A Review of the Food and Drug Administration Pipeline and Proposed California Legislation on Medicinal Psychedelics

Abstract

Psychedelic and empathogenic compounds show promise for a variety of conditions. However, studying these compounds can be highly complex, be very expensive, and have substantial patient safety concerns. Here, the authors will review 8 late-phase medicinal psychedelic studies in the Food and Drug Adminisration (FDA) approval pipeline. The authors will include a review of the FDA’s recent denial of the New Drug Application for 3-4-methylenedioxymethamphetamine with adjuvant psychotherapy for posttraumatic stress disorder from Lykos Therapeutics of San Jose, California (formerly the Multidisciplinary Association for Psychedelic Studies Public Benefit Corporation). Additionally, the authors will discuss the parallel legislative proposals in California to legalize psychedelic compounds for adult use. These legislative efforts reflect an alternative and less expensive pathway, but they do not make as thorough of an evaluation for drug safety. The authors will propose that the FDA remains the appropriate agency to evaluate and approve the use of this class of proposed therapeutics.

Introduction

In 2017, the Food and Drug Administration (FDA) recognized the promise of psychedelics with the first breakthrough therapy designation (BTD) given to Lykos Therapeutics for the treatment of posttraumatic stress disorder (PTSD) with 3-4-methylenedioxymethamphetamine (MDMA) with adjuvant psychotherapy. Introduced by the FDA in 2012, BTD is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drugs may demonstrate substantial improvement over available therapy on a clinically significant endpoint. ¹ In 2019, esketamine, the active enantiomer of ketamine, became noteworthy as the only FDA-approved psychedelic for mental illness, with a nasal spray for treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal thoughts or actions. ²

In the spring of 2024, a review of the entire FDA pipeline reflected 25 FDA stage 1 and 35 FDA stage 2 psychedelic studies. This review will focus on the 7 FDA phase 3 studies: 2 for ketamine and 5 for psilocybin. This review will also focus on the recently denied New Drug Application (NDA) for MDMA with adjuvant psychotherapy (Table 1). ^3,4

Table 1:

Food and Drug Administration late-phase psychedelic trials

FDA late-phase psychedelic trials	Research group
MDMA with psychotherapy to treat PTSD (NDA)	Lykos Therapeutics
Ketamine treatment in AUD (phase 3)	Awakn Life Sciences
Ketamine to treat patients with postcomatose disorders of consciousness (phase 3)	University of Liège, Belgium
Psilocybin for MDD (phase 3)	Usona Institute, Wisconsin
Psilocybin-assisted therapy and TRD (phase 3)	University of North Carolina
Psilocybin for TRD (phase 3; 2 studies)	Compass Pathways
Psilocybin frontline clinician study (phase 3)	University of Washington

AUD, alcohol use disorder; FDA, Food and Drug Administration; MDD, major depressive disorder; MDMA, 3-4-methylenedioxymethamphetamine; NDA, New Drug Application; PTSD, posttraumatic stress disorder; TRD, treatment-resistant depression.

Although psychedelic compounds are touted as generally safe, it is important to note that rare but serious adverse effects exist with their use. The highest chance for this is seen in unsupervised, nonmedical settings. ^5,6 The safety of their widespread use therefore should be rigorously investigated. For example, there is literature that reports serotonin (5-HT) syndrome and hepatitis after a single-dose recreational ingestion of MDMA. ⁷ Also, psilocybin literature has noted increased suicidality for a subset of patients. ⁸ In addition, the research on the potential for addiction to psychedelic compounds is mixed. Considering these compounds low risk is supported by literature demonstrating rapid tachyphylaxis. ⁹ In addition, it is believed these compounds agonize the 5-HT2C receptor, a function that reduces the dopaminergic activity of neuronal circuits that drive addiction. ¹⁰ By contrast, a recent editorial published by the American Society of Addiction Medicine points out that despite the rapid tolerance and limited physical withdrawal of many psychedelic compounds, there is concern for persistent mental preoccupation with use, compulsion for repeated use, and continued use despite harm. ¹¹ In 2023, the Stanford Director of Addiction Medicine testified to the California State Legislature that the paucity of competent psychedelic reporting systems hinders the understanding of harms. Reflecting upon 2 decades of clinical experience along with a literature review, she expressed concern that psychedelics pose a public health threat. ¹²

The authors also review recent defeated legislation in California, including California Senate Bills (SBs) 58, 1012, and 803. In 2023, SB 58 was an attempt at decriminalization of medicinal psychedelics. In early 2024, SB 1012 was proposed to legalize psychedelics for treatment by psychedelic facilitators outside the scope of the Medical Board of California. Finally, in the summer of 2024, SB 803 proposed a pilot study in 3 counties (Santa Cruz, San Francisco, and San Diego) for the prescription of psychedelics by physicians licensed in the California Medical Board. ^13–15

FDA Approval Process

The FDA oversees drug development and approval in the United States. The FDA follows a 5-step process for drug approval beginning with drug development and discovery. After this first step, only a relative few will move on to the preclinical research stage, where studies are conducted to determine drug toxicity. After this, phase 1 clinical trials begin as small-scale studies in target populations (a few hundred patients) that last several months and aim to understand the drug’s safety and dosage. Approximately 70% of drugs successfully move on to phase 2. Phase 2 studies seek to understand the drug’s efficacy and side effects in a slightly larger population over a period of months to several years. Of these candidate compounds, 33% will continue to phase 3 investigations. Phase 3 studies are large-scale, with hundreds to thousands of participants over 1–4 or more years. This last phase of research determines the drug’s efficacy and monitors for adverse effects. A total of 25% to 30% of phase 3 study drugs successfully move forward to an NDA. ¹⁶

The FDA has 6–10 months to review an NDA, which determines approval for clinical use. The fifth and final step pertains to FDA safety monitoring while the drug is newly approved. Not surprisingly, the FDA drug development process is expensive. In 2019, estimates of total average prelaunch research and development costs ranged from $161 million to $4.54 billion. ¹⁷

MDMA With Psychotherapy to Treat PTSD

In 2017, the first FDA psychedelic BTD designation of MDMA with adjuvant psychotherapy for PTSD expedited the development of 2 Lykos phase 3 trials, MAPP1 (multisite phase 3 studies of MDMA-assisted therapy for PTSD) and MAPP2. MDMA acts to increase 5-HT through 3 primary mechanisms (Figure 1). First, it acts on the serotonin transporter to block 5-HT reuptake and stimulate 5-HT release. Next, it disrupts the function of vesicular monoamine transporter 2, which maintains the 5-HT gradient in the presynapse. Finally, it inhibits monoamine oxidase-A and monoamine oxidase-B, which are involved in 5-HT metabolism. MDMA also acts on the dopamine transporter and norepinephrine transporter to a lesser extent. ¹⁸

Figure 1:

The MDMA mechanism of action. 5-HT = serotonin; MAO = monoamine oxidase; MDMA = 3-4-methylenedioxymethamphetamine; SERT = serotonin transporter; VMAT2 = vesicular monoamine transporter 2. Created in BioRender. Dahdouh, G. (2024) BioRender.com/u58q232

Clinical evidence suggests that the increase in these monoamine neurotransmitters is responsible for MDMA’s distinctive cognitive effects. Animal models have demonstrated that MDMA can enhance fear memory extinction, modulate fear memory reconsolidation, and bolster social behavior. MDMA can produce stimulant-like acute effects including heightened moods, increased self-confidence and extroversion, intensification of sensory perception, and confusion. ¹⁹ On August 9, 2024, the FDA denied the NDA for MDMA with adjuvant psychotherapy for PTSD, requesting an additional phase 3 study from Lykos, citing flawed design of the MAPP1 and MAPP2 studies. These 2 Lykos phase 3 studies were touted as multisite, randomized, and double blinded in design, and the data appeared to show promising outcomes. Participants in the treatment arm showed a greater reduction in their Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders 5 (CAPS-5, DSM-5) scores, indicating a decrease in PTSD symptoms, and had higher rates of remission when compared to the placebo arm. ^20,21

Prior to the FDA’s decision, the results of the Lykos MAPP1 and MAPP2 trials were reviewed by an FDA advisory committee on June 4, 2024. The 11-member Psychopharmacologic Drugs Advisory Committee (PDAC) meeting noted the promise of the proposed treatment but recommended 9–2 against approving MDMA-assisted therapy, specifically troubled by faulty study design. The most prominent concern was the selection bias of study participants in the MAPP1 and MAPP2 studies, as 40% of the studies’ participants had previous exposure to MDMA. This design fault exacerbated the inherent challenge of functional unblinding within psychedelic research. ²²

Due to the distinct acute side effects, the PDAC did note the inherent difficulty of designing a double-blinded psychedelic clinical trial. The FDA had unsuccessfully requested Lykos to mask the identity of the placebo, suggesting the use of Niacin or low-dose MDMA that would have enough physiological effect to limit recognizability of the placebo. The exaggerated functional unblinding in MAPP1 and MAPP2 led to an expectation bias of the participants, therapists, and independent raters. This may have enhanced the effect of active treatment and blunted the effect of placebo treatment. Further, there was a lack of ethnic diversity of study participants, raising doubts of effectiveness and generalizability. Regarding durability, unease was expressed that the analysis did not take ongoing psychotherapy and selective serotonin reuptake inhibitors (SSRIs) into consideration, suggesting the MDMA treatment results were artificially inflated. ²² Regarding the adjuvant psychological intervention with MDMA used in the study, the PDAC noted that MAPP1 and MAPP2 used a psychotherapy unique to Lykos. As there already are known effective psychological treatments for PTSD, a stronger NDA application could have included either cognitive behavioral therapy or eye movement desensitization and reprocessing in a 2 × 2 design to help with selection and expectation bias. In summary, the PDAC felt the credibility of the trials, statistical significance, and external validity was negatively impacted. ²²

The PDAC added disappointment with the dearth of safety data in the MAPP1 and MAPP2 studies, which also did not capture positive side effects to evaluate MDMA abuse and diversion potential. The group was encouraged that patients appeared to benefit from MDMA with adjuvant psychotherapy but had unease about the trials’ integrity. ²²

In the NDA denial of August 9, 2024, concurring with the PDAC, the FDA asked Lykos to further study the safety and efficacy of the treatment with another phase 3 trial, noting the substantial limitations in the data. The FDA added that it encouraged research and drug development, furthering innovation in psychedelic treatment. ²³

In a troubling development, on August 10, 2024, the journal Psychopharmacology retracted 3 Lykos phase 2 trials articles due to the inclusion of data from a patient who was sexually assaulted by a study therapist. ²⁴

On September 6, 2024, the FDA hosted a hybrid public meeting entitled “Advancing Treatments for PTSD” in support of the FDA’s ongoing focus on understanding the medical need for PTSD treatment with the goal of facilitating treatment development. The meeting featured a panel discussion with federal partners to explore efforts to accelerate treatment development for PTSD, including psychedelic drug development. Panelist Paula Schnurr, PhD, from the National Center for PTSD noted that 14% of Veterans Affairs (VA) patients have PTSD, and 30% have a mental illness. Importantly, VA Acting Director of the Clinical Science Research and Development Service Miriam Smyth, PhD, reported that in January 2024, the VA began actively soliciting psychedelic research for PTSD and depression, and they stated they would announce the selected investigations in the fall. ²⁵ On December 3, 2024, the VA announced their first funding of a psychedelic study in 6 decades, looking at MDMA-assisted therapy for veterans with both PTSD and alcohol use disorder (AUD). ²⁶

The 2 Ketamine Phase 3 Trials

Ketamine conventionally has been administered as an intravenous anesthetic, particularly in the context of achieving shorter-term sedation. Administration at subanesthetic doses, however, induces psychedelic effects, which include a detachment from the environment and body and mood enhancement. These effects have been hypothesized to arise from ketamine’s activity as a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor on inhibitory GABAergic neurons (Figure 2). The suppressed gamma-aminobutyric acid (GABA) secretion results in the prevention of inhibition of glutamatergic neurons, and thereby enhances presynaptic glutamate release. The increased glutamate exocytosis activates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, resulting in an increased excitatory neurotransmission and further stimulating brain-derived neurotrophic factor release. ²⁷

Figure 2:

Ketamine mechanism of action. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF = brain-derived neurotrophic factor; GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-aspartate; PYR = pyramidal neuron; mTORC1 = mechanistic target of rapamycin complex 1. https://biorender.com/u58q232 Created in BioRender. Dahdouh, G. (2024) https://BioRender.com/p75l433

The most common ketamine treatment-induced side effects include headache, nausea, and increased blood pressure, in addition to psychotomimetic side effects (hallucinations, depersonalization, and dissociation). These side effects have been noted to be transient and mild with the capability of being reduced in magnitude with subsequent ketamine treatment. Moreover, there is a lack of sufficient data concerning longer-term adverse effects, which represents an area for further investigation. ²⁸

Ketamine for Treatment of AUD

Ketamine is being investigated as an agent to treat patients with AUD. One early study found that 3 subanesthetic doses of intravenous ketamine in combination with therapy resulted in an elevated 1-year abstinence rate of 66%, as compared to a 24% abstinence rate in a conventional treatment control group (the current standard of care). ²⁹

Awakn Life Sciences just began recruiting for a phase 3 trial to evaluate the efficacy of ketamine-associated psychotherapy in the treatment of severe AUD. This trial builds on the findings of the 2022 phase 2 trial, entitled “Adjunctive Ketamine with Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder.” This phase 2 trial investigated the efficacy of ketamine infusions alone, with a saline placebo, and in increasing abstinence in AUD participants. It also included a pilot ketamine and mindfulness-based relapse therapy regime in promoting or otherwise increasing abstinence in AUD participants. ³⁰

Recently detoxified adults were assigned to 1 of 4 treatment arms: 3 weekly ketamine infusions (0.8 mg/kg) + psychological therapy, 3 saline infusions + psychological therapy, 3 ketamine infusions + alcohol education (serving as an active control for psychological therapy), and 3 saline infusions + alcohol education. Primary outcomes of the study included self-reported percentage days abstinent and confirmed alcohol relapse at 3 and 6 month follow-up periods. A substantial increase in abstinent days was observed in the group treated with ketamine compared to the group treated with a placebo. In particular, the group treated with ketamine and psychotherapy exhibited a mean difference of 10.1% more abstinent days (95% CI = 1.1, 19.0). However, the greatest abstinence was associated with the group treated with ketamine and psychological therapy, with a mean difference of 15.9% more days abstinent (95% CI = 3.8, 28.1). With respect to relapse likelihood (odds of relapse into AUD), which was similarly investigated at 3 and 6 month follow-up periods, the group treated with ketamine and psychological therapy, relative to the placebo and psychoeducation arm, displayed no significant difference (Table 2). ³⁰

Table 2:

Summary of phase 2 trial: Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder (2022) ³⁰

Treatment arm	Primary outcomes	Mean difference in days abstinent (%)	95% CI	Relapse likelihood (relative to saline + alcohol education)
Ketamine (0.8 mg/kg) + psychological therapy	Increase in days abstinent; greatest abstinence among all groups	15.9	3.8, 28.1	No significant difference
Ketamine (0.8 mg/kg) + alcohol education	Increase in abstinent days relative to placebo group	10.1	1.1, 19.0	No significant difference
Saline infusions + psychological therapy	Control for ketamine arm	4.2	−6.8, 15.2	No significant difference
Saline infusions + alcohol education	Placebo (control for ketamine and therapy groups)	Baseline	N/A	Baseline

The main assessments of safety included examinations of kidney and liver function, vital signs, urine screens to rule out drug abuse, and an examination of effects of ketamine administration through a visual analog scale, with no notable adverse effects or results being detected. ³⁰

The new phase 3 trial involves the novel therapeutic AWKN-P001: intravenous ketamine in conjunction with psychosocial support for severe AUD. The trial is a collaborative effort between Awakn, the University of Exeter, and a partnership between the National Institute of Health and the Medical Research Council. Participant recruitment is presently occurring. Results are expected in the first half of 2027, which may help the authors clarify the role that ketamine could play in the future treatment of patients with AUD.

Ketamine Trial for Treatment of Postcomatose Disorders of Consciousness

Ketamine is also being studied by the University of Liege, for its effects on consciousness in patients with postcomatose disorders of consciousness. Although ketamine is not fully understood, its inhibitory properties on N-methyl-D-aspartate (NMDA) receptors are being investigated for potential positive effects on damaged neuronal pathways. In a study published in Nature Neuroscience entitled “Ketamine Triggers a Switch in Excitatory Neuronal Activity Across Neocortex,” it was shown that when ketamine was given to mice, activation of previously silent neurons was seen. ³¹

This phase 3 study, which is currently recruiting, will investigate whether this effect may be seen in humans. A total of 3 populations of patients with disorders of consciousness will be studied: those with unresponsive wakefulness syndrome (opening their eyes spontaneously but demonstrating only reflexive behavior), those in a minimally conscious state (with clear but minimal or inconsistent awareness), and those who have emerged from a minimally conscious state (with the ability to exhibit functional interactive communication or functional use of objects). ³²

These participants will either receive an IV infusion of ketamine dosed at 50 mg/mL or a placebo IV infusion of saline. The study will be organized into 3 phases, with the study purpose to measure new signs of conscious behaviors and higher brain complexity following ketamine infusion. In the baseline phase, brain imaging will be used to assess brain function prior to the ketamine infusion. Imaging will be done with fMRI, PET scans, and electroencephalogram. In the experimental phase, there will be 2 sessions spaced 5 days apart where ketamine or the placebo will be infused. The investigators will assess for new signs of consciousness by using the Simplified Evaluation of CONsciousness Disorders (SECONDs) scale, along with using transcranial magnetic stimulation and electroencephalogram imaging to measure brain activity. ³² The SECONDs scale consists of 6 items: observation, command-following, visual pursuit, visual fixation, oriented behaviors, and arousal. There will also be 2 conditional items: communication and localization to pain. Based on this, a score of 0–8 will be given, with 0 being the least conscious to 8 being the most conscious. ³³ Results are expected in May 2026. ³²

The 5 Psilocybin Phase 3 Trials

Psilocybin is a type of serotonergic hallucinogen found in certain types of mushrooms that has been used in the past to induce an altered state of consciousness within different brain structures. Its active metabolite, psilocin, is an agonist at the serotonergic receptors, 5-HT1A and 5-HT2A, to disrupt the cortico-striato-thalamo-cortical circuits. Psilocin works in 2 pathways (Figure 3): by stimulating 5-HT2AR inhibitory GABA release to decrease pyramidal (PYR) neuron excitability, along with by increasing PYR neuron activity. The first pathway involves direct activation of an interneuron by 5-HT2AR, which increases GABA levels, leading to inhibition of PYR neurons. This pathway leads to a decrease of 5-HT2AR expression in the prefrontal cortex and the hippocampus. The second pathway utilizes direct stimulation of PYR neurons at 5-HT2AR, which leads to an increase in excitatory glutamate levels. Glutamate then acts on the prefrontal cortex to increase brain-derived neurotrophic factor through the AMPA and NMDA neuroplasticity mechanism. ³⁴

Figure 3:

Psilocybin mechanism of action. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF = brain-derived neurotrophic factor; GABA = gamma-aminobutyric acid; 5-HT1A = serotonin 1A receptor; 5-HT2A = serotonin 2A receptor; NMDA = N-methyl-D-aspartate; PYR = pyramidal neuron. Created in BioRender. Dahdouh, G. (2024) https://BioRender.com/p06e459

Recently, the prevalence of TRD and MDD has increased. Although there is a lack of conformity on how TRD is properly diagnosed, MDD is classified as TRD after the failure of at least 2 different antidepressant medications. The current treatments for MDD and TRD include antidepressants, antipsychotics, psychotherapy, transcranial magnetic stimulation, vagus nerve stimulation, esketamine, and electroconvulsive therapy. ² These treatments take time to take effect and can be variable in response rates. ³⁵

Psilocybin is also being studied as a possible treatment for burnout. An FDA phase 2 study that was sponsored by the Brain and Cognition Discovery Foundation showed a significant decrease in Montgomery–Asberg Depression Rating Scale (MADRS) scores once participants had repeated doses of psilocybin. ³⁶ In the United States, there are currently 5 phase 3 clinical trials that focus on psilocybin and its effects on mental health disorders.

The adverse effects of psilocybin on mood can include paranoia, anxiety, euphoria, fear, altered perception, psychosis, and hallucinogen persisting perception disorder. Hallucinogen persisting perception disorder is also known as flashbacks, which are not always considered a harmful experience. There are reports of suicidal behavior, which merit further research. Physiologically, psilocybin can cause severe headaches, nausea, and blood pressure instability. ^5–8

Psilocybin for Treatment of MDD

The Usona Institute is recruiting a phase 3 study consisting of 240 participants who have met the DSM-5-TR criteria for MDD. The purpose of this study will be to evaluate the efficacy, safety, and tolerability of 25 mg psilocybin vs placebo in adults with MDD. This will be assessed by the difference between groups in change in depressive symptoms from baseline to day 43 after the dose. The study will also characterize the durability of initial treatment effect and subsequent response to optional psilocybin 25 mg readministration during the 1-year follow-up period. Notably, participants will split into 3 groups that will initially receive either psilocybin 25 mg, psilocybin 5 mg, or an inactive placebo. Progress of the participants will be measured through their MADRS, Clinical Global Impression Scale-Severity (CGI-S), and Sheehan Disability Scale (SDS) scores. This study is estimated to be completed in April 2026. ⁴

Psilocybin for Treatment of TRD

The University of North Carolina is recruiting 20 individuals for a phase 3 study to look at the therapeutic potential of psilocybin on TRD. The primary endpoints of this study will be to see if psilocybin-assisted therapy improves symptoms of TRD and to follow treatment durability over 1 year. This study will look at the effect of varying doses of 25 mg siplocybin on 2 different patient groups. One group will receive one dose of 25 mg psilocybin, and the second group will receive 2 doses of 25 mg spilocybin and will be followed by measurements with Hamilton Depression Rating Scale (HAM-D-17) and Quick Inventory of Depressive Symptomatology (QIDS), along with by rate of remission. The University of North Carolina expects completion of this study in September 2026. ³⁷

COMP360 for Treatment of TRD (2 Studies)

COMP360, a proprietary synthetic form of spilocybin developed by Compass Pathways, is being explored for its potential to treat TRD. Initial investigations have focused on identifying suitable dosages, with subsequent studies expanding to efficacy.

The phase 2 study of COMP360, published in November 2022 in The New England Journal of Medicine, evaluated the efficacy of single doses at 25 mg, 10 mg, and 1 mg strength in adults with TRD. The study included 233 participants, distributed in 3 equal groups. The primary endpoint for this study was the change from baseline to week 3 in MADRS score. The group taking a dose of 25 mg exhibited the most significant reduction in MADRS scores compared to the group taking 1 mg (P < .001). However, the group taking a dose of 10 mg did not show a statistically significant difference when compared to the group taking 1 mg. Although a variety of adverse events did occur in 77% of the participants (including headache, nausea, and dizziness), there were only 4 participants who dropped out of the study because of an adverse event experience. A total of 2 patients were from the group taking a dose of 25 mg, and the other 2 patients were from the group taking a dose of 10 mg. For the other 20 patients who withdrew, reasons other than adverse events were more common from all arms of the study. Of note, suicidal ideation, suicidal behavior, and self-injury occurred in all groups, with the authors recommending clinical vigilance for future psilocybin trials. ³⁸

Building on phase 2 findings, the 2 currently recruiting Compass Pathways phase 3 studies aim to evaluate the efficacy of COMP360 in conjunction with psychotherapy for adults with TRD. The first phase 3 study with 255 participants will aim to assess the efficacy and safety of a single dose of Comp360 25 mg vs placebo for reducing symptom severity in TRD, when administered with psychological support. This will be assessed in a 6-week, single- dose, double-blind, placebo-controlled part of the study (Part A). Durability of efficacy and long-term safety and the efficacy and safety of retreatment will be assessed in a 20-week, single-dose, double-blind retreatment (Part B) and a 26-week open-label treatment (Part C). Efficacy will be assessed at week 6 using the MADRS and SDS. ^3,4

The second phase 3 study will last up to 16 weeks and involve 568 participants, with the primary endpoint to assess the efficacy of COMP360, administered with psychological support in adult participants with TRD, in improving symptoms of depression. Participants will be randomized into 3 groups in a 2:1:1 ratio to receive doses of 25 mg, 10 mg, and 1 mg, respectively. The study will be designed to last 16 weeks, including a screening period of 3–10 weeks and a follow-up period of 6 weeks. Efficacy will be assessed at week 6 using the MADRS and SDS. ^3,4

In March 2024, the cofounders of Compass Pathways resigned, which was a substantial development, considering the fact that the ongoing trials anticipate completion by mid-2025. ³⁹

Psilocybin for the Treatment of Depression and Burnout

The University of Washington, funded by Cybin, just completed a phase 3 trial of 30 participants to investigate the short- and long-term effects of psilocybin-assisted psychotherapy on symptoms of depression experienced by physicians, advanced practice practitioners, and nurses with frontline work exposure during the COVID-19 pandemic. A total of 15 of the 30 participants were physicians. The results were published December 5, 2024 in JAMA Network Open. ⁴⁰

The experimental group received single-dose siplocybin 25 mg with psychotherapy, while the control group received a placebo of single-dose Niacin of 100 mg with psychotherapy in an attempt to mitigate functional unblinding. Participants who had used psychedelics within the previous 12 months were excluded. The psilocybin compound was provided by the Usona Institute. Efficacy was assessed using 5 scales: MADRS, Stanford Fulfillment Index, PTSD Checklist for DSM-5, Moral Injury Symptoms Scale, and the Beck Depression Index. These measurements were taken over 24 weeks, with the primary measure being the MADRS measurement at week 4. ⁴⁰

The study reported a substantial decrease in symptoms of depression as measured with the MADRS from baseline to day 28 of psilocybin administration, which was sustained for most of the participants at 6 months. The change in symptoms of burnout did not reach statistical significance, but the authors stated this small trial may have been inadequately powered for this outcome. ⁴⁰

No serious physiological adverse events occurred. The most serious psychiatric adverse event occurred on day 28 after a patient received open-label psilocybin and had transient suicidal ideation. Of interest for future psilocybin studies, the authors reported that all 30 participants were unable to distinguish whether they had received psilocybin or Niacin immediately after ingestion, but all 30 participants correctly reported what they had received 2 hours later. ⁴⁰

The California State Legislature

There have been several California State Legislature initiatives to expand access to psychedelics in the last 3 years. ⁴¹ During an attempt at decriminalization of medicinal psychedelics last summer, the Stanford Director of Addiction Medicine testified to the California State Legislature that SB 58 underestimated the harms of psychedelics while overestimating therapeutic benefits. As a medical expert witness in the opioid litigation against Purdue pharmaceuticals and others, she later alluded to the similarities between the promotion of medicinal psychedelics today and that of opioids in the 1990s, based on unsubstantiated claims of high benefit and low risk. ¹¹

The California State Legislature supported SB 58 in 2023, which Governor Newsom subsequently vetoed on October 7. His veto statement last fall included, “I urge the legislature to send me legislation next year that includes therapeutic guidelines. I am, additionally, committed to working with the legislature and sponsors of this bill to craft legislation that would authorize permissible uses and consider a framework for potential broader decriminalization in the future, once the impacts, dosing, best practice, and safety guardrails are thoroughly contemplated and put in place.” ⁴²

Demonstrating the need for a cautious and safe approach, 15 days after Governor Newsom’s veto, an off-duty Alaska Airlines pilot who used psilocybin for self-treatment of depression attempted to crash a San Francisco–bound passenger plane with 84 passengers aboard. The pilot recently said his behavior was unfathomable. ⁴³

As a response to Governor Newsom’s veto statement, on February 5, 2024, SB 1012 was introduced. It proposed to legalize psychedelics for treatment by psychedelic facilitators outside the scope of the Medical Board of California. ¹³ The California Medical Association Council of Legislation opposed SB 1012 unless amended, citing patient safety and scope of practice concerns. ⁴⁴ SB 1012 subsequently stalled in the California Senate Appropriations Committee on May 16 due to the California state budget deficit. ⁴¹

However, on June 6, SB 803 appeared as a new midsession bill, which proposed a pilot study in 3 counties (Santa Cruz, San Francisco, and San Diego). The bill proposed the prescription of medicinal psychedelics by physicians licensed by the Medical Board of California, but it was withdrawn due to persistent patient safety concerns. ¹³

Cost and Financial Support: The Elephant in the Room

As noted, recent estimates of total average prelaunch research and development costs ranged from $161 million to $4.54 billion. The average cost for an FDA trial was $4 million for phase 1, $13 million for phase 2, and $20 million for phase 3, or $41,000 per patient. Financial variables for the FDA trial process included the number of patients, length of endpoint, and type of endpoint. In addition, with a smaller effect size, more patients were needed. Also, longer trials added to the expenses. Finally, expensive endpoints, including a physician administering the measure or an MRI, added costs. ^17,45

Not surprisingly, the cost of the legislative process is substantially lower than it is for a full FDA trial. In California, the average amount of money raised for an election for the State Senate is $1.1 million, and it is $800,000 for an election for the State Assembly. Additionally, the range for most recent California state ballot propositions is between $8 million and $18 million. ⁴⁶

Of note, Lykos faced financial headwinds last year, stopping clinical trials in Europe. ⁴⁷ After the FDA NDA denial in August 2024, the company laid off 75 of its 100 employees. ⁴⁸

Conclusion

This article reviewed the current clinical trials and results for psychedelics, as well as the challenges, costs, and current safety data. This article also reviewed the recent California legislative efforts that would expand legal use of these compounds. Clinicians and patients may be understandably flummoxed by the approval process for psychedelics, considering the extensive failed California legislative efforts of the last 3 years, along with the August 9, 2024 FDA NDA denial of the unsuccessful Lykos application for MDMA with adjuvant psychotherapy.

The authors are encouraged by the reports of positive outcomes in some clinical trials, recommend continued vigilance in study rigor, and overall agree that serious adverse effects were rare. However, real but rare risks that do exist include psychosis, mania, suicidality, accidental deaths, and extended neurologic difficulties. ^5–8,49 Additionally, the addictive potential of these compounds is still unclear. Therefore, an additional purpose of the federal government regarding psychedelics for medical use should include a pathway for ongoing funding of high-quality scientific inquiry via FDA phase 3 research to help address lingering questions in this field. The 2024 launch of a VA research program dedicated to studying psychedelics could be a promising solution. Psychedelics have shown potential, but if they are implemented poorly, particularly via state legislatures or state ballot propositions, they could unlock substantial safety concerns, which could eclipse important clinical benefit. The complexities here support the opinion that the FDA should be the sole approval authority for psychedelics in the United States.