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Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials

This very stringent meta-analysis (including 6 trials, n=536) concludes that a single session/dose of LSD treatment has short-term (<6 months) effects on alcoholism (less misuse, more abstinence) but no positive long-term outcomes (>12 months).

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Authors

Krebs, T. S.
Johansen, P. Ø.

Published

January 1, 2012

Journal of Psychopharmacology

meta Study

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Abstract

Assessments of lysergic acid diethylamide (LSD) in the treatment of alcoholism have not been based on quantitative meta-analysis. Hence, we performed a meta-analysis of randomized controlled trials in order to evaluate the clinical efficacy of LSD in the treatment of alcoholism. Two reviewers independently extracted the data, pooling the effects using odds ratios (ORs) by a generic inverse variance, random effects model. We identified six eligible trials, including 536 participants. There was evidence for a beneficial effect of LSD on alcohol misuse (OR, 1.96; 95% CI, 1.36-2.84; p = 0.0003). Between-trial heterogeneity for the treatment effects was negligible (I² = 0%). Secondary outcomes, risk of bias and limitations are discussed. A single dose of LSD, in the context of various alcoholism treatment programs, is associated with a decrease in alcohol misuse.

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Research Summary of 'Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials'

Introduction

Alcohol causes substantial global harm and remains difficult to treat: alcoholism (alcohol dependence) contributes notably to mortality and disability and many patients fail to achieve recovery with existing interventions. Earlier clinical investigators reported that single, supervised doses of lysergic acid diethylamide (LSD), given alongside psychosocial treatments, produced profound subjective experiences that were claimed to reduce relapse, but these reports had not been synthesised with modern systematic review methods. Krebs and colleagues therefore set out to perform a quantitative meta-analysis of randomized controlled trials to evaluate whether LSD, administered as a single dose within alcoholism treatment programmes, affects subsequent alcohol misuse. The aim was to pool trial data to estimate efficacy, examine follow-up intervals, and assess adverse events and risk of bias across the trials.

References (9)

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Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)

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A clinical study of LSD treatment in alcoholism

Methods

The investigators searched PubMed and PsycINFO without language restrictions using terms for LSD (including lysergic, lysergide, psychedelic*, hallucinogen*) combined with alcohol-related terms (alcohol*, addict*, dependence). Search results were screened by title and abstract, full texts of potentially relevant publications were retrieved, reference lists inspected, and experts contacted. The study protocol pre-specified inclusion and exclusion criteria and primary/secondary outcomes. Included studies were randomized controlled trials of LSD for alcoholism; control conditions could be any type of treatment and active controls of up to 50 mcg LSD were allowed. Participants with schizophrenia or psychosis were excluded from the meta-analysis. Two reviewers independently extracted trial data and assessed risk of bias using Cochrane domains (sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting). Extracted items included intervention details (dose, control, additional treatments), participant characteristics, outcome measures and timing, and trial features (year, location, funding). Primary outcomes were measures of alcohol misuse at the first reported follow-up; secondary outcomes were alcohol misuse at short-term (~3 months), medium-term (~6 months) and long-term (~12 months) follow-up. Abstinence and adverse events were also extracted where reported. Categorical alcohol outcomes were dichotomised into 'improved' versus 'not improved' based on categories indicating clear, substantial improvement. Continuous and categorical data were pooled using the generic inverse variance method with a random effects model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) in Review Manager 5.0. Heterogeneity was quantified with the I2 statistic (the percentage of total variation across trials attributable to between-trial heterogeneity). Participants lost to follow-up were conservatively counted as not improved. In a post hoc analysis the authors computed pooled benefit differences (risk differences) and derived the number needed to treat (NNT = 1/benefit difference) where dichotomised data were available. Description of the included trials was integrated into the methods. Six randomized trials (with additional reports on three) were included, totalling 536 adults (325 assigned to full-dose LSD, 211 to control). Most participants were male inpatients recruited from alcohol treatment programmes. Single oral LSD doses ranged approximately from 210 mcg (3 mcg/kg) to 800 mcg, with a median around 500 mcg. Preparatory, supportive and integration procedures varied markedly between trials: some provided minimal orientation and simple observation during the drug session, while others offered more clinical guidance, music and comfortable surroundings; review sessions after the drug session were generally limited. Outcome measures included maintained abstinence, alcohol use rating scales and composite alcohol/social adjustment scales; one trial reported a continuous percentage change in time abstinent.

Results

Six eligible randomized controlled trials were pooled. For the primary outcome—improvement in alcohol misuse at the first reported follow-up—the pooled odds ratio comparing LSD to control was 1.96 (95% CI 1.36–2.84; p = 0.0003). Using dichotomised data from five trials, 185 of 315 (59%) LSD recipients versus 73 of 191 (38%) control patients were classified as improved at first follow-up; the pooled benefit difference was 16% (95% CI 8%–25%; p = 0.0003), corresponding to a number needed to treat of six. When analysed by follow-up interval, LSD showed a significant effect at short-term follow-up (2–3 months): pooled OR 1.85 (95% CI 1.14–3.00; p = 0.01), and at medium-term follow-up (6 months): pooled OR 1.66 (95% CI 1.11–2.47; p = 0.01). The effect was not statistically significant at long-term follow-up (approximately 12 months): pooled OR 1.19 (95% CI 0.74–1.90; p = 0.47). Between-trial heterogeneity was negligible for the primary, short-term and medium-term analyses (I2 = 0%); heterogeneity was low at long-term follow-up (I2 = 15%). Among three trials reporting maintained abstinence, LSD was associated with higher odds of abstinence at the first reported follow-up (OR 2.07; 95% CI 1.26–3.42; p = 0.004) and at short-term follow-up (OR 1.80; 95% CI 1.07–3.04; p = 0.03), but not at medium-term follow-up (OR 1.42; 95% CI 0.65–3.10; p = 0.38). Heterogeneity for abstinence was negligible at first and short-term follow-up (I2 = 0%) and moderate at medium-term follow-up (I2 = 44%). Five trials reported eight acute adverse reactions to LSD without lasting harm. Reported acute events included two participants who 'acted bizarrely', agitation in one participant, a grand mal seizure in one patient who had a prior history of alcohol-withdrawal seizures and very short alcohol abstinence, and other unspecified transient adverse reactions; mild nausea, vomiting and agitation were also reported and were generally relieved by supportive measures. One trial noted that around one-third of LSD recipients briefly experienced vivid perceptual or thought experiences on one or a few occasions within a year after LSD, typically after drinking alcohol. No trials reported lasting detrimental effects on psychosocial functioning; two of three trials reporting employment outcomes found improved employment after LSD. Risk of bias assessments found no trials with high risk for sequence generation or allocation concealment, though methods were often underdescribed. Two trials had high risk for inadequate blinding because allocation was concealed only until the possible LSD session; four trials used double-blind designs with active placebos. Outcome assessment blinding was low or unclear risk in most trials; several used allocation-blind interviewers. Two trials had high risk due to incomplete outcome data because participants who did not complete intended treatment or who received additional LSD doses were excluded. Two trials were judged at high risk for selective outcome reporting, and one trial showed baseline imbalance on some sociodemographic variables though groups were matched on baseline alcohol misuse. Sensitivity analyses showed the primary outcome remained statistically significant when excluding any two of the four larger trials or when excluding trials judged to have high risk on specific bias domains. Excluding the two trials with non-blinded control conditions increased the LSD effect. Secondary outcomes were more sensitive: removing the single trial with the most favourable result in each secondary analysis rendered those outcomes non-significant (p ≥ 0.06); secondary analyses were based on only three to five trials each.

Discussion

Krebs and colleagues interpret their pooled analysis as evidence that a single supervised dose of LSD, given within a range of alcoholism treatment programmes, is associated with reduced alcohol misuse at first follow-up and up to about 6 months, with effects that were not statistically significant at 12 months. The beneficial effect on maintained abstinence was seen at early follow-up (1–3 months) but not at 6 months. Authors note the pattern—initial benefit that may wane by 12 months—is consistent with earlier non-randomized and open-label reports and with a quasi-randomized study showing benefit at 3 months. Possible reasons the approach has been overlooked are discussed: the individual randomized trials were underpowered and often non-significant on their own; investigators may have discounted moderate or transient effects; early non-randomized studies were poorly reported creating confusion about the evidence base; and sociopolitical barriers complicated regulatory approval for LSD research. The authors state that a single dose of LSD compares favourably with commonly prescribed pharmacotherapies for relapse prevention (naltrexone, acamprosate, disulfiram) based on pooled benefit-difference calculations cited in the paper. On mechanism and subjective effects, the investigators remark that many participants reported insights, increased self-acceptance and motivation following the LSD experience; they also note similarities in subjective and neurobiological effects between LSD and other classic psychedelics (mescaline, psilocybin, dimethyltryptamine) and ethnographic claims that such substances have been used to support sobriety. Regarding safety, the authors state that LSD is widely regarded as physically safe but can produce acute psychiatric adverse events such as anxiety or confusion; they recommend administration in comfortable settings with informed participants. Key limitations acknowledged by the authors include limited trial descriptions of populations and diagnostic methods, too few trials to explore dose-response or treatment-context effects, the possibility of unpublished or missed trials, variable preparation and support across trials (including some trials that concealed the possibility of LSD or provided minimal preparation), difficulties with blinding (some trials used low-dose LSD as active placebo which may attenuate observed differences), and heterogeneity in primary outcome measures. The authors recommend further research, including trials testing repeated LSD doses, stratified analyses to identify subgroups with differential benefit or risk, combinations with contemporary relapse-prevention treatments, and evaluation of shorter-acting psychedelics such as mescaline, psilocybin or dimethyltryptamine.

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INTRODUCTION

Alcohol is said to cause more overall harm than any other drug. Alcohol contributes to about 4% of total mortality and about 5% of disability adjusted life-years to the global burden of disease. Despite the often extreme individual and social consequences of alcohol misuse, many users find it challenging to stop drinking. Alcoholism, also called alcohol dependence, continues to be difficult to treat, and many patients do not achieve recovery from existing treatments. Numerous clinical investigators have claimed that treating alcoholics with individual doses of lysergic acid diethylamide (LSD), in combination with psychosocial interventions, can help to prevent a relapse of alcohol misuse, for example, by eliciting insights into behavioural patterns and generating motivation to build a meaningful sober lifestyle. LSD is wellknown for inducing spectacular and profound effects on the mind. It has previously been used in standard treatment programs for alcoholism at many clinics, but, unfortunately, assessments of the clinical value of LSD have not been based on formal systematic review and metaanalysis. Hence, we have performed a quantitative evaluation of the effectiveness of LSD for alcoholism, based on data from randomized controlled clinical trials.

SEARCH STRATEGY AND SELECTION CRITERIA

We searched the PubMed and PsycINFO databases , without language restrictions, using the following terms: LSD, lysergic, lysergide, psychedelic*, or hallucinogen*; and alcohol*, addict*, or dependence. We independently inspected the search results by reading the titles and abstracts. We retrieved each potentially relevant publication located in the search and assessed it for inclusion, subsequently examining the reference lists of eligible studies and relevant review articles. We supplemented our search for trials by contacting experts. If publications lacked important information, we attempted to contact study investigators and institutions. We specified inclusion and exclusion criteria and defined primary and secondary outcomes in the meta-analysis study protocol. We included randomized controlled trials of LSD for alcoholism, in which control condition involved any type of treatment, including doses of up to 50 mcg LSD as an active control. If a trial included multiple randomized treatment arms, all participants in the eligible LSD arms and all participants in the eligible control arms were pooled for analysis. We excluded participants with schizophrenia or psychosis from analysis, as psychosis is recognized as a contraindication for treatment with LSD.

DATA EXTRACTION

Both reviewers independently extracted data and rated the risk of bias of each included trial. Differences between the reviewers were resolved through discussion. The following were recorded from each trial where available: intervention characteristics (LSD dose, control condition, additional treatments); participant characteristics (number, gender, age, inclusion and exclusion criteria); information given to the participants on the study and the effects of LSD; trial characteristics (publication year, location, funding source); outcomes (primary and secondary outcomes, time of follow-up, method of outcome assessment); evaluation of each domain of the Cochrane risk of bias assessment tool (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting). Primary outcomes were alcohol misuse, defined as alcohol use or consequences of alcohol use, as systematically measured by interview or self-report at the first reported follow-up. Secondary outcomes were alcohol misuse at short-term (approximately 3 months), medium-term (approximately 6 months) and long-term (approximately 12 months) follow-up. We also extracted data on abstinence, reports of adverse events and any other secondary outcomes.

DATA ANALYSIS

Categorical data on alcohol misuse were dichotomized into 'improved' or 'not improved'. We counted as 'improved' outcome categories indicating clear, substantial improvement in alcohol misuse. Dichotomous and continuous outcome data were pooled using the generic inverse variance method with a random effects model. We calculated the effects of intervention results with estimates of pooled odd ratios (ORs) and 95% confidence intervals (CI) using Review Manager 5.0 (Nordic Cochrane Centre, Cochrane Collaboration). The percentage of outcome heterogeneity attributable to between-trial heterogeneity was assessed by the I 2 statistic. Participants lost to follow-up were counted as not improved. In a post hoc analysis of trials with available dichotomized data, we calculated the pooled benefit difference on improvement in alcohol misuse at first follow-up and also calculated the number needed to treat. The benefit difference (also known as the risk difference) for each trial is the percentage of improved patients in the LSD group minus the percentage of improved patients in the control group. The number needed to treat is the inverse of the pooled benefit difference and provides an estimate of the average number of patients needed to be treated with LSD rather than without LSD to achieve one additional patient with improved outcome on alcohol misuse.

DESCRIPTION OF STUDIES

We identified six eligible randomized controlled trials, including additional reports on three of the trials. Details of the search are shown in Figure, details of the included studies are shown in Tablesand. Among the excluded studies were five nonrandomized controlled trials, one quasi-randomized controlled trial (allocation by alternating assignment), two randomized controlled trials without any outcome data related to alcohol use (both measured only general psychological variables), and one randomized controlled trial without extractable outcome data on alcohol misuse (this trial reported only 'no statistically significant difference' between LSD and control groups on alcohol misuse at 12 months follow-up). The six eligible trials included a total of 536 adults; of these 325 (61%) had been randomly assigned to receive full-dose LSD and 211 (39%) to a control condition. Participants were male inpatients, except for two females and a small number of day-care patients in one of the trials. All participants were seeking treatment for 'alcoholism' as their primary problem and had been admitted to alcohol-focused treatment programs before clinical trial recruitment, see Table. Note, the DSM-I defined alcoholism as a 'well established addiction to alcohol without recognizable underlying disorder' (American Psychiatric. Among the reported exclusion criteria, trials excluded potential volunteers with 'psychiatric complications', with a 'past history of schizophrenic reaction or severe affective disorder', or overt psychosis. One trial included a subgroup of patients with schizophrenia, which we excluded from the meta-analysis. Two trials included additional non-randomized control groups or non-randomized sub-studies, which we also excluded from the meta-analysis. Single oral doses of LSD ranged from approximately 210 mcg (3 mcg/kg) to 800 mcg, with a median dose of 500 mcg, see mg), ephedrine sulphate (60 mg), or non-drug control conditions, see Table. Before the experimental drug session, all participants had equivalent treatment within each trial; however, between the trials the preparation for the experimental drug session varied from minimal to extensive, with most studies providing brief orientation, often with little or no description of the possible effects of LSD. During the experimental drug session, the most common treatment was simple observation with brief reassurance by clinic staff, only three studies included treatment groups who received clinical interviews, psychotherapy, or active guidance. In four studies, the experimental drug session took place in comfortable surroundings with music available. After the experimental drug session, only one study included multiple review sessions focused on discussing the experiences during the drug session, while the other studies provided only one brief review session or no review session at all. See Tableand the original study publications for details of the treatment protocols. Each trial used clearly defined, standardized methods to assess outcomes on alcohol misuse, although methods varied between trials, see Table. Extracted dichotomous or categorical outcomes included maintained abstinence from alcohol, alcohol use rating scales, or composite alcohol use and social adjustment rating scales; the one continuous outcome was percentage change in time abstinent from alcohol. Based on examining each categorical scale, outcome categories labelled 'slight or questionable', 'moderate', or 'fair'were counted as 'unimproved'; however, note that including these outcome categories indicating possibly trivial improvement as 'improved' does not substantially change the results.

EFFECT OF LSD ON ALCOHOL MISUSE

The pooled odds ratio on improvement in alcohol misuse between the LSD and control groups was 1.96 (95% CI, 1.36-2.84; p = 0.0003) at the first reported follow-up, see Figure. Among the five trials with dichotomized data, 185 of 315 (59%) LSD patients and 73 of 191 (38%) control patients were improved at the first reported follow-up, and the pooled benefit difference was 16% (95% CI, 8%-25%; p = 0.0003), or, equivalently, the number needed to treat is six. Including an estimated dichotomized outcome for the one trial that reported only continuous outcome data does not change the calculated pooled benefit difference or number needed to treat. There was a significant beneficial effect of LSD on alcohol misuse in the short-term and medium-term, which was not statistically significant in the long-term, see Figure. At short-term follow-up (2-3 months post-treatment), three trials reported treatment response, and the pooled odds ratio between the LSD and control groups was 1.85 (95% CI, 1.14-3.00; p = 0.01). At medium-term follow-up (6 months post-treatment), five trials reported treatment response, and the pooled odds ratio between the LSD and control groups was 1.66 (95% CI, 1.11-2.47; p = 0.01). At long-term follow-up (12 months post-treatment), four trials reported treatment response, and the pooled odds ratio between the LSD and control groups was 1.19 (95% CI, 0.74-1.90; p = 0.47). Heterogeneity of the between-trial treatment outcome was negligible in the pooled comparisons for alcohol misuse at the first reported follow-up, short-term follow-up and medium-term follow-up (I 2 = 0%, for all p ≥ 0.60 for the χ 2 test), and heterogeneity was low at long-term follow-up (I 2 = 15%, p = 0.32 for the χ 2 test).

EFFECT OF LSD ON ABSTINENCE FROM ALCOHOL

Among the three trials that reported maintained abstinence from alcohol use, there was a beneficial effect of LSD at the first reported follow-up (1-3 months post-treatment) (OR, 2.07; 95% CI, 1.26-3.42; p = 0.004) and short-term follow-up (2-3 months post-treatment) (OR, 1.80; 95% CI, 1.07-3.04; p = 0.03), which was not statistically significant at medium-term follow-up (6 months posttreatment) (OR, 1.42; 95% CI, 0.65-3.10; p = 0.38), see Figure. Heterogeneity of the between-trial treatment outcome was negligible in the pooled comparisons for abstinence at first reported follow-up and short-term follow-up (I 2 = 0%, for both p ≥ 0.38 for the χ 2 test), while heterogeneity was moderate at medium-term follow-up (I 2 = 44%, p = 0.41 for the χ 2 test).

ADVERSE EVENTS

Five trials reported a total of eight acute adverse reactions to LSD, without any lasting harmful effects. Trial investigators did not specifically mention whether there were adverse events among participants in the control conditions. During the LSD experience, two people 'acted bizarrely', one person became agitated, another person had a grand mal seizure during a period of agitation (this patient had a history of alcohol withdrawal seizures and had been abstinent from alcohol for only a few days)and two people had unspecified 'adverse reactions'. In the days after LSD, one person experienced transient 'moderate confusion'and one person had a transient 'adverse reaction'. Additionally, investigators in one trial reported mild adverse reactions to LSD in a small number of participants, including nausea, vomiting and 'moderate agitation' that was relieved by social support, relaxation, or changing the lights and music. Furthermore, in one trial, about a third of the participants who received LSD reported briefly experiencing 'any perceptual thought or feeling experience which impressed the patient with its vividness and which was clearly related to the [LSD] experience' on one or a few occasions within a year after LSD, typically after using alcohol, while participants in another trial specifically did not mention such experiences at follow-up.

OTHER OUTCOMES

Other reported trial outcomes were difficult to assess and summarize in detail, owing to large variation in the approaches between the trials and lack of data for statistical analysis. However, no trials reported any detrimental effects of LSD on psychosocial functioning or other outcomes. Of note, two of the three trials that reported data on employment found statistically significant improvements in employment in participants who received LSD compared to those assigned to control conditionsbut not.

RISK OF BIAS

Based on the definitions from the Cochrane risk of bias assessment tool, no trials were judged to have a high risk of bias related to sequence generation or allocation concealment. All trials used random assignment and attempted to conceal allocation; however, most trials did not describe methods in detail. Two trials were judged to have a high risk of bias due to inadequate blinding of patients or staff because treatment allocation was concealed only until the time of the possible LSD session; the other four trials used double-blind designs with active placebos. All trials were judged to have low or an unclear risk of bias due to blinding of outcome assessment; in four trials outcome was assessed by treatment-independent, allocation-blind interviewers, in one trial the outcome assessor was not explicitly described as allocationblindand in the remaining trial outcome assessment was collected by self-report questionnaire, confirmed by telephone interview with a close relation. Two trials were judged to have a high risk of bias due to incomplete outcome data because participants were excluded if they did not complete the intended treatment programor if they received additional doses of LSD. Retention rates were generally high, see Table, but two studies had substantial rates of missing participants at follow-up. However, authors of both of these trials expressed that missing participants had probably relapsed to problem alcohol use, consistent with the strategy of considering missing participants as unimproved. Two trials were judged to have a high risk of bias because of possible selective outcome reporting; both of these trials de-emphasized evidence for a treatment effect at short-term follow-up and gave more detailed outcome data on alcohol misuse at medium-term or late-term follow-up; note, we were not able to obtain the protocol for any of the trials. One trial was judged to have a high risk of bias due to baseline imbalance; in this trial, participants who received full-dose LSD were less likely than control participants to be divorced, and more likely to have four or less prior admissions for alcohol treatment, or to have graduated from highschool. Importantly, however, also in this trial the treatment groups were matched on baseline ratings of alcohol misuse.

SENSITIVITY ANALYSIS

For the primary outcome, improvement on alcohol misuse at first follow-up, the beneficial effect of LSD remained statistically significant (p ≤ 0.02) when excluding any two of the four larger trials, with or without excluding either or both of the two smaller trials. In a series of post hoc sensitivity analyses, excluding all trials with a high risk of bias on each domain of the Cochrane risk of bias assessment tool did not substantially change the primary outcome. In particular, the effect of LSD increased and remained significant when we excluded the two trials that used non-blinded control conditions without an active placebo. Furthermore, the primary outcome did not change when we limited analysis to the four trials reporting outcome specifically on alcohol use, rather than composite scores of alcohol use and social functioning, or when we excluded the two trials with lower retention rates. The findings on secondary outcomes of alcohol misuse at short-term and medium-term follow-up and abstinence at first and short-term follow-up are more sensitive to removing trials. In particular, none of the secondary outcomes remain statistically significant (p ≥ 0.06) after removing the trial with the most favourable effect of LSD in each respective analysis. Note that the analyses of secondary outcomes are based on only three to five trials each.

DISCUSSION

In a pooled analysis of six randomized controlled clinical trials, a single dose of LSD had a significant beneficial effect on alcohol misuse at the first reported follow-up assessment, which ranged from 1 to 12 months after discharge from each treatment program. This treatment effect from LSD on alcohol misuse was also seen at 2 to 3 months and at 6 months, but was not statistically significant at 12 months post-treatment. Among the three trials that reported total abstinence from alcohol use, there was also a significant beneficial effect of LSD at the first reported follow-up, which ranged from 1 to 3 months after discharge from each treatment program. The findings from randomized controlled trials of a sustained treatment effect of a single dose of LSD on alcohol misuse, which may fade within 12 months, are consistent with many reports of clinical experience and with data from most non-randomized controlled and open-label studies of LSD for alcoholism (reviewed in Mangini (1998)). In particular, a quasi-randomized trial reported beneficial effects of LSD on alcohol misuse at 3 months posttreatment. Additionally, four nonrandomized controlled studies reported beneficial effects of LSD on alcohol misuse at follow-up periods ranging from 6 to 18 months. However, these studies were poorly described. Also consistent with our findings, three controlled studies, excluded from this meta-analysis because the control groups were non-randomizedor because of lack of extractable data, reported no significant treatment effect of a single dose of LSD on alcohol misuse at 12 to 18 months follow-up. Importantly, in theandstudies, the comparison group did not volunteer to possibly receive LSD, probably creating selection bias (see, for example,on differences between alcoholics who volunteer and those who decline to participate in an LSD study), and in thestudy all patients were administered the tranquilizer chlorpromazine during the acute LSD effects, probably attenuating the LSD effects. Additionally, in a randomized controlled trial of a single dose of LSD for heroin addiction, daily urine test data covering the entire follow-up period showed a significantly lower rate of relapse in the LSD group compared to no drug group at 3, 6, 9 and 12 months posttreatment. Given the evidence for a beneficial effect of LSD on alcoholism, it is puzzling why this treatment approach has been largely overlooked. Based on reviewing the literature, we have four suggestions for why this happened. First, the randomized controlled trials were underpowered and most did not reach statistical significance when considered individually. Second, trial authors expected unrealistic results and tended to discount moderate or short-term effects. Third, early non-randomized clinical trials were poorly described and had methodological problems, creating the mistaken impression that well-designed studies did not exist. Finally, the complicated social and political history of LSD led to increasing difficulties in obtaining regulatory approval for clinical trials (reviewed in Mangini (1998)). The effectiveness of a single dose of LSD compares well with the effectiveness of daily naltrexone, acamprosate, or disulfiram, see Tablefor data from recent meta-analyses of these three commonly prescribed, approved medications for reducing relapse in alcohol dependence.. Pooled benefit differences calculated using a random-effects, inverse variance method. Benefit difference = % patients with beneficial outcome in experimental -% patients with beneficial outcome in control. Number needed to treat (NNT) = 1/(benefit difference). Regarding the effects of the LSD experience, investigators of one trial noted, 'It was rather common for patients to claim significant insights into their problems, to feel that they had been given a new lease on life, and to make a strong resolution to discontinue their drinking'. Investigators of another trial noted, 'It was not unusual for patients following their LSD experience to become much more self-accepting, to show greater openness and accessibility, and to adopt a more positive, optimistic view of their capacities to face future problems'. The subjective effects and neurobiological mechanisms of LSD are similar to other psychedelic substances such as mescaline (contained in peyote and other psychedelic cactus), psilocybin (magic mushrooms) and dimethyltryptamine (ayahuasca) that have been used by humans for thousands of years, and in clinical studies the effects of psychedelics are often regarded as highly valued and meaningful. Regular consumption of peyote and ayahuasca have been claimed by indigenous groups to be helpful in maintaining sobriety from alcohol and other addictive drugs. Estimates of the rate of adverse events of LSD in alcoholics and others should include data from non-randomized as well as randomized trials. Based on extensive animal research and human experience, there is now widespread recognition that LSD and similar psychedelic substances are physically safe, but acute psychiatric adverse events such as anxiety and confusion should be anticipated, and LSD administration should occur in a comfortable environment with informed participants. Several matters in this meta-analysis deserve discussion. First, trials typically lacked detailed descriptions of the populations studied, including diagnosis methods. However, all participants were recruited into the trials after admission to alcohol treatment programs with a primary diagnosis of alcoholism, making it likely that the patients are representative of typical clinical practice. Second, there were not enough trials to examine the effect of LSD dose or other treatment variables; all of the trials used a high or very high dose of LSD and employed different treatment frameworks. Third, it is possible that additional randomized controlled trials were never published or were missed by our literature search. Fourth, three trials either concealed that LSD might be usedor gave very little information about its likely effects, and in two of these trials participants were left alone in a room during much of the LSD effects; including people who might be reluctant to participate in a trial of LSD or who were unprepared for the LSD effects may have attenuated the treatment effect and increased the risk of adverse events. Fifth, blinding is a common problem to clinical trials of active interventions, including most pharmacological and behavioural treatments; most trials included in this meta-analysis attempted to minimize risks of bias related to blinding by using active placebos and/or using explicitly treatment-independent, allocationblind interviewers for outcome assessment. However, the use of low-dose LSD as an active placebo in two of the trials may have attenuated the between-group treatment effect. Finally, primary outcome measures on improvement in alcohol misuse varied between trials; however, all of the clinical trials used standardized questionnaires. Additionally, three trials also reported data on the same clearly-defined outcome: maintained abstinence from alcohol use. It is uncommon for a psychiatric drug to have a positive treatment effect for months after a single dose. Indeed, investigators of one LSD trial noted, 'most alcoholics report a waning of the initial inspiration, euphoria, and good intentions gleaned from the LSD experience when they are again confronted with the former stresses and difficulties in their lives'. As suggested by many investigators, repeated doses of LSD -for example weekly or monthly -might elicit more sustained effects on alcohol misuse than a single dose of LSD. We need further data on whether subgroups of individuals exist for whom LSD present an increased beneficial effect or risk for adverse events. Future clinical trials could combine a range of doses of LSD with current evidence-based alcohol relapse prevention treatments. As an alternative to LSD, it may be worthwhile to evaluate shorter-acting psychedelics, such as mescaline, psilocybin, or dimethyltryptamine.

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