Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences

Over the past two decades there has been a renewed scientific interest in hallucinogenic substances such as psilocybin and ketamine. Majić and colleagues place this revival against a history in which psychedelics were used both to model psychosis and as therapeutic tools; modern neuroimaging and improved methodological standards have prompted fresh hypotheses about their mechanisms. Earlier work emphasised that psychedelic-assisted therapy produces altered states of consciousness (ASCs), including intense mystical or peak experiences and a subsequent ‘‘afterglow’’, and proposed these subjective phenomena as central to therapeutic benefit. More recent approaches have also posited pharmacological, experience-independent mechanisms, particularly in the case of ketamine. This review aims to re-evaluate historical and contemporary concepts about how psychedelics may produce therapeutic effects. Majić and colleagues focus primarily on classical serotonergic hallucinogens and include specific reference to ketamine, while excluding MDMA and ibogaine from detailed consideration. They outline neurophenomenological issues, survey therapeutic models and clinical applications, and examine the evidence linking particular subjective experiences (for example, mystical peak experiences and afterglow periods) to clinical outcomes.

The extracted text presents this work as a narrative re-evaluation rather than a formal systematic review; no clear search strategy, date range, databases searched, or explicit inclusion/exclusion criteria are reported in the provided extraction. Instead, Majić and colleagues synthesise evidence from historical clinical reports (1950s–1970s), recent controlled trials, neuroimaging studies, animal research relevant to receptor pharmacology, questionnaire-based investigations of ASCs, and selected meta-analytic results where available. Emphasis is placed on integrating neurophenomenological perspectives with empirical clinical findings. The review describes commonly used assessment instruments for drug-facilitated ASCs (for example, Dittrich's APZ questionnaire and its successor, the 5D-ASC, as well as the Hallucinogen Rating Scale and the Phenomenology of Consciousness Inventory), and it refers to the Pahnke–Richards Mystical Experience Questionnaire when discussing mystical or peak-type experiences. The authors also discuss methodological challenges specific to psychedelic research, including difficulties with ‘‘online’’ assessment during acute drug effects, the retrospective nature of most subjective reports, impairment of blinding in placebo-controlled trials by obvious psychotropic effects, and the influence of set and setting on experience. Where clinical trial designs are described in the text, the review reports on both older uncontrolled clinical series and more recent controlled studies (including double-blind, placebo- or active-controlled designs in some cases), as well as meta-analytic summaries for particular indications. The extraction does not provide detailed information on study selection, data extraction procedures, or risk-of-bias assessment methods used by the reviewers themselves.

Neurophenomenology and measurement: The review summarises conceptual work on ASCs and their temporal profile, noting that acute psychedelic effects may include a rare, intense peak or mystical experience followed by a transient afterglow period of elevated mood and openness that can last approximately two weeks to one month. Assessment has relied largely on retrospective questionnaires; Dittrich's APZ and the refined 5D-ASC are presented as the common standards, with one 5D-ASC factor labelled 'spiritual experiences' proposed as an operational indicator of mystical-type experiences. Phenomenology of peak experiences: Majić and colleagues describe Pahnke's nine-characteristic account of the psychedelic peak/mystical experience (including unity, transcendence of time/space, positive mood, sacredness and ineffability) and note that peak experiences were sometimes followed by persistent positive changes in attitude and behaviour. The Good Friday (Pahnke) experiment and a later, better-controlled psilocybin study are reported: in the latter, 58% of subjects given psilocybin had complete mystical experiences, and in a 14-month follow-up more than 50% rated the session among the most personally meaningful experiences of their lives, with 64% reporting increased well‑being or life satisfaction. Neural substrates: Molecular pharmacology is summarised with emphasis on 5-HT2A receptor involvement for classical psychedelics; two psilocybin studies in which pre-treatment with the 5-HT2A antagonist ketanserin attenuated drug effects are cited. Dynamic causal modelling of MEG data is reported to implicate modulation of pyramidal cells. Ketamine's NMDA antagonism is discussed alongside converging glutamatergic pathways that may link serotonergic psychedelics and ketamine. Network-level neuroimaging findings include decreased activity in anterior and posterior cingulate cortices and reduced coupling between medial prefrontal and posterior cingulate regions during psychedelic states; a PET study associated ‘‘oceanic boundlessness’’ (OBN) with fronto‑limbic‑striato‑parietal changes and ‘‘dread of ego dissolution’’ (DED) with thalamic hyperactivity and reduced orbitofrontal activity. Therapeutic models and ritual contexts: Two historical psychotherapeutic approaches are characterised. Psycholytic therapy (PLT) used repeated low-to-moderate doses alongside psychodynamic psychotherapy to loosen defences and facilitate insight, whereas psychedelic (peak) therapy (PDT) used infrequent high doses to induce a peak experience within a carefully prepared and supported three‑phase model (preparation, drug session guided by therapists, integration). The review also discusses traditional ritual use (for example peyote and ayahuasca/Santo Daime/União do Vegetal), noting that regular ritualised ingestion may produce sustained afterglow-like states and communal or pro‑social effects. Clinical indications and empirical findings: - Substance addiction: Early trials (1950s–1970s) were methodologically weak but suggested potential benefits. A recent meta-analysis identified six randomized controlled trials of a single high-dose LSD administration for alcohol misuse (total n=536) reporting beneficial effects at first follow-up (4 weeks to 12 months); doses were 450–800 μg LSD and individual study sizes ranged from 10–132. The reviewers note that therapeutic preparation and follow-up were present in studies showing benefit. Ketamine psychedelic psychotherapy (KPT) studies are reported: in a double‑blind, active placebo‑controlled trial of 70 heroin addicts, only the high-dose ketamine group experienced psychedelic states and showed significantly higher abstinence rates over 23 months, plus reductions in craving and improvements in anhedonia and emotional openness. - Terminal illness (cancer-related anxiety/depression): Earlier LSD/DPT studies at Spring Grove and other centres reported meaningful reductions in fear of death and improved interpersonal relationships when sessions included careful set, setting and integration. A recent within-subject, double‑blind, placebo‑controlled study of psilocybin in 12 patients with advanced cancer found reduced anxiety at 1 and 3 months and improved mood at 6 months after a single low-to-moderate dose; patients reported increased empathic rapport and diminished fear of death. These effects were linked in reports to ego‑free or transcendence experiences. - Obsessive–compulsive disorder (OCD): Anecdotal early reports indicated resistance to LSD's psychological effects in some OCD sufferers. One controlled study exposed nine treatment-resistant OCD patients to four single-dose psilocybin sessions (low to very high doses) and reported consistent immediate reductions in core OCD symptoms for all participants; effects were rapid but highly transient, typically lasting somewhat longer than 24 hours. The small sample size and lack of a control group limit inference. - Depression: Ketamine has substantial evidence for rapid antidepressant effects in treatment-resistant unipolar and bipolar depression and for suicidal ideation; these effects are often short-lived. The reviewers note that ketamine’s antidepressant action has generally been interpreted as pharmacodynamic and largely independent of a phenomenological psychedelic state, as sub-psychedelic doses produce clinical benefit in many trials. - Cluster headache and other indications: An online survey of 53 cluster headache sufferers who had used LSD or psilocybin reported high efficacy for aborting attacks, terminating cluster periods and extending remission; interestingly these effects appear independent of the psychedelic experience, and non‑hallucinogenic ergoline derivatives (for example BOL‑148) are noted as promising. The review also mentions other historical indications such as narcissistic personality disorder, psychosomatic conditions, sexual dysfunction and PTSD, often drawing on small samples or clinical series. Relationship between subjective experiences and therapeutic outcomes: Evidence is heterogeneous. For addiction and end‑of‑life anxiety, psycho‑spiritual or peak experiences are often linked to better outcomes in older and some contemporary reports. For OCD and ketamine treatment of depression, therapeutic effects may occur independently of mystical-type experiences, suggesting distinct pharmacological pathways. The review emphasises the sparse, small-sample and mixed-quality nature of much of the evidence, and the confounding influence of set, setting, preparation and integration on outcomes.

Majić and colleagues interpret the literature as indicating that psychedelic drugs can exert therapeutic effects through multiple, partially overlapping mechanisms. In some contexts — notably addiction treatment and relief of existential anxiety in terminal illness — psycho‑spiritual peak experiences and the subsequent afterglow are proposed to contribute materially to clinical benefit. These experiences may catalyse shifts in self‑concept, values and interpersonal relatedness that are harnessed by psychotherapeutic processes. Conversely, the review highlights indications in which pharmacological mechanisms appear to predominate. Ketamine's rapid antidepressant action, for example, is commonly attributed to glutamatergic and neuroplastic effects that are, at least in many trials, largely independent of an overt psychedelic phenomenology. Similarly, some reports of benefit in cluster headache or OCD suggest therapeutic effects that can occur without a sustained mystical experience, implying that direct receptor‑mediated or network‑level actions also matter. The authors acknowledge major methodological limitations across the literature: many early studies were uncontrolled or small; blinding is inherently difficult when drugs produce obvious subjective effects; retrospective assessment of ASCs is vulnerable to bias; and set and setting substantially moderate both experiences and outcomes. They therefore recommend standardised assessment of ASC phenomena (for example using the 5D‑ASC and validated mystical experience measures), the systematic incorporation of preparation and integration into clinical protocols, and more rigorous trial designs that attempt to separate experiential from pharmacological contributions. Finally, the review frames practical and scientific implications without overclaiming. The investigators suggest that psychedelic interventions may be considered to have at least four distinct therapeutic roles: as pharmacological agents with neurochemical action, as adjuncts to psychotherapy that facilitate psychological work, as analgesics in certain pain syndromes, and as facilitators of spiritual or self‑transcendent experiences. They call for future research to clarify which mechanisms are most relevant to particular disorders and patients, to identify neural correlates linking subjective experience and long‑term change, and to explore personalised approaches that account for set, setting and individual differences.

The review concludes that systematic assessment of drug‑facilitated altered states of consciousness in controlled clinical trials is necessary to determine which subjective experiences contribute to therapeutic outcomes. Majić and colleagues note that, despite regulatory and methodological hurdles, neuroimaging and psychometric tools now permit more precise study of the relationship between phenomenology and neuronal mechanisms, and they urge further research to elucidate how acute experiences, afterglow periods and lasting neurobiological changes interact to produce long‑term clinical benefits.