Therapeutic (Sub)stance: Current practice and therapeutic conduct in preparatory sessions in substance-assisted psychotherapy-A systematized review

Thal and colleagues situate their review within the resurgence of clinical interest in substance-assisted psychotherapy (SAPT), noting that a range of compounds have been used as adjuncts to psychotherapeutic work, including serotonergic psychedelics (e.g. LSD, psilocybin), MDMA, ketamine, and complex agents such as ibogaine. Earlier research and contemporary trials point to a strong influence of non-pharmacological factors on outcomes — in particular psychological preparation before dosing, support during the drug-assisted session, and post-session integration. The authors highlight ongoing debates about whether the acute subjective effects (mystical-type experiences, emotional breakthroughs, ego dissolution, challenging experiences) are necessary mediators of long-term therapeutic change or might instead be biomarkers of receptor activation and plasticity.

The paper reports a systematized review conducted to extract and synthesise guidance about the preparatory stage of SAPT, with a particular focus on serotonergic psychedelics and MDMA. The investigators followed PRISMA 2020 guidance as closely as possible but did not perform meta-analysis or a formal risk-of-bias assessment because included sources were heterogeneous in intervention, design, clinical target and outcome measures, and the review aimed to capture procedural details rather than pooled effect sizes. Electronic searches covered MEDLINE (OVID), PsycINFO (OVID) and the Cochrane Library up to February 1, 2022, supplemented by reference‑list checks and consultation with field experts. Results were managed in EndNote. Inclusion criteria were broad: sources had to describe classic psychedelics or MDMA used within a psychotherapeutic intervention and report methods or theory relevant to preparation, screening, safety measures or therapist conduct; clinical-trial participants were required to meet recognised diagnostic criteria where applicable. Exclusions comprised in vitro or animal work, anthropological reports of indigenous ritual use, microdosing studies, inaccessible full texts, and languages other than English or German. The review encompassed a wide range of documents (clinical trials and protocols, treatment manuals, qualitative studies, case reports, reviews, opinion pieces and book chapters) and was limited to individual therapy settings while drawing applicable insights for group work where relevant. Selection was performed in two waves (initial search July 1, 2019; update February 1, 2022) by pairs of independent reviewers with reported interrater agreement statistics; disagreements were resolved by discussion with co-authors. Data extraction captured study design, sample size and eligibility, diagnostic and screening tools, safety measures, substances and doses, session counts, therapist team composition, set and setting, preparatory session content and methods, and therapist roles/prerequisites. The authors define terminology used in the review, preferring the terms "therapist" for the practitioner and "client" for the recipient, and introduce the concept of "therapeutic stance" to denote therapist roles, attitudes, adaptability and conduct across the preparatory phase.

Searches and screening produced 83 sources included in the final synthesis. These comprised 24 clinical trials (total N = 536), one preliminary trial report, follow-ups and pooled analyses, treatment manuals and a range of qualitative, descriptive, observational and theoretical contributions. Safety and screening. Across sources there was clear consensus that thorough preparation and safety procedures are essential. Key preparatory elements identified were set, setting, medical and psychiatric screening, substance selection and dosing, and plans for integration. The literature represented in recent clinical trials describes serotonergic psychedelics (at recommended doses) as physiologically safe and non-addictive with no reported long-term adverse effects in trials; MDMA at trial doses was also described as generally safe and tolerable. Nonetheless, acute adverse reactions such as transient anxiety, psychotic thinking, headache, fatigue and nausea occur, and challenging sessions have been reported. Modern practice therefore emphasises pre-assessment to exclude physiological or psychiatric contraindications. Recommended medical screening typically includes history and physical examination, ECG, haematology and biochemistry, alcohol breath test, urinalysis and pregnancy testing. Medications that may interact with the investigational compound (tricyclics, monoamine oxidase inhibitors, lithium, SSRIs, antipsychotics, and serotonergic supplements) are commonly exclusionary, although the authors report mixed evidence on the impact of SSRI exposure on acute safety and treatment response. Set and setting, and contextual preparation. The review reiterates the classic set-and-setting framework: "set" comprising the client's mindset (expectations, intentions, personality, prior experiences, therapeutic relationship) and "setting" the physical, social and cultural environment. The concept has been extended by some authors to a "matrix" incorporating the person's surrounding environments before, during and after therapy. Contemporary clinical sites are typically controlled, comfortable, non-clinical-feeling rooms (living-room style), with safety measures (secure exits, removal of dangerous objects), opportunities to recline, and therapists seated nearby. Music delivered through headphones is a near-universal feature; playlists are sometimes curated with client input in preparation sessions. Eyeshades are commonly used to direct attention inward. Proposals to harness nature‑based preparatory activities (e.g. horticulture, forest bathing) have been suggested but not yet implemented in modern clinical trials. Physiological and emergency preparation. Because many compounds affect cardiovascular parameters, a physician should be available for monitoring and resuscitation if needed; antihypertensives, anxiolytics or antipsychotics have been used to manage severe reactions, with the emphasis that pharmacological interruption should be a last resort. Protocols for discussing precautionary measures during preparation sessions are standard in recent trials. Psychological preparation. Preparatory contact varies widely: older studies ranged from none to highly structured procedures, while recent models typically include one to four preparatory sessions, with 2–3 sessions common among reviewed sources reporting counts. Psychoeducation about expected acute and longer-term psychological effects, side effects and risks is included in the majority of recent trials (15 of 24). Preparation commonly addresses therapeutic approach, setting intentions (intention setting), expectation management, and rehearsal of coping strategies for difficult experiences (encouraging approach rather than avoidance). Clinicians are advised to monitor life events and postpone dosing when acute destabilising circumstances are present. The authors report that social support after dosing is important but not yet standardised in trials. Measurement of client expectancy (for example with the Stanford Expectations of Treatment Scale) has been proposed to inform management of expectancy effects. Therapeutic stance and therapist configuration. Most contemporary trials employ mixed-gender co-therapist teams throughout the process; advantages include shared workload during long dosing sessions and potential safety and rapport benefits. Therapist roles are flexible and adapted to the client's needs; a noncritical, supportive, empathic stance is consistently recommended. The literature describes a set of core competencies (citing Phelps) including empathetic abiding presence, trust enhancement, spiritual intelligence, knowledge of pharmacology and effects, therapist self-awareness and ethical integrity, and proficiency in complementary techniques. Complementary methods noted include breathwork, guided imagery, meditation, narrative and existential approaches, and somatic therapies. Desired therapist characteristics include compassion, authenticity, patience, openness, responsiveness and capacity to contain highly emotional states. Establishing a robust therapeutic relationship during preparation — sometimes involving multiple sessions and meetings in the administration environment — is repeatedly emphasised as central to later outcomes. Therapist personal experience and training. The role of therapists' personal experience with psychedelic compounds is described as controversial: some practitioners and historical precedents consider first‑hand experience valuable for empathy and tolerance, whereas others caution about threats to objectivity and ethical conduct. A variety of formal training programmes for psychedelic therapists are noted, though the literature largely lacks empirical evaluation of how therapist training, characteristics or personal history influence client outcomes. Other findings. Preparatory content may be tailored to clinical targets and therapeutic modality (e.g. motivational-behavioural for substance use, acceptance and commitment therapy for depression, humanistic approaches). Challenging acute experiences are discussed as potential mediators of benefit provided clients can relate to them adaptively; consequently, preparation commonly includes strategies and an action plan for handling difficult material.

Thal and colleagues interpret their synthesis as indicating broad agreement in the field that careful preparation prior to administration sessions is important, yet substantial heterogeneity exists in how preparation is operationalised across models and trials. They emphasise that preparatory sessions typically aim to build therapeutic rapport, provide psychoeducation about substances and risks, set intentions, attend to logistics and interpersonal boundaries, and rehearse coping strategies for difficult experiences. According to the authors, appropriate preparation and coordinated integration planning may reduce client resistance and plausibly enhance therapeutic benefit, but the evidence base for specific preparatory elements remains limited. The review positions its findings relative to earlier and contemporary research by noting that much of the procedural guidance currently in use derives from clinical experience, first‑wave literature and diverse trial protocols rather than from systematic empirical comparisons. As a result, many recommendations — for example on the optimal number or content of preparatory sessions, the value of therapist self‑experience with substances, or the best configuration of set and setting variables — remain provisional. Key limitations acknowledged by the authors include the heterogeneity of included sources, the predominance of experiential and descriptive material rather than rigorous empirical studies focused on preparatory procedures, and the inability of the review to quantify effects or perform risk-of-bias assessment given its aims. They therefore call for timelier and more rigorous qualitative and quantitative research directly assessing how different approaches to preparation influence acute experience and long-term outcomes, and for longitudinal independent safety studies. Implications noted by the authors include the need to standardise and empirically validate screening procedures, safety protocols, psychoeducation content and measures of therapeutic alliance and expectancy in SAPT trials. Training programmes for therapists should incorporate the competencies and attitudes highlighted in the review, but the authors stress that empirical study of how therapist factors impact outcomes is required before firm practice recommendations can be made. Overall, the paper frames preparatory work as an integral but understudied component of SAPT deserving targeted investigation.

The authors conclude that preparatory sessions are regarded across the literature as important for SAPT, yet approaches vary widely and most guidance is grounded in clinical experience rather than direct empirical evidence. Typical preparatory aims are to establish therapeutic alliance, educate clients about expected effects and risks, set intentions, and discuss logistics and safety plans. Therapist qualities such as empathy, presence, integrity and responsiveness are repeatedly recommended. Thal and colleagues call for focused empirical research to determine which elements of preparation most strongly influence safety and therapeutic outcomes, noting that current evidence is insufficient to draw conclusive statements about the relative importance of different preparatory practices.