Producing Altered States of Consciousness, Reducing Substance Misuse: A Review of Psychedelic-Assisted Psychotherapy, Transcendental Meditation and Hypnotherapy

: A set of interventions that can produce altered states of consciousness (ASC) have shown utility in the treatment of substance misuse. In this review, we examine addiction-related outcomes associated with three common interventions that produce ASCs: psychedelic-assisted psychotherapy (PP), Transcendental Meditation (TM) and hypnotherapy (HT). While procedurally distinct, all three interventions are associated with some common phenomenological, psychological, and neurobiological features, indicating some possible convergent mechanisms of action. Along with addiction and mental health outcomes, these common features are reviewed, and their impact on substance misuse is discussed. While our review highlights some mixed findings and methodological issues, results indicate that PP and TM are associated with significant improvements in substance misuse, alongside improvements in emotional, cognitive and social functioning, behavior-change motivation, sense of self-identity, and meaning. In contrast, and despite its broader acceptance, HT has been associated with mixed and minimal results with respect to substance misuse treatment. Authors identify key research gaps in the role of ASC interventions in addiction and outline a set of promising future research directions.


Introduction
Addiction is defined as a chronic, compulsive need to engage in a behavior despite its harmful effects and/or the individual's wish to stop [1].The prevailing mechanistic understanding is of a complex interplay of biological, psychological, and social factors, and available treatments target one or a combination of these determinants.A number of treatment modalities that entail the production of an Altered State of Consciousness (ASC) have shown promise in treating various substance use disorders [2,3], yet the nature and strength of the evidence remain unclear.This review explores treatment outcomes associated with substance misuse interventions that produce ASCs and describes alterations in key biopsychosocial measures relevant to addiction.
While definitions of ASCs vary and are frequently imprecise, we can arrive at a useful operationalization through "change in the overall pattern of subjective experience" [4], a "qualitative… not just quantitative shift" [5], and a "sufficient deviation" [6] within a wide range of mental functions [4], and crucially within "Primary Consciousness" [7].That is, ASCs are a noticeable (often dramatic) and qualitative alteration to the fundamental "fabric of awareness", typically accompanied by alterations to perception, cognition, and affect.The intentional induction of ASCs through a range of methods is commonplace throughout history and across cultures.A number of phenomenological and neurobiological features appear common across diverse induction methods such as hypnosis, sensory deprivation, trance, meditation, and psychedelic drugs [8].These include fragmentation and sometimes loss of a sense of selfhood, changes in the experience of space and time, novel perspectives and the perception of novelty, cognitive changes, perceptual distortion, and emotional lability [9][10][11].
A wide range of ASC induction methods have been used to treat different forms of substance use disorders within ceremonial, self-medicating, and clinical settings [8].This review explores three ASC therapies that have been empirically explored as treatments for substance misuse to a greater degree than other interventions: psychedelic-assisted psychotherapy (PP), Transcendental Meditation (TM), and hypnotherapy (HT).
PP involves administration of a psychedelic substance (here, we use the term broadly to include "classical" psychedelics as well as related substances that have substantial overlapping features, including LSD, Psilocybin, Ketamine, Ibogaine, Mescaline, Ayahuasca, and MDMA), usually accompanied by psychotherapeutic or ceremonial support.Within modern clinical trials, psychedelic interventions are typically embedded within a socalled "set and setting" protocol of extra-pharmacological support across at least three distinct treatment phases: preparation, dosing, and integration [12].An ASC that results from therapeutic doses of a classical psychedelic is frequently reported as one of the most personally meaningful and challenging experiences of an individual's life [13].
Various forms of meditation can be broadly defined as practices of paying attention to present moment percepts in a sustained way and without judgement [14,15].The TM approach is based on a silent repetition of a personalized mantra [16] and is taught by certified teachers during a standardized four-day induction process.Participants are then expected to continue their practice independently for 15 to 20 min, twice a day.TM emphasizes attainment of "transcendental consciousness", an ASC that is devoid of thoughts or emotions.
Hypnosis is a state of trance, induced by narrowing of attention to specific stimuli with the use of repetitive sounds, mantras or visuals, followed by suggestion of sleep-like relaxation [17].In a therapeutic setting, the state of relaxation and surrender is leveraged by the hypnotherapist who may persuade immediate or future actions, thoughts, and feelings without requiring the participants' conscious control [18].
Of these induction methods, PP is associated with the most reliable and intense ASCs, to the extent that effective placebo blinding is very difficult to achieve [19].HT and TM are less reliable in producing ASCs, and the literature associated with these procedures rarely provides clear assessment of the production or characteristics of an ASC.In therapies that employ TM or psychedelics, the acute ASC experience is largely left uninterrupted, with the role of the therapist being limited to supporting or facilitating the experience.Talk therapy takes place predominantly either before or after that experience.In contrast, the state of hypnosis is induced for the duration of talk therapy, and the main therapeutic input occurs during that state.
Herein, we review the literature on the efficacy and related biopsychosocial outcomes associated with PP, TM and HT interventions that target substance misuse.We also consider the role of ASC in precipitating these effects, examine the limitations of each method, and suggest future directions for research.

Method
Authors reviewed the articles on trials of interventions involving PP (18), TM (10) or HT (13) where at least one outcome related to substance misuse was measured (Figure 1).No restrictions were applied for the type of control condition (including no intervention), type of addiction outcome, or publication date.The following inclusion criteria were applied: (i) human participants, (ii) use of primary data, (iii) empirical neurobiological, psychological or behavioral data, and (iv) peer-reviewed status.
A systematic search was conducted on 10th of August 2020 by two reviewers (ADS, PP) using Medline, Embase and PsycINFO.Abstracts, titles and keywords were searched with the following terms: (addiction OR dependence OR abstinence OR alcohol OR drug OR smoking OR cessation OR cigarettes OR tobacco OR nicotine OR cocaine OR heroin OR methamphetamine OR amphetamine OR stimulant) AND ("Transcendental Meditation" OR Hypnotherapy OR Hypnosis OR LSD OR "Lysergic acid diethylamide" OR Psilocybin OR psilocin OR "Magic mushroom" OR Ketamine OR Ibogaine OR Iboga OR Ayahuasca OR DMT OR dimethyltryptamine OR MDMA OR 3,4-Methylenedioxymethamphetamine OR mescaline OR trimethoxyphenethylamine OR peyote OR "San pedro" OR "2C-B" OR "2,5-dimethoxy-4-bromophenethylamine" OR hallucinogen OR psychedelic).

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Two authors (ADS, PP) scanned titles and abstracts of all articles in search results, independently applying eligibility criteria.Reference lists of included papers were scanned, and an additional six papers were found and manually added.A total of 41 articles that met the inclusion criteria were identified across the three treatment approaches.

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For each included trial, data were extracted independently by the authors.Substance use and abstinence results based on biochemical markers or self-reports were accepted.Quantitative and qualitative reports on biopsychosocial outcomes were extracted from results and discussion sections.Included studies, extracted data and study limitations were compared, and any discrepancies resolved through consensus decision making.
PP produced significant improvements in key outcome measures directly implicated in abstinence, notably cravings [27,30,32], withdrawal symptoms [25,28,32], and urgency of use [33].In non-treatment-seeking cocaine addicts, PP induced strong, significant increases in motivation to change [30].In detoxified, treatment-seeking inpatients, PP aided change by significantly increasing self-reported "self-actualization" (full realization of one's potential) and internal locus-of-control sense of agency over the outcome of life events [26].
Krupitsky and colleagues [26,27] investigated the relation between treatment outcomes and dosage/dose frequency, evaluating 2.0 vs. 0.2 mg/kg of ketamine and single vs. three doses repeated at 1-month intervals, and found a significant association between the maintenance of abstinence over 12-24 months and dose strength [26] as well as a higher number of doses [27].A positive correlation was also observed between intensity of psychedelic experience (strength of peak experiences) and treatment outcomes [34].
One fatality was ruled to be the direct result of ibogaine administration [28].With no definable pathology identified in postmortem examination, coronial enquiry ruled that this fatality was associated with a failure in the duty of care by the treatment provider.Cardiac arrhythmias related to Ibogaine ingestion have been reported, with pre-existing comorbidities and substance misuse being attributed to the majority of documented deaths [35].

PP Limitations
As indicated in Table 1, many of the reviewed trials were open-label with no control groups [25,33], some failed to achieve adequate blinding in placebo-controlled trials [27], some had high rates of drop out 25-50% over 3-18 months [23,24,26], and in some trials the samples were relatively small and homogenous, e.g., in [31].Due in part to recent media hype and largely positive attitudes towards PP in the general public in places like the US, patients who volunteered for PP may have had strong positive expectancies resulting in a larger placebo component than is typical [20,22].Several studies were inconsistent in their dosing regimen or lacked details regarding dosage and timing of drug delivery [20,28,29,31,32], lacked clarity on how outcome measures were obtained or verified [23,24,26], or did not report concurrent psychotherapy or other treatments [31,32].Early studies and ritualistic settings used vague diagnostic metrics [24,29,31,32].Many recent studies predominantly used self-report measures without biological verification [22,[24][25][26][31][32][33].In one study, biological verification was inconsistent with self-reports [28].
There were also notable differences in treatment approach across reviewed studies, with clinical vs. ritualistic settings [31,32] and varying forms and amounts of psychotherapeutic support [20,22,24,26,27,29].Such heterogeneity limits the ability to draw overall conclusions about therapeutically important aspects of the treatment approach.

TM Outcomes
As indicated in Table 2, TM led to significant reductions from baseline in the use of cigarettes [39,40], alcohol [39,[41][42][43], prescribed psychotropics [39,44], and most illicit drugs [39,45] except for hallucinogens [39].Significant group effects showed that TM was superior to no treatment [39,40], counselling [41,43,45], exposure therapy [44], cranial electrical stimulation [43], and psychiatric medication [42].Only two studies showed non-significant group effects.Among students who perceived no negative consequences of substance use, TM was associated with reductions only in alcohol use and only among men [47].The use of other substances and substanceby-gender interactions were not significantly different between TM and no treatment groups.Nonetheless, everyone in the TM group improved significantly on biopsychosocial measures, including anxiety, depression, hostility, and coping, while controls worsened [48].In another study, a robust residential program combined with pharmacological management of withdrawal symptoms was equally effective to TM in alleviating psychological symptoms of AUD, including alcohol urge, craving strength, and craving frequency [42].A notable limitation was that half of the controls in this study practiced meditation despite being instructed not to, potentially compromising the comparison condition.
Numerous other biopsychosocial measures improved following TM, while controls showed no change [43,46] or more frequently worsened [41,[43][44][45][46]48]. TM led to significant improvements in functions critical to addressing addiction, most prominently coping skills [45,47,48].Alcohol use, relapse rates, and withdrawal symptoms improved among AUD patients [42,43].TM practice was an effective replacement for pharmacological treatment of PTSD, leading to reduced use of prescription medication and alcohol along with significant reductions in PTSD symptoms; the comparison condition-exposure with cognitive processing therapy-led to increased use of medication and worsening of psychological symptom severity [44].Compared with counselling, TM was associated with greater improvements in stress habituation, PTSD symptoms including emotional numbness, and adjustment scores, including insomnia, employment status and family problems [41].TM also led to improvements in general psychological well-being, most frequently significant and substantial reductions in stress and anxiety, e.g., in [41,45], depression, e.g., in [41,43,48] and anger, e.g., in [43,45,46].Significant improvements were also observed in interpersonal relationships, including increased compassion and social interest as well as reduced hostility [41,43,[46][47][48].Numerous participants reported feeling better physically, with reductions in insomnia, fatigue, psychomotor retardation, and hypertension [41,43,[45][46][47][48]. Adherence to TM was also linked to increased participation in other beneficial activities, including sport and reading [43,46].
Higher frequency of TM practice contributed to better substance use outcomes [39,40,42,45], but not biopsychosocial outcomes, which improved even following irregular practice, e.g., in [42].Participants generally attributed the major source of their improvements to TM, e.g., in [42,46], thought it should be implemented at other prisons nationwide [46] and often returned to practice after relapsing [45].Others requested to start the TM program sooner than anticipated [45] or extend the intervention phase [46].

TM Limitations
Potential conflicts of interest were apparent across a number of trials.Two studies were co-funded by a TM-promoting foundation [42,44] and in several studies at least one author was affiliated with a private TM institution [39,42,43,47,48], although these affiliations do not necessarily imply biased results.
Several studies used TM as an adjunct to some other treatment, making it difficult to distinguish TM's unique impact [42,43,45,46].While TM induction is standardized and the 4-day instruction program is comparable across studies, control conditions were not always clearly described, especially in older studies, e.g., "counselling" [39][40][41]45,46].

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22% quit in a month prior to the survey; 65% had a smoke-free period since instruction
Only three studies reported significant between-group differences, with HT alone producing larger benefits than no treatment for smoking [59]; HT with counselling and supportive phone calls associated with considerably higher smoking abstinence rates than supportive phone calls alone [54]; and HT with psychotherapy linked to considerably higher rates of successful methadone withdrawal, lower illicit drug use, and lower withdrawal symptoms than psychotherapy alone [58].
Two studies considered the roles of practice regularity and hypnotic susceptibility in their analysis.Regular HT practice led to significant improvements in self-esteem, anger, and impulsivity in AUD compared with CBT therapy or stress management, which had significantly better outcomes on these variables than irregular HT practice [60].In another study, when analyzing only participants with high hypnotic susceptibility, differences between HT and relaxation in smoking reduction became significant [59].Similarly, high hypnotic susceptibility was a predictor of better substance use outcomes [50] and biopsychosocial outcomes [60] wherein participants reported high hypnotizability scores, but not in a study with generally low hypnotizability scores [52].

HT Limitations
HT was predominantly used as an adjunct therapy rather than a stand-alone treatment, e.g., in [55,56,58].The majority of reviewed studies did not use standardized, reproducible hypnotic induction [49,51,[54][55][56]60], while others lacked any clear description of the procedure [53,[57][58][59].Whether achieving a hypnotic state is linked to clinical outcomes is unclear based on the evidence from the four studies that addressed it [50,52,59,60] and is inconclusive across the literature more generally [62,63].On the other hand, relaxation, which is commonly an integral component of HT, has been shown to play an important role in alleviating addiction symptoms, e.g., in [64], and some studies have found it to be the most useful component of HT intervention, e.g., [49].

Substance Misuse Treatment Efficacy
Based on the studies reviewed above, PP and TM appear to be promising treatments for substance abuse and are linked to improved psychosocial well-being in patients receiving treatment for addiction; in contrast, there is little support for the efficacy of HT in treating addiction.
Reviewed studies demonstrated predominantly significant and moderate, e.g., in [27], or substantial, e.g., in [20], efficacy of PP across various classical psychedelics and related pharmacotherapies (LSD, psilocybin, ketamine, ibogaine) in the treatment of a range of substance dependencies (cocaine, opiate, alcohol, tobacco) when compared with psychotherapeutic controls, low-dose active comparisons, and benzodiazepine.Across six open-label studies, significant moderate improvements in abstinence rates were found from baseline to follow-up (ranging from 6 to 12 months).In one qualitative study, moderate reductions in substance use and craving were reported.Studies demonstrating a reduction in addictive behavior also found significant, predominantly moderate improvements across various biopsychosocial outcomes, ranging from comorbid psychiatric diagnoses to regulation of the sense of self and internalization of locus of control and improved relationships.
Similarly, TM led to significant improvements from baseline (6 of the 10 studies) across addiction outcomes for the use of tobacco, alcohol, marijuana, opiates, or stimulants (two studies' results were not significant, and significance was not reported in another two studies).These effects were either moderate or large.TM performed better than a range of control interventions, including various psychotherapeutic approaches and psychotropic treatments, and between-group differences were significant in 7 of the 10 studies.This was true for all reviewed cohorts (veterans, youth, inpatients, outpatients).Moreover, TM reliably improved broader biopsychosocial factors and alleviated psychological symptoms that are recognized risk factors for addictive behavior.When measured, biopsychosocial outcomes were significantly improved from baseline and when compared with control conditions in all but one study.
In contrast, evidence for the efficacy of HT in treating addictions was weak, showing no advantage over comparison addiction interventions and only small advantages over no intervention.Disparities in study design, substantial shortage of information, and questionable motivations of participants were key limitations in assessing the efficacy of HT.
Whilst HT and TM studies reported no adverse events or side effects, PP can be associated with adverse events (usually minor) and requires considerable training of the associated clinicians and care before, during and after the therapy.While the classical psychedelics are physiologically very safe, one fatal event occurred as a direct result of administration of Ibogaine, although post-mortem examination could not identify a clear pathology that was the cause of death [28].

Biopsychosocial Benefits
Both PP and TM led to improvements across a wide range of emotional, cognitive, interpersonal, and intrapersonal factors.Conversely, biopsychosocial outcomes are rarely considered in HT interventions, highlighting a difference in approach to TM and PP studies.In line with the current understanding of the psychosocial determinants of addiction, improvements in addictive behaviors following PP and TM may be related to the psychosocial benefits associated with those two interventions.
Indeed, the non-directive approach of PP and TM may afford a range of psychosocial benefits through supporting a patient-led process, and an emphasis on the individual's particular acute and post-acute experiences and insights.In contrast, HT induces an ASC in order to provide an intervention that explicitly addresses the target behavior.That is, HT for addiction is typically constrained to a specific problematic behavior, while PP and TM emphasize useful and meaningful ASCs that may produce a wide range of psychosocial changes.This latter emphasis may allow for TM and PP to address more fundamental factors in addictive behaviors than HT, and thereby lead to better results.

Study Quality and Limitations
Early PP studies lack sufficient methodological rigor, with inconsistent dosing regimens, lack of clarity on outcome measures and poorly reported statistical analysis.In contrast, the more recent, well-controlled and analytically rigorous studies used small and heavily screened samples (for some good reasons), limiting generalizability to a broader patient population.Moreover, placebo blinding is difficult across most high-dose PP trials, and patient self-recruitment alongside substantial positive public interest in PP all potentially contribute to inflated expectancy effects.
Various concerns around corporate and quasi-religious motivations have been associated with TM [65].Tight corporate control of certification, aggressive marketing, overly positive reports, substantial financial gains for the teachers, and promotion of supernatural abilities (e.g., levitation) have contributed to strong critique of the TM community.While results reviewed here are promising, most of the TM studies (7 of 10) suffered from potential conflicts of interest.Moreover, similarly to PP, older TM studies showed less methodological rigor, often using unvalidated tools to measure intervention outcomes, and failing to provide a clear, reproducible account of the full procedure, for example, in relation to control interventions.
Finally, HT interventions for substance addiction showed weak and mixed findings.Inconsistencies in induction procedures and definitions of hypnotic state limit conclusions that can be drawn from this research.Of note, the commonly hypothesized link between hypnotic depth and therapeutic effects has not been established, e.g., in [52,62,63].Also, participant experiences often appear indistinguishable from those undergoing relaxation interventions [66], and when identical interventions are labelled as either relaxation or hypnosis, reports of suggestibility and involuntariness increase more in the latter [67], suggesting that outcomes may in part depend on expectancy effects or demand characteristics.These limitations suggest that where substance misuse benefits have been reported in a minority of studies, these may be accounted for by factors like suggestibility or therapeutic alliance, rather than the hypnotic state.
Lastly, in contrast to many modern PP studies, both TM and HT are unreliable in their ability to induce an ASC, and the majority of reviewed studies failed to include markers of achieving an ASC.Therefore, it is difficult to assess whether the production or characteristics of an ASC during these interventions was associated with beneficial outcomes.

Future Directions
Many of the studies reviewed herein failed to measure acute altered state experience, making it difficult to evaluate whether and which of these may be related to beneficial addiction treatment outcomes.However, contemporary PP literature has found that features of the acute subjective psychedelic experience, such as oceanic boundlessness, ego dissolution or universal interconnectedness, most often measured by Mystical Experiences Questionnaire (MEQ) or Five Dimensions of Altered States of Consciousness Scale (5D-ASC) are one of the most robust predictors of clinical benefit across a number of indications including cancer-related distress [68], depression [69], or substance abuse [22].These and similar measures should be incorporated across interventions such as TM and HT to determine whether certain kinds of altered state experiences are important for producing clinical benefit.Well-validated ASC measures and constructs should be used to assess a wide range of features commonly associated with ASC experience, thereby increasing specificity and consistency across studies.
Indeed, mental health benefits appear to be linked to subjective features of the acute ASC experience across a number of ASC interventions [70].Therefore, it may be useful to consider the utility for various other ASC induction methods in the treatment of addictions, including sensory deprivation, neurofeedback, tactile sound systems, hypnagogic lights, virtual reality, and so on.If beneficial, they could offer a feasible adjunct to current treatments.Moreover, potential synergistic effects of combining two or more ASC interventions should be explored [71].
While some studies have found better clinical outcomes following a longer period of meditation, e.g., [72], or a higher number of psychedelic doses [27], typically, the duration of meditation has been short, e.g., only two of the reviewed TM studies provided followup sessions for longer than 6 months [43,46] and the number of psychedelic doses was limited, e.g., one to three doses, [27].Future studies could extend program duration or number of sessions to determine optimal program length using designs that can assess cumulative effects.Adding an assessment of cost effectiveness would further contextualize optimal program length within economic considerations.
Lastly, it has been speculated that an inherent need to achieve altered states may motivate drug-seeking behaviors that can lead to addiction [10,73].Future work should explore this claim, and then determine whether providing beneficial ASC interventions (including those induced by psychedelic drugs) could mitigate the need to engage in harmful drug use that can lead to dependence and addiction.One implication of this could be to expand the use of ASC interventions from treatment to prevention.

Conclusions
The effects of PP on substance misuse outcomes indicated promise and warrant further, more rigorous investigation.Results of TM were also encouraging, and findings should be replicated by researchers with no ties to TM institutions.In contrast, and despite some beneficial effects, evidence suggested that HT may not be an effective treatment for substance misuse.Moreover, PP and TM reliably led to biopsychosocial improvements (e.g., reductions in stress, anxiety, or depression; improved coping skills and interpersonal relationships; increased self-efficacy or sense of purpose) that were not observed in comparison conditions in this review.Some of those benefits, including renewed sense of self or increased understanding of the meaning of life, are not commonly reported in other trials of addiction treatments [74].A key question is whether certain subjective aspects of the acute ASC associated with both PP and TM are important for driving clinical change.Moreover, given the potential role of biopsychosocial change in successful treatment of addiction [75], future research could investigate whether the impact of ASC interventions on substance misuse is mediated by improvements in biopsychosocial functioning.

Figure 1 .
Figure 1.PRISMA flow diagram of study selection.

Table 1 .
Summary of 18 PP studies in addiction that met the inclusion criteria.

Table 2 .
Summary of 10 TM studies in addiction that met the inclusion criteria.

Table 3 .
Summary of 13 HT studies in addiction that met the inclusion criteria.