Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: a systematic review

Psychedelic treatments have re-emerged in psychiatric research over the past two decades after earlier work in the mid-20th century. Recent clinical studies report promising efficacy signals across several indications: a 57% response rate at day 7 after a single ayahuasca administration in treatment‑resistant depression (TRD), reductions in heavy drinking days in alcohol use disorder (AUD), sustained abstinence in some tobacco-smoking cohorts (67% abstinence at 12 months after psilocybin in one report), and improvements in anxiety and depressive symptoms in patients with life‑threatening cancer. The biological mechanisms proposed to underlie these effects include agonism at serotonin receptors (notably 5‑HT2A), downstream glutamatergic activation and neurotrophic effects, transient modulation of the default mode network (DMN) with subsequent reintegration, and possible anti‑inflammatory actions. Clinical efficacy is also thought to depend heavily on ‘‘set and setting’’ and on psychotherapeutic support provided before, during and after dosing sessions. Romeo and colleagues set out to identify clinical and biological predictors of response to psychedelic interventions in psychiatric and addictive disorders. The investigators conducted a systematic review to determine which baseline characteristics, aspects of the acute psychedelic experience, imaging markers or other measures were associated with subsequent clinical outcomes, with the stated aim of better defining which patients are most likely to benefit from these treatments.

The review protocol was registered on PROSPERO (CRD42020180489) and followed PRISMA recommendations. The investigators searched MEDLINE, PsycInfo, Web of Science and Scopus for papers published from January 1990 to May 2020, using search terms for ayahuasca, psilocybin and lysergic acid diethylamide in combination with a range of psychiatric and substance‑use disorder terms. ClinicalTrials.gov was also searched. Inclusion criteria were: English language peer‑reviewed publication, studies in patients with psychiatric or addictive disorders, use of psychedelic compounds, and an analysis of predictive factors of psychedelic response. Reference lists of identified articles were checked for additional reports. Study selection and data extraction were performed by one author and verified by a second. Quality assessment used study‑appropriate tools: a modified Newcastle–Ottawa Scale for open‑label uncontrolled trials, the Cochrane Collaboration tool for randomised double‑blind trials, and a checklist for retrospective database studies. Extracted data included sociodemographic variables, baseline clinical measures (which varied by indication), measures of the acute psychedelic experience (for example the Mystical Experience Questionnaire, MEQ; the 5‑Dimensional Altered States of Consciousness scale, 5D‑ASC; and the Hallucinogen Rating Scale, HRS), plus biological, imaging or physiological predictors when reported. Twenty studies met the inclusion criteria. The corpus included two AUD studies, three studies of tobacco smokers (two of which used the same cohort with six‑ and twelve‑month follow‑ups), two studies of mixed cannabis/opioid/stimulant users, one obsessive‑compulsive disorder (OCD) study, nine TRD studies, three retrospective online surveys spanning multiple substances, and one ibogaine study in opioid use disorder. Most interventional studies used psilocybin at broadly similar doses (around 20–30 mg per 70 kg), while at least one study administered ayahuasca and the ibogaine study used a 15 mg/kg dose. The review is descriptive; no pooled meta‑analytic effect estimates are reported.

Across indications, the most consistent finding was that greater intensity of the acute psychedelic experience predicted better clinical outcomes. This relationship was reported for AUD, tobacco use disorder, TRD and for short‑term improvements in anxiety and depressive symptoms among patients with life‑threatening cancer; no association was observed in the single small OCD study. Alcohol use disorder: In the two AUD studies the intensity of the acute experience, measured by the MEQ, 5D‑ASC and HRS, correlated with reductions in AUDIT‑C scores at three months, fewer drinking and heavy‑drinking days at four weeks, reduced craving and increased alcohol‑abstinence self‑efficacy at one week. Baseline AUD severity measures and psychedelic dose were also associated with improved AUDIT‑C at three months. Dose correlated with both the mystical and insight components of the experience, which in turn related to outcomes. No consistent associations were found for sex, age, spiritually significant prior experiences, or age at first drink. Tobacco smoking: Studies reported that quitters had higher alterations of consciousness during the session than persistent smokers. Consciousness alteration was associated with reductions in craving and with lower urinary cotinine at six and/or twelve months; associations with CO measures were inconsistent. Measures reflecting personal meaning, spiritual significance and impact on wellbeing after the session were linked with quitting or reduced smoking, and higher scores on these measures correlated with greater smoking‑abstinence self‑efficacy at six months. Baseline alexithymia scores were higher in relapsers than in those maintaining abstinence. Confidence to abstain and older age at the time of the psychedelic experience predicted better outcomes. Several demographic and use‑history variables were not associated with prognosis. Other substance use disorders: An ibogaine study in opioid users reported greater response among patients using prescribed opioids (56%) versus heroin users (44%); responders reported stronger insight contributions and more spiritually meaningful experiences. A separate study of mixed cannabis/opioid/stimulant users found that reductions in use were associated with age at experience, baseline disorder severity and experiential variables (insight and meaning), whereas MEQ scores and administered dose were not associated in that dataset. Across studies dose tended to correlate with intensity and insight in some samples. Obsessive‑compulsive disorder: The single small study reported no association between session intensity (HRS) and OCD severity measures. Treatment‑resistant depression: Multiple studies in TRD linked greater acute experience intensity with larger reductions in depressive symptoms. In an ayahuasca trial, improvement at day 7 correlated with the MEQ subscale ‘‘transcendence of time and space’’ and with HRS perception subscale. In psilocybin studies, aspects of altered consciousness such as ‘‘experience of unity’’, ‘‘spiritual experience’’ and ‘‘blissful state’’ related to improvement at week 5; oceanic boundlessness (OBN), a construct related to mystical experience, was highlighted as the best predictor of symptom reduction. One study used automated speech analysis of autobiographical memory responses and reported that positivity in word‑level emotional valence could distinguish responders from non‑responders with 85% accuracy. A single study found no differences in baseline personality traits (neuroticism, extraversion, openness, agreeableness, conscientiousness) between responders and non‑responders at month 3. Neuroimaging predictors in TRD (from the same open‑label cohort): Day‑1 changes in resting‑state and task‑related functional connectivity were associated with later clinical response. Increased ventromedial prefrontal cortex (vmPFC) to bilateral inferior‑lateral parietal cortex connectivity or decreased parahippocampal–prefrontal connectivity at day 1 predicted response at week 5. An increased amygdala response to fearful versus neutral faces at day 1 associated with response and remission at early time points. A reduction in rumination correlated with decreased vmPFC–right amygdala connectivity. However, some amygdala connectivity measures did not correlate with standard clinical scales at later time points. Cancer‑related anxiety/depression: Intensity of the mystical experience was associated with improvements in depressive and anxiety scores at short follow‑up (week 5 or 6) and with measures of quality of life, meaningfulness and attitudes toward death at week 5; these associations were not present at a 4.5‑year follow‑up in the datasets reported.

The investigators conclude that the single most consistent predictor of positive clinical response to psychedelics across a range of psychiatric and addictive indications is the intensity of the acute subjective experience, notably mystical or oceanic‑boundlessness‑type phenomena. This finding held for AUD, tobacco dependence, TRD and short‑term outcomes in cancer‑related anxiety and depression, while no clear signal emerged in the solitary small OCD study. Romeo and colleagues and co‑authors discuss possible mechanistic explanations linking acute subjective intensity to therapeutic benefit. One pathway is direct pharmacology at cortical 5‑HT2A receptors: intensity of mystical or altered‑consciousness experiences correlates with neocortical 5‑HT2A receptor occupancy and with plasma psilocin levels in experimental work. Downstream effects may include glutamatergic activation of frontal cortex and induction of neurotrophic factors such as BDNF and GDNF, promoting neuroplasticity. Imaging data from TRD samples were interpreted as consistent with an acute ‘‘reset’’ of DMN integrity (acute disintegration followed by reintegration) and with altered vmPFC–amygdala dynamics that may permit greater emotional engagement rather than the emotional blunting often observed with conventional antidepressants. The authors also note potential anti‑inflammatory effects and dopaminergic modulation as additional mechanisms that could be relevant, particularly in addictive disorders. Contextual and psychological moderators are emphasised as important determinants of the acute experience quality and therefore of outcome. Factors identified in the reviewed studies included dose, aspects of set and setting (therapeutic environment, preparatory sessions, music and therapist support), expectancy, spiritual or religious orientation, baseline confidence to change (for example smoking abstinence self‑efficacy), and age at time of experience. Psychotherapeutic adjuncts and therapist competence were suggested to interact with drug effects by reducing anxious apprehension and focusing attention. The investigators also highlight some candidate predictive markers identified in single studies: greater positivity in speech content in TRD, baseline alexithymia in smokers, and several imaging markers in TRD cohorts. The authors acknowledge important limitations in the evidence base. These include the small number of eligible studies, frequent small sample sizes, repeated analyses from the same cohorts, inclusion of retrospective online surveys that are subject to recall bias, short follow‑up in some reports (for example a 24‑hour OCD study), and heterogeneity of methods across studies, which complicates cross‑study comparison. On that basis they argue for further clinical research to replicate and extend these findings, to clarify biological predictors and to examine how different psychotherapeutic approaches influence psychedelic efficacy.