Virtual Reality and Psychedelics for the Treatment of Psychiatric Disease: A Systematic Literature Review

Psychedelic (hallucinogenic) substances and virtual reality (VR) are presented as two distinct but potentially complementary approaches with therapeutic promise in psychiatry. The introduction situates psychedelics historically and notes renewed interest in their capacity to catalyse psychotherapeutic change, shorten therapy duration, and treat conditions such as depression, anxiety and addiction. VR is described as a matured technology with expanding clinical applications, from exposure therapies for anxiety to rehabilitation after stroke; some investigators have explored its ability to mimic aspects of the mystical or transcendental experiences associated with psychedelics. Ortiz and colleagues set out to synthesise recent clinical evidence on the medical applications of both VR and psychedelics for psychiatric disorders. The review aimed to identify peer‑reviewed clinical trials and case studies that objectively measured therapeutic success, to describe the disorders and interventions studied, and to highlight gaps — notably the scarcity of research combining VR and psychedelic‑assisted therapy — to inform future research directions.

The study is a systematic literature review conducted using PRISMA methods. Searches were run in PubMed, Medline, Embase, the Cochrane Library, Scopus and Web of Science, supplemented by manual screening of reference lists. Search terms included combinations of “Psychedelic”, “Hallucinogen”, “Virtual Reality”, “VR” and a range of psychiatric disorder terms (for example, “Depression”, “PTSD”, “Eating disorders”, “Addiction”, “Gender Dysphoria”, “Schizophrenia” and “Anxiety”). The extracted text does not report explicit date limits for the search. Inclusion criteria specified peer‑reviewed clinical trials or case studies written in English that addressed the use of psychedelics and/or VR for psychiatric disorders and that objectively measured therapeutic success. Excluded materials included qualitative studies and non‑clinical investigations; the authors also excluded studies unrelated to psychiatric pathology. The review process identified initial records from database searches and additional records from other sources, after which duplicates and ineligible titles/abstracts were removed and full texts screened for eligibility. A final set of 23 manuscripts met the criteria and were analysed. The review summarised study characteristics (year, sample, methods, outcome measures and results) in tables, although those tables are not fully reproduced in the extracted text.

The review included 23 manuscripts: 11 investigated VR‑based therapies and 12 addressed psychedelics or psychedelic‑assisted therapies. Overall, the authors report that the included studies showed symptomatic improvement across conditions, though effect onset and duration varied by intervention and substance. VR studies: Eleven trials addressed VR interventions. These covered specific phobias (social anxiety, arachnophobia, kinesiophobia), eating disorders, PTSD (combat‑related and military samples), gambling disorder, preoperative anxiety in children, and a psychotherapeutic VR approach for schizophrenia with auditory verbal hallucinations. - Social anxiety disorder: A three‑arm randomised trial (n=59) compared CBT with VR exposure (n=17), CBT with in‑vivo exposure (n=22) and a waiting list (n=20). Outcomes included LSAS‑SR, SPS, SIAS and FNE; the authors report reliable change in 76.5% of the VR group versus 68.3% in the in‑vivo exposure group. - Spider phobia: A Swedish parallel‑group randomised non‑inferiority trial (n=100) compared one‑session treatment (OST) with virtual reality exposure therapy (VRET). In‑vivo behavioural avoidance tests (BAT) and follow‑ups at 3 and 12 months were used; both groups improved, supporting VRET as an effective intervention for spider phobia. - PTSD: A randomised controlled trial of trauma management therapy (TMT) versus exposure therapy in veterans (n=92) reported a mean CAPS reduction of 41.7 points and that 42%–50% of participants maintained clinically significant changes to six months. A separate trial in 162 active‑duty soldiers compared Prolonged Exposure, VRET and waitlist; both PE and VRET showed significant symptom and suicidal ideation reductions relative to waitlist, though PE and VRET were not directly contrasted in the extracted text. - Eating disorders: One controlled Spanish study (n=34 females) compared CBT alone to CBT augmented with VR body‑image techniques and reported greater and sustained improvements in body‑image measures in the VR‑augmented group, maintained at one‑year follow‑up. A multicentre European randomised study comparing virtual reality cue‑exposure therapy (VR‑CET) with additional CBT (A‑CBT) included patients with bulimia nervosa and binge eating disorder; VR‑CET produced larger reductions in overeating, purging, food craving and anxiety at six months, with large effect sizes. - Kinesiophobia/chronic pain: A hybrid implementation–effectiveness study in 16 veterans used commercially available VR apps across graded intensities during physical therapy; 38% exceeded the Minimum Clinically Important Difference on one fear‑of‑movement scale and a small effect size was observed after removing an outlier. - Preoperative anxiety: A Solomon four‑group randomised design in 40 children (age 6–12) used simulated operative walkthroughs and reported significant reductions in preoperative anxiety on the Yale Preoperative Anxiety Scale in the intervention groups. - Schizophrenia with auditory verbal hallucinations: A Phase II randomised partial‑crossover trial (n=19) offered virtual‑avatar exposure and therapist‑led dialogue; measures of auditory verbal hallucinations (PSYRATS), beliefs about voices (BAVQ‑R), PANSS, BDI‑II and quality‑of‑life improved significantly after the VR intervention. - Gambling disorders: Several small studies evaluated VR for cue induction and exposure. VR induced craving in frequent gamblers comparably to real‑world cues. Randomised comparisons of imaginal exposure versus VR immersion (two VR sessions added to CBT or replacing imaginal exposure) reported reductions in craving in both groups with no significant differences; therapists reported greater utility and information from VR immersion. Safety assessments suggested VR did not produce longer‑lasting urges than imaginal exposure. Psychedelic studies: Twelve studies examined psychedelic agents (ketamine, psilocybin, ayahuasca and MDMA), with ketamine and psilocybin the most represented. - Ketamine: A double‑blind, controlled multiple‑crossover study in geriatric patients (n=16) administered subcutaneous ketamine at ascending doses (0.1–0.5 mg/kg) with midazolam included as an active control in some sessions; blinded MADRS ratings yielded acute response and remission in 11 of 16 participants (68.8%). An intranasal ketamine double‑blind crossover study in 20 treatment‑resistant depressed patients reported significant improvement in depressive symptoms within 24 hours versus saline. Additional ketamine investigations included EEG cordance as a predictor of response (n=27) and perioperative S‑ketamine in older surgical patients (n=80) showing decreased postoperative depression scores; one randomised study assessed high versus low psychedelic doses of intramuscular ketamine combined with psychotherapy in heroin dependence (n=70) and reported improvements in anxiety, depression and related measures in both dose groups, though full abstinence outcomes are not clearly reported in the extracted text. - Psilocybin: Open‑label and randomised studies reported benefits across conditions. A small open study in alcohol dependence (n=10) combined a 12‑week psychosocial intervention with two open psilocybin sessions and found large pre–post reductions in drinking and related psychological measures. Two open trials in treatment‑resistant depression (n=19 and n=20) administered 10 mg then 25 mg one week apart with psychological support and reported rapid and sustained antidepressant and anxiolytic effects lasting up to six months for most participants. A randomised, double‑blind, two‑session crossover trial in 51 cancer patients with life‑threatening diagnoses compared low‑dose and high‑dose psilocybin; clinician‑rated depression and anxiety scales showed large, sustained effects with 6‑month clinical response rates of 78% (depression) and 83% (anxiety). Smaller controlled studies with niacin as an active comparator also reported significant reductions on anxiety and depression scales and long‑term positive life changes attributed to psilocybin, although sample sizes were small. - Ayahuasca: A parallel‑arm double‑blind randomised placebo‑controlled trial in treatment‑resistant depression (35 allocated, 29 analysed) compared a single dosing session of ayahuasca to placebo; HAM‑D change from baseline to day 7 showed rapid antidepressant effects in the ayahuasca group. Nausea and vomiting were common (around 57% vomited) but no other major adverse effects were reported. - MDMA: A Phase II randomised, double‑blind dose‑response trial in 26 military veterans and first responders with chronic PTSD compared 30 mg, 75 mg and 125 mg MDMA in conjunction with psychotherapy. Higher doses (75 mg and 125 mg) with psychotherapy produced significantly greater decreases in CAPS scores than the 30 mg condition. Adverse events were frequent (85 events reported by 20 participants) and four serious events occurred, of which one was possibly related to MDMA administration. Adverse events and limitations: Across the reviewed studies, adverse effects were generally transient and pharmacological—nausea and vomiting with ayahuasca, physiological and dissociative effects with ketamine and acute physiological stress in some MDMA sessions. The authors repeatedly highlight small sample sizes, heterogeneous methods and levels of immersion in VR studies, occasional technical failures, and the limited breadth of disorders and substances studied.

Ortiz and colleagues interpret the collective evidence as supportive of both VR and psychedelics as promising therapeutic tools for a range of psychiatric conditions, while emphasising important caveats. They note that most reviewed studies reported statistically significant improvements in symptoms and quality of life, including in some treatment‑resistant cases, but sample sizes were often small and some trials lacked adequate control groups or statistical power. The discussion stresses differences across studies in VR hardware and software, immersion level and therapist skill, all of which may influence outcomes; technical problems in some trials were noted as potential sources of bias. For psychedelic research, legal and logistical constraints have limited the evidence base and shaped the distribution of substances studied — ketamine is common because of its clinical availability, while psilocybin research is re‑emerging but still limited by regulatory barriers. The authors acknowledge that few trials examined a broad range of pathologies and none combined VR and psychedelic interventions in the same protocol. They therefore call for further research with larger samples, standardised and purpose‑designed therapeutic VR software, higher methodological rigour, and exploration of combined VR‑psychedelic approaches. Safety profiles reported in the reviewed studies were described as acceptable overall, with the most notable physiological adverse events appearing in ketamine and MDMA trials; the authors caution that such events were mostly transient. In sum, while both approaches show therapeutic potential, definitive conclusions are constrained by limited and heterogeneous evidence, and the authors recommend more robust clinical evaluation before wide clinical adoption.

The review concludes that VR interventions demonstrated safety and significant efficacy in specific contexts, notably phobias (social, kinesiophobia, spiders), eating disorders, PTSD, gambling disorder, preoperative anxiety and as adjunctive approaches for schizophrenia. The psychedelics examined (principally ketamine, psilocybin, ayahuasca and MDMA) showed positive effects for depressive and anxiety disorders, alcohol dependence and PTSD, with generally mild and transient adverse reactions in most studies. Ortiz and colleagues underscore the need for further research across different mental illnesses and populations, including larger, better‑powered trials and investigation of combined VR and psychedelic‑assisted therapies.