Anesthesiology
October 1, 2023
Akash Goel, Yeshith Rai, Shayan Sivadas et al.
29 citations
Chronic pain affects about 1.5 billion people worldwide. Current treatments like opioids and non-opioid drugs can cause side effects, addiction, or fail to relieve pain. Psychedelics such as LSD and psilocybin may alter pain perception through serotonin receptor activation, anti-inflammatory effects, and synaptic remodeling. This scoping review identified 21 human studies on psychedelics for pain. Few clinical trials exist, and sample sizes are small, limiting clinical use. Overall, psychedelics show promise for analgesia in certain headache disorders and cancer pain. Future research should examine combining psychotherapy with psychedelics for chronic pain.
Chronic Stress
January 1, 2022
Sarah Kuburi, Anne-Marie Di Passa, Vanessa K Tassone et al.
14 citations
A systematic review of neuroimaging studies on psychedelics for major depressive disorder found that psilocybin, ayahuasca, and LSD alter brain activity and connectivity in ways linked to antidepressant response. Key changes include amygdala activity and functional connectivity alterations, shifts in medial and ventromedial prefrontal cortex connectivity, and decreased global brain network modularity. One ayahuasca study reported increased limbic activity. The evidence, based on only four datasets, suggests the default mode and limbic networks may be important targets for future research, but more data are needed to confirm these preliminary findings.
Eur Neuropsychopharmacol
November 7, 2025
Mikkel Højlund, Helin Y. Kafali, Begüm Kırmızı et al.
12 citations
A living systematic review with meta-analysis examined the efficacy, safety, and all-cause discontinuation of serotonergic psychedelics and MDMA for treating mental disorders. The review found that these substances show promise in reducing symptoms of conditions such as depression, anxiety, and post-traumatic stress disorder, with some evidence supporting their therapeutic potential. However, the authors note that the overall quality of evidence is limited by small sample sizes, short follow-up periods, and methodological concerns. Safety profiles varied, with most adverse events being mild to moderate, though serious adverse events were reported in some studies. The review emphasizes the need for larger, more rigorous trials to confirm these findings.
Canadian Journal of Pain
November 8, 2024
Jiwon Lee, Kaylyssa Philip, Hance Clarke et al.
3 citations
A proposed clinical trial design for psilocybin as a treatment for neuropathic pain, called the PEACE-PAIN trial, is supported by patient survey responses but could be improved by adding detailed discussions of the existing evidence on efficacy, safety, tolerability, and management of adverse effects. The finding that individuals with prior psychedelic use are interested in participating has important implications for the trial's inclusion and exclusion criteria.
JMIR Research Protocols
April 17, 2024
Akash Goel, Bhavya Kapoor, Hillary Chan et al.
2 citations
Chronic pain affects about 8 million Canadians (20%) and costs the healthcare system over US $60 billion yearly. This paper describes the planned protocol for a pilot randomized controlled trial testing three treatments: intravenous ketamine alone, cognitive behavioral therapy with mindfulness meditation (CBT/MM), or a combination of both. The primary goal is to assess feasibility—recruitment, consent, withdrawal, adherence, missing data, and adverse events—in 30 participants over 20 weeks. Secondary outcomes include changes in pain intensity and pain interference at week 20. Recruitment had not started as of November 2023; the study is expected to complete by December 2025. Results will inform a larger trial.
PLoS One
January 1, 2024
Josh Martin, Fatemeh Gholamali Nezhad, Alice Rueda et al.
2 citations
Ketamine shows rapid antidepressant effects in major depressive disorder, including treatment-resistant depression, but many patients do not respond, and predicting who will benefit is difficult. This study will examine computational mechanisms behind changes in the auditory mismatch negativity response after intravenous ketamine, linking them to neural causes using a hierarchical Bayesian model and a neural mass model. Thirty patients with treatment-resistant depression will undergo EEG recordings during an auditory mismatch negativity task before three of four ketamine infusions, with depression, suicidality, and anxiety assessed throughout. The findings may improve understanding of treatment response and resistance, and model parameters could enable single-patient treatment predictions.
Journal of Pain Research
June 1, 2022
Sandra J Drozdz, Akash Goel, Matthew W Mcgarr et al.
2 citations
Ketamine-assisted psychotherapy (KAP) can, in specific circumstances, initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms, while encouraging rapport and treatment engagement, and promoting abstinence in patients addicted to other substances. A systematic review of seventeen articles including 603 participants found that combining ketamine with psychotherapy, provided before, during, and after ketamine sessions, can maximize and prolong benefits despite much variance in how KAP is applied. Additional large-scale randomized controlled trials are warranted to understand better the mutually influential relationships between psychotherapy and ketamine in optimizing responsiveness and sustaining long-term benefits in patients with chronic pain.
Pharmacology Research & Perspectives
April 1, 2026
Jordana Kazdan, Karim S Ladha, M. Ishrat Husain
Major Depressive Disorder and chronic pain often co-occur, worsening symptoms and prognosis, yet treatments typically address each condition separately. Serotonergic psychedelics like psilocybin, DMT, and LSD show promise for both depression and pain. This narrative review examines mechanisms—including 5-HT2A receptor modulation, anti-inflammatory effects, neuroplasticity, altered brain network dynamics, and psychological influences—that could target both conditions simultaneously. The authors argue that existing evidence supports psychedelics as a unified therapeutic approach for comorbid MDD and chronic pain, providing a rationale for future clinical trials.
Canadian journal of anaesthesia = Journal canadien d'anesthesie
September 1, 2025
Mindy Lu, Victoria Tucci, Nandana D. Parakh et al.
Most patients with chronic pain at a Toronto pain clinic were willing to join a clinical trial testing MDMA-assisted therapy for pain relief. Among 42 patients surveyed, 76% expressed willingness to participate in the EASE-Pain trial, which compares MDMA with an active placebo. White/European participants were more likely to be willing than nonwilling. The main motivators were pain relief (62%) and seeking alternatives to ineffective treatments (26%). Common concerns included side effects (43%), impacts on comorbidities (19%), and stigma associated with MDMA (19%). The findings suggest that protocol modifications, such as better patient education on drug effects, may improve trial enrollment and acceptability.
BJPsych Open
September 12, 2025
Karim S Ladha, Jiwon Lee, Gabriella Mattina et al.
A pilot trial tested the feasibility of a four-week course of nitrous oxide compared with midazolam (an active placebo) for treatment-resistant depression. Forty participants were randomly assigned to weekly one-hour inhalations of either 50% nitrous oxide or 50% oxygen plus intravenous midazolam. Recruitment, withdrawal, adherence, and missing data rates met feasibility criteria. Depression severity, measured by the MADRS scale, changed by -20.5% in the nitrous oxide group and -9.0% in the placebo group. Adverse events were mostly mild to moderate and transient. The results support conducting a full-scale trial.
PLoS One
January 1, 2024
Karim S Ladha, Jiwon Lee, Gabriella Mattina et al.
A pilot trial will test whether weekly inhaled nitrous oxide is feasible and preliminarily effective for treatment-resistant depression compared with the active placebo midazolam. Forty participants will receive either nitrous oxide (1 hour at 50% concentration) plus intravenous saline or oxygen (1 hour at 50% concentration) plus intravenous midazolam once per week for 4 weeks, with 6 weeks of follow-up. Feasibility will be assessed by recruitment and withdrawal rates, adherence, missing data, and adverse events. The main exploratory clinical outcome is change in depression scores at day 42. Results will guide a future definitive trial.
Acta Psychiatrica Scandinavica
August 1, 2022
Helen Liu, Jaimie Kerzner, Ilya Demchenko et al.
A systematic review of published studies and ongoing clinical trials on nitrous oxide (N2O) for psychiatric disorders identified five published articles, four of which focused on depression. Three randomized controlled trials (RCTs) for treatment-resistant depression and major depressive disorder suggest that N2O has preliminary feasibility with rapid-acting effects on depressive symptoms. Ten ongoing trials are exploring N2O for depression, post-traumatic stress disorder, bipolar disorder, obsessive-compulsive disorder, and suicidal ideation. Typical treatment involves a single session of 50% N2O for 60 minutes, though 25% is also being tested. Larger-scale RCTs with repeated doses and follow-up beyond one month are needed to confirm efficacy and sustainability.