal, posterior parietal, and sensory cortices are modulated by the claustrum (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e). In this model, the claustrum, which is rich in serotonergic receptors, creates a circuit through glutamatergic afferents from the prefrontal cortex and glutamatergic efferents to the prefrontal, posterior parietal, and sensory cortices allowing for the modulation of synchronicity between networks. Additionally, the claustrum is extensively linked with cortical and subcortical regions (\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e). In brain imaging studies, it has been shown that the claustrum is functionally connected to the DMN and task positive network, activates when a cognitive task is presented, and is active when DMN activity is suppressed (\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e), an effect that can be modulated by psilocybin (\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e). While not depicted by Doss and colleagues in their proposed model schematic (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e), preclinical findings in feline (\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e) and primate (\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e) models shown the claustrum receives serotonergic inputs, which have been suggested to originate from the dorsal raphe (\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e). Studies into the role of claustrum in potentially mediating states consciousness have been limited by its size, shape, and location, however theories have been postulated as early as 2005 (\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e) and have been summarized elsewhere (\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlongside these models, it is possible that the underlying generalized mechanism of psychedelics is driven through unlocking a window of neuroplasticity. Indeed, it has been shown that psychedelics such as psilocybin, LSD, ibogaine, and MDMA can open critical periods of social learning (\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e). This, alongside neurobiological mechanisms such as psychedelic-mediated or BDNF-induced neuroplasticity (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), could provide a temporary critical period for the brain to transform affected neurotransmission under the guidance of clinician-led psychotherapy, which could facilitate the cognitive flexibility of a participant in a clinical trial setting. Thus far, it is unclear if these mechanisms and proposed models are neurobiologically connected or act as independent therapeutic mechanisms following administration of a psychedelic to produce notable, long-lasting improvement for participants in clinical trials. By further elucidating the neurobiological changes brought about by psychedelic interventions through functional imaging accompanied by clinical behavioral scales between healthy and affected participants, these mechanisms may become clearer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLimitations:\u003c/h2\u003e \u003cp\u003eOur systematic search has several limitations that should be considered when interpreting our findings. First, we only utilized the clinicaltrial.gov database to capture registered, ongoing clinical trials, which may have resulted in missed potential hits that are registered in other clinical trial databases. For the clinical trials detected, multiple reporting errors or missing information existed across trials, such as the dose of the psychedelic being administered, how often the dose was given, listing outcomes in the trial description but not the outcomes and endpoints sections, and, in some cases, endpoints or experimental groups that did not match the trial description. Although we resolved these issues manually in most cases by either identifying the information in a different section or not including that measure in analysis, there were two clinical trials that had to be excluded for reporting issues that could not be resolved by the authors. Lastly, for our visualization of clinical trial endpoints, it is possible that measures may be taken more often than just the primary endpoints, including long-term follow-up studies that could extend efficacy and neuroimaging measures beyond what is depicted (\u003cb\u003eFig.\u0026nbsp;5\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThrough our scoping review approach, we captured 165 ongoing registered clinical trials with a treatment intervention using a classic psychedelic and tracked trial characteristics and methodological approaches to better understand trends in experimental design, identify possible gaps in research, and identify specific clinical trials that are addressing current critiques or unanswered questions in the field. Most clinical trials were early phase, actively recruiting, administering psilocybin, measuring depressive symptoms, and are expected to be completed in the next two years. Additionally, we identified 15 unique psychedelic analogues that are being tested for market approval. From this, we hope this scoping review can serve as a snapshot to describe the current state of clinical psychedelic research, and the trends and recommendations discussed herein could be used to increase scientific rigor and trial-to-trial continuity to aid in advancing the field.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Dr. Anna Kruyer and Nathan Koorndyk for reading the manuscript and providing constructive feedback.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDeclaration of Interest:\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest linked with any content of this manuscript.\u003c/p\u003e\n\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eThe authors have no funding to declare that supported this work.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCollaborators GBDMD (2022) Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. 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Nature 618(7966):790\u0026ndash;798\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Cincinnati","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"psychedelics, psilocybin, depression, psychiatric disorders, clinical trials","lastPublishedDoi":"10.21203/rs.3.rs-8544354/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8544354/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAims:\u003c/h2\u003e \u003cp\u003eThe investigation of psychedelics as potential therapies has expanded dramatically in the past decade, leading to their study in a wide range of conditions. Here, we characterize all ongoing clinical trials utilizing a psychedelic intervention with the goals of identifying trends in experimental design and application and discuss how findings from individual, ongoing clinical trials may address current unanswered questions or recommendations from the field.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eA scoping review approach was used to identify registered clinical trials at ClinicalTrials.gov that listed a classic psychedelic as intervention criteria. All ongoing clinical trials were characterized by their study criteria, experimental design, and clinical trial status. When available, specific psychedelic analogs are included with their representative trial.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eWe identified 165 ongoing clinical trials that utilize a treatment intervention with a classic psychedelic. Most clinical trials were early phase, actively recruiting trials based in the United States for depression. Comparisons of experimental design criteria revealed that psychedelics are mostly administered a single time and use either an open-label, single-arm design, or a parallel-assignment, quadruple-blinded, active-placebo design. In our search, we found that only six trials explicitly report blinding effectiveness as a trial outcome and that 33 different placebos are being used as a control across psychedelic trials.\u003c/p\u003e\u003ch2\u003eConclusion and Implications:\u003c/h2\u003e \u003cp\u003eMultiple clinical trials have been initiated that have the potential to shed insight on common critiques and unanswered questions in the field. Despite this, some areas warranting clarity remain, such as identifying a proper placebo or improving participant masking rates. We hope that insights from this review will help inform the reader of the status for clinical psychedelic research and inspire initiation of new clinical trials that may address the shortcomings discussed herein.\u003c/p\u003e","manuscriptTitle":"The mushrooming of the psychedelic renaissance: A scoping review identifying trends in ongoing clinical trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 07:13:49","doi":"10.21203/rs.3.rs-8544354/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"09e57f89-19dc-4467-9a6b-f8debdd8e0e1","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60767367,"name":"Clinical Pharmacology"},{"id":60767368,"name":"Psychiatry"}],"tags":[],"updatedAt":"2026-01-16T17:29:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 07:13:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8544354","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8544354","identity":"rs-8544354","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}