SYSTEMATIC REVIEW published: 21 January 2020 doi: 10.3389/fpsyt.2019.00943 Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized- Controlled Clinical Trials Juan José Fuentes 1, Francina Fonseca 1,2,3, Matilde Elices 1,4, Magí Farré 5,6 and Marta Torrens 1,2,3* 1 Institut de Neuropsiquiatria i Addiccions, Hospital del Mar, Barcelona, Spain, 2 Addiction Research Group (GRAd), Neuroscience Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain, 3 Psychiatry Department, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain, 4 Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain, 5 Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol (IGTP), Badalona, Spain, 6 Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Spain Lysergic acid diethylamide (LSD) was studied from the 1950s to the 1970s to evaluate behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic Edited by: diseases and addiction. However, most of the studies were not performed under Stefan Borgwardt, contemporary standards, and it has taken several decades for a resurgence of interest in University of Basel, Switzerland LSD research and its therapeutic potential for psychiatry. The aim of this review is to identify Reviewed by: controlled and randomized clinical trials that assess the potential use of LSD in psychiatry. Oscar Prospéro-García, National Autonomous University PRISMA guidelines for systematic review were followed. A literature search of PubMed and of Mexico, Mexico Psychedelic bibliography from Multidisciplinary Association for Psychedelic Studies Jason Wallach, University of the Sciences, (MAPS) databases was performed as well as a manual search of references from United States evaluated studies. Only randomized-controlled clinical trials were included. Study quality *Correspondence: was systematically calculated by using the Cochrane Collaboration Tool for assessing risk Marta Torrens of bias. A final selection of 11 articles was made after considering inclusion and exclusion mtorrens@parcdesalutmar.cat criteria. LSD was administered to 567 patients in a dose ranging from 20 to 800 mcg. Specialty section: Despite the design heterogeneity of clinical trials, positive results were observed, thus This article was submitted to revealing the therapeutic potential of LSD to reduce psychiatric symptomatology, mainly in Psychopharmacology, a section of the journal alcoholism. The vast majority of authors describe significant and positive short-term Frontiers in Psychiatry changes in patients, despite the fact that in some studies an important homogenization Received: 28 August 2019 was observed between the LSD treatment group and control group at long-term follow-up. Accepted: 28 November 2019 Published: 21 January 2020 Multiple variables regarding LSD treatment therapeutic approach and quality of experience Citation: were revealed and related to therapeutic outcomes. LSD is revealed as a potential Fuentes JJ, Fonseca F, Elices M, therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in Farré M and Torrens M (2020) the treatment of alcoholism. Despite the difficulty of designing proper double blind clinical Therapeutic Use of LSD in Psychiatry: A Systematic Review of trials with this substance, new studies that conform to modern standards are necessary in Randomized-Controlled Clinical Trials. order to strengthen our knowledge on its use and open new doors in the future. Front. Psychiatry 10:943. doi: 10.3389/fpsyt.2019.00943 Keywords: lysergic acid diethylamide (LSD), hallucinogens, therapeutic use, psychiatric disorders, addiction Frontiers in Psychiatry | www.frontiersin.org 1 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD INTRODUCTION age of the subject) (25, 26). Recently LSD has been used in microdoses as low as 10 mcg to enhance performance (27). Since its discovery in 1938 by Swiss chemist Albert Hofmann (1), The usual mental effects of LSD are distortion of sense of time lysergic acid diethylamide (lysergide, LSD) has maintained an and identity, alteration in depth and time perception, visual unstable relationship with psychiatry. Hofmann synthesized LSD hallucinations, sense of euphoria or certainty, distorted in an effort to develop ergot derivatives with the goal of reducing perception of the size and shape of objects, movements, color, postpartum hemorrhage. Some years later, after accidentally sounds, touch and body image and delusions (28). getting into contact with a small dose, he was the first subject Concerning safety, the administration of classical in history to experience its effects (2). At the end of the 1940s, hallucinogens carries some risks. One of them is the so-called there was great interest among psychiatrist in the potential use of “bad trip” or “challenging experience”, described as an acute state LSD as a therapeutic agent (3), which was actually marketed by of anxiety, dysphoria and confusion, which can lead to Sandoz laboratories under the brand name “Delysid” in the unpredictable behavior in uncontrolled or unsupervised 1950s (4) and used in several psychiatric departments in environments (29). Another possible risk is the exacerbation of Europe and America. Even the US Army and CIA psychotic disorders or the generation of prolonged psychotic experimented with this substance as a truth serum, and LSD reactions, which could be related to the subject's previous was further investigated by the US Army as a potential predisposition (30). Although no contemporary study has incapacitating agent, however without success (5). After its reported psychosis after the administration of classical prohibition in USA in 1967, due to an increase in popularity hallucinogens, an adequate screening of previous psychotic and its association with counter-cultural movements, it has taken episodes and the patient's vulnerability is necessary for the use several decades for a resurgence of interest in its therapeutic of these substances (31). Another possible adverse effect is a potential for psychiatry (6–9). modest increase in blood pressure and heart rate; therefore, LSD is part of the pharmacological group known as “classical patients with severe cardiovascular disease should be excluded hallucinogens” or “psychedelics” (term coined by Osmond in from the administration of this agent. Other usual absolute 1957) (4), sharing its chemical structure with psilocybin and contraindications are pregnancy, epilepsy or paranoid dimethyltryptamine (DMT) as a variant of indolamine (chemical personality traits (32). The remaining adverse effects should structure similar to the neurotransmitter serotonin) (10). not limit its therapeutic use (31, 33). The term “classical hallucinogen” is a widely accepted As a recreational drug, LSD does not entail physical synonym in the literature, with a greater emphasis on the dependence as withdrawal syndrome, as do most of these alteration of the perception that these substances cause (11), substances (opioids, cocaine, cannabis and methamphetamine) although its use has been controversial as it does not specify the (34). Its frequent or long-term use can lead to tolerance, and after effect of these agents in consciousness and the self, as indicated a single dose, emotional, physical and mental stability is quickly by recent psychological and biological studies (12–14). LSD recovered (35, 36). Likewise, classical hallucinogens in general, could also be defined, from an anthropological perspective, as and LSD in particular, exhibit very low physiological toxicity, an “entheogen”, which implies that users experience (mainly in a even at very high doses, without any evidence of organic damage religious, shamanic or spiritual context) an altered state of or neuropsychological deficits (36, 37) associated with their use. consciousness: “as if the eyes had been cleansed and the person Their safety has recently led to considering LSD as one of the could see the world as new in all respects” (15). safest psychoactive recreational substances (38–42). Classical hallucinogens are psychoactive substances that are However, LSD remains one of the most stigmatized and believed to mediate their effects mainly through an agonist legally restricted agents among psychoactive substances. It is activity in the serotonin 2A receptor (5-HT2A) (16). still included in Schedule I of the United Nations classification of Experimental studies have previously shown that the use of 5- drugs, restricting its use in research and making it difficult to HT2A antagonists attenuate the main effects of these substances, potentially use it as a therapeutic tool in medicine. This both in rats (17, 18) and human subjects (19–22). classification has recently been questioned by various authors Other receptors which may contribute to the effects of these (8, 43). A few decades ago, anecdotal reports of suicidal acts in agents are the serotonin 2C and 1A receptors, as well as other recreational users were published, and intensely emphasized by effects in the dopaminergic and noradrenergic system (16). the media (44, 45). These attempts are in contrast with some Likewise, these are potent regulators of transcription factors, recent population studies, which show significant associations which could mediate a potential mechanism of action in the between the use of a single dose of classical hallucinogens and a synaptic structure with greater persistence of their effects over decrease in the likelihood of psychological distress and suicide time (23, 24). (46–48). Other recent studies also established a clear link LSD is one of the most potent classical hallucinogens between life-time use of classical hallucinogens and a lower available, with active doses between 0.5 and 2 mcg/kg (100– probability of developing mental problems, as well as a positive 150 mcg per dose). Its half-life is approximately 3 h, varying association, although non-significant, regarding several variables between 2 and 5 h, and its psychoactive effects are prolonged over related to mental health (49, 50). Nevertheless, the time (up to 12 h depending on the dose, tolerance, weight and unpredictability of subject behavior makes it necessary to Frontiers in Psychiatry | www.frontiersin.org 2 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD adequately control the environment and monitor the reaction of potentially related to therapeutic outcomes. This is with the aim each individual. of informing a discussion on the benefits and challenges of Regarding its therapeutic potential, LSD was used from the integrating contemporary classic hallucinogens research into 1950s to the 1970s to achieve behavioral and personality changes, modern clinical trial designs and providing a guide for further as well as remission of psychiatric symptoms in various disorders research involving LSD as a therapeutic agent. (30, 51). LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction (52). During that time, it was also observed that LSD together with suitable METHODS accompaniment during its administration, could reduce pain, anxiety and depression in patients with advanced cancer (53–55) Data Acquisition and Search Strategy Other studies involving larger patient samples also established its This study was conducted according to the requirements safety and promising results in patients with terminal cancer (56, established in the Preferred Reporting Items for Systematic 57). Studies in schizophrenic patients, however, reached less Review and Meta-Analysis (PRISMA) protocols (66). response to the same dose (58) and worse clinical outcomes (59) Pubmed database was searched for the following terms: compared with non-schizophrenics patients, and negative effects [“lysergic acid diethylamide” OR “LSD” OR “lysergic acid on these patients have been described, both in LSD experience diethylamide” (MeSH Terms)] OR “lysergic acid”) AND itself and later benefits (60, 61). The data indicate that the [“therapeutics”(MeSH Terms) OR “mental disorder” (MeSH responsivity of schizophrenic patients to the administration of Terms) OR “therapy” OR “psychotherapy” OR “treatment”]. In lysergic acid is less than that of normal subjects. addition, the Multidisciplinary Association for Psychedelic Prediction of individual responses to LSD depends on several Studies (MAPS) Psychedelic Bibliography (www.maps.org) was variables, some of which were already discussed at the also consulted. To ensure literature saturation, the electronic international LSD therapy conference in 1965 (52). LSD search was supplemented by a manual review of the reference reaction involves a series of complex interactions between lists from eligible publications. Two authors independently doses, “set” (thoughts, mood and expectations of the subject screened the titles and abstracts yielded by the search against prior to treatment) and “setting” (the physical and interpersonal the inclusion criteria. Full reports for all titles that appear to meet environment in which the subject undergoes treatment) (30). the inclusion criteria were obtained. Reviewers resolved Three different major approaches to LSD use as a treatment were disagreements by discussion. The search was limited to the then applied to clinical research: “psycholytic therapy”, time period compressed between 01-01-1950 and 05-05-2019, “psychedelic-chemotherapy” and “psychedelic-peak therapy” based on the results obtained in the reference search. (62). In psycholytic therapy, mainly practiced in Europe, low- Search results were examined by two authors (JJF and FF) moderate doses (25-200 mcg) of this drug were used in more reading the titles and abstracts. Each potentially relevant than one therapeutic session of psychodynamic orientation. In publication found during the search was retrieved and assessed psychedelic-chemotherapy, drug use itself was emphasized at for its use in this review after inclusion and exclusion criteria relatively high doses (200 mcg or more), with a very limited or were specified. absent psychotherapeutic approach. As for psychedelic-peak therapy (or “psychedelic therapy”), it involves administering a Data Items single and relatively high dose with the aim of triggering a Dosage, frequency and duration of the treatment, for both mystical-type experience (“peak experience” or “ego experimental and control interventions were extracted. dissolution” as synonyms). This approach should include the Patient's characteristics (including age, gender and diagnosis) proper prior preparation of the patient (set) and a comfortable and inclusion/exclusion criteria were extracted together with environment during the session (setting), as well as a discussion country, trial design, trial size, and length of follow up. For on it during subsequent follow-up sessions with the subject non-pharmacological comparators, type, frequency and duration (after-care related to LSD session) (63). Mystical experiences of the intervention were extracted, if appropriate. are referred to as those in which a sense of unity with the As studies with different diagnostic groups were included, environment is experienced achieving a vivid transcendental outcomes varied depending on the psychiatric condition under experience at an emotional, cognitive and ego-structural level, study. In any case, change scores from baseline or endpoint were after a previous and personal therapeutic preparation (64). The extracted. Side effects and overall tolerability were also studied. aim is to catalyze rapid and fundamental changes in the value system and self-image of the subject (65). Eligibility Criteria Despite the foregoing, most clinical studies involving the use Randomized controlled trials of LSD as a therapeutic tool for of LSD were published between the 1960s and 1970s, up to the psychiatry were included. This review included only randomized strict prohibition of its use in research. Obviously, most of these controlled clinical trials involving patients with a diagnosis of studies were not performed under contemporary standards. The mental illness. Experimental studies in healthy volunteers were purpose of this systematic review is to identify controlled and excluded. Trials with no control group or not randomized, randomized clinical trials that assess the potential use of LSD in animal studies, observational studies, review papers, qualitative psychiatry and identify variables controlled by the researcher as studies, case reports, opinion pieces or comments, letters or Frontiers in Psychiatry | www.frontiersin.org 3 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD editorials, conference abstract, posters and books chapters were was observed in studies on the therapeutic use of LSD excluded. Of interest were interventions using LSD, as a stand- in alcoholism. alone treatment or as an adjunctive treatment. Only studies The detailed description of all studies included and their main comparing LSD with other interventions were included. Active results can be found in Tables 1 and 2. and non-active comparators were included. Place and Publication Date of the Study Quality Assessment Among the selected clinical trials, 3 were carried out in Canada, 7 The Cochrane Collaboration risk of bias assessment tool was in the USA and 1 in Switzerland. Tables 1 and 2 show these used to determine the quality of the studies (67). This tool clinical trials ordered by date of publication. Note the important involves an assessment of six specific domains: 1) sequence 41-year interval between the study by (63); and the modern study generation, 2) allocation concealment, 3) blinding of by Gasser et al. (75). participants, 4) personnel and outcome assessors, 5) incomplete outcome data, and 6) selective outcome reporting Quality Assessment of Studies and other sources of bias. The tool was applied to each RCT A summary of risk of bias is presented in Table 3. Based on the independently by two authors. Discrepancies were resolved definitions provided by the Cochrane risk of bias assessment tool through discussion with a third author. (67), no trials were assessed to show a high risk of bias related to sequence generation, and all trials used random assignment. Moreover, all trials attempted to conceal allocation, but most of RESULTS them were judged to have unclear risk of allocation concealment (63, 65, 69, 71–73) because did not describe methods in detail. A total of 3,668 papers were identified through the search in Five trials (59, 70, 71, 73, 74) were judged to have a high risk Pubmed, and 12 additional records were found through other of bias due to blinding of patients or staff. In two of them (59, 70), sources (manual search based on review papers and meta- treatment allocation was concealed only until the time of the analysis). After the removal of duplicates and exclusion based possible LSD session, and in the other three trials (71, 73, 74) no on titles or abstracts, 43 papers were screened in more detail for attempt of blindness or to single blind was made or designed. eligibility. Subsequently, another 32 were excluded, which The rest of them (62, 65, 68, 69, 72, 75) used double-blind resulted in the 11 papers used in this systematic review. This designs with active placebo, but in “Smart et al.” blinding of one process is described in the PRISMA flowchart (Figure 1). The of the two control groups (control group without active placebo) quality of the great majority of the clinical trials found did not was not explicitly described. conform to modern standards, with a non-randomized control All trials were judged to have low or an unclear risk group or without control group itself. The highest quality of trials of bias due to independent and blind assessment. In one FIGURE 1 | PRISMA flowchart of selected abstracts and articles. Frontiers in Psychiatry | www.frontiersin.org 4 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD TABLE 1 | Details of studies: design, diagnosis and measurement. Clinical LSD dosage (n) Control (n) Blinding Target condition/ Measures (time horizon) Trial; Inclusion criteria (Country) Smart et al. 800 mcg (10) 60 mg Double-blind Alcoholics, “long history Drinking History Questionnaire, Abstinence (6 months) (68); ephedrine (not to “no of excessive and Maudsley personality inventory, Haigh-Butler Q, Rorschach, Wechsler (Canada) sulfate (10) drug” group) uncontrolled drinking” Adult Intellingence Scale No drug (10) Independent (Male and assessors female) Hollister et 600 mcg (36) 60 mg d- Double blind Alcoholic Veterans, “acute Drinking Behaviour Scale (2, 6 months) al. (69); amphetamine Independent alcoholic episode within 2 (USA) (36) assessors weeks of admission; all problem drinkers” (Male) Ludwig et 3 mcg/kg No drug (44) Double blind Alcoholics, “up to 4 Behaviour Rating Scale (6, 12 months) al. (70); 210 mcg mean until LSD previous admissions for Abstinence (1, 3 months) (USA) (132) session treatment of California Psychological Inventory Independent alcoholism” (Male) assessors Johnson 300 mcg initial dose 3.75 g Sodium Single blind Alcoholics in outpatient Abstinence, Drinking practice/consequences (12 months) Differential (71); + 264 mcg mean Amytal + 30 Independent treatment (Male and Personality Inventory, Quick test, Hidden Figures test (Canada) (48) mg assessors female) Methedrine (22) / No drug (25) Bowen et al. 500 mcg (22) 25 mcg LSD Double-blind Alcoholic Veterans under Adjustment scale (12 months) (72); (USA) (22) Independent voluntary treatment for No drug (15) assessors alcoholism (Male) not mentioned Denson and 50-300 mcg (163 No drug (26) No attempt Alcoholic and neurotic Eysenck Personality Inventory, IPAT Objective Anxiety Scale, Sydiaha mean) in of blind patients (Male and Minnesota Multiphasic Personality Inventory, Lorr Multi-dimensional (73); subsequent dosage Independent female) Rating Scale, Background Questionnaire for Non-Schizophrenic (Canada) + 5 mg assessors Patients (BFQNSP) (6, 12 months) dextroamphetamine prior to LSD (25) Pahnke et 450 mcg (73) 50 mcg LSD Double-blind Alcoholics under Drinking Behaviour Scale, Global Adjustment (6 months) al. (62); (44) Independent voluntary treatment (USA) assessors for alcoholism (Male) Tomsovic 500 mcg (32) *non- Usual Double-blind Alcoholics with 12 years Drinking Adjustment Scale (3, 6, 12 months) Blewett and and schizophrenics treatment (45) until LSD average of problem Chwelos Scales Edwards *non- sesión drinking (Male) (59); (USA) schizophrenics Self-report assessment Savage and 300-450 mcg (37) Usual No attempt Narcotic addicts in Global adjustment rating scale, Abstinence (6, 12 months) McCabe treatment of blind Maryland (74); (USA) (37) Independent correctional institutions assessors (Male) Savage et 350 mcg (31) 50 mcg LSD Double-blind Patients with Psychiatric evaluation profile, Katz Adjustment Scale, Global al. (65); (32) Independent psychoneurotic diagnosis, adjustment scale (6 months) (USA) Usual assessors “depressed and anxious” Block Design, Digit Span, Digit Symbol, Progressive Matrices, treatment (33) (Male and female) Embedded Figures, Benton Visual Retention Test, Minnesota Multiphasic Personality Inventory, Eysenck Personality Inventory, Personal Orientation Inventory Gasser 200 mcg (8) 20 mcg LSD Double blind Anxiety associated with State-Trait Anxiety Inventory, European Cancer Quality of Life et al. (75); (3) Independent life- threatening deseases Questionnaire, SCL-90-R, Hospital Anxiety and Depression Scale, (1 (Switzerland) assessors patients (Male week, 2, 12 months) and female) trial (72) the outcome assessor was not explicitly described them (62, 65, 68–71, 74, 75) had independent and allocation- as allocation-blind and in another one (59) the assessment blind assessors. was collected by self-report questionnaire, confirmed by Two trials (62, 72) were judged to have a high risk of bias due telephone interview with a close relative or friend. The rest of to incomplete outcome data, because participants were excluded Frontiers in Psychiatry | www.frontiersin.org 5 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD TABLE 2 | Details of studies: set, setting and main findings. Clinical Treatment program Pre-LSD session LSD session Setting Main findings Trial; (Country) Smart et al. Therapeutic community Brief orientation 3h interview and no full- Waist belt to bed Improvement in total abstinence/ (68); (group and individual time observation No music/visual longest period of abstinence for all (Canada) therapy) stimuli groups No significant differences between groups Hollister Short therapy on alcohol Brief orientation Brief supportive reassurance Music stimuli Significant improvement for LSD et al. (69); withdrawal (7 days) (focus on the self) Visual stimuli group (2 months) in Drinking (USA) (comfortable Behavior Scale scores furniture) No significant differences at 6 months Ludwig et al. Intensive milieu therapy (30 Brief orientation 3h of therapy (psychedelic Not described Significant improvement in pre-post (70); (USA) days) Group therapy therapy (44) hypnodelic treatment evaluation for all groups therapy (44), or silent Significant improvement in BRS for all observation (44)) groups in every period No significant differences between groups Johnson Milieu therapy Brief orientation 4h of therapy (active Waist belt to bed Significant improvement across all (71); (24h hospitalization) interviewing to focus No music/visual groups on most drinking indices (Canada) particularly on current stimuli No significant differences between problems) groups Bowen et al. Group therapy (60 days) Group lectures on possible Supportive reassurance Music stimuli No significant differences between (72); (USA) drug effects (focused particularly on non- Visual stimuli groups at 1 year after LSD session. verbal introspection) (flowers, pictures, “tasteful furniture”, mirror) Denson and Not described (24 h) Not reported Not described Not described Positive results in general health Sydiaha (73); (general hospital (BFQNSP) for LSD group (Canada) setting) No other significant differences Pahnke et al. Intensive individual therapy Extensive individual Therapy for eliciting a “peak Music stimuli Significant improvement in Global (62); (49 days) preparation for treatment or transcendental experience” Visual stimuli Adjustment and Drinking Behavior for (Canada) (flowers, pictures, LSD group “comfortable living Significant relationship between room”) better Global Adjustment and peak-experiences Tomsovic Group therapy (90 days) Lectures and reviews of Supportive reassurance (not Music stimuli Improvement in abstinence for LSD and treatment intentions focused on extensive talking) Visual stimuli group (significant for control sub- Edwards (flowers, colorful group 1) (59); drapes, pictures, No differences between lysergide (Canada) hand mirror, scenic experience measures view) and benefit Savage and Brief residential psychedelic Preparatory psychotherapy Psychedelic therapy Not described Significant improvement in total McCabe psychotherapy (4-6 weeks) (24 h) focused on positive abstinence for LSD group Not (74); (USA) in outpatient clinic program patient-therapist significant differences in global relationship adjustment scale Savage et al. Brief hospitalization, Preparation based on the Psychedelic therapy Not described Significant improvement in majority of (65); (USA) psychedelic psychotherapy psychedelic model of pre-post-treatment measures for (4-8 weeks) psychotherapy (3-5 weeks) LSD group Not significant differences between groups at 6 months Gasser et al. Continuous Two preparatory Psychedelic therapy Music stimuli Significant improvement in State-Trait (75); psychotherapeutic process psychotherapy sessions Visual stimuli not Anxiety Inventory (STAI) scores for (Switzerland) lasting several months “Set”, based on the described “Safe, LSD group at 2 months (outpatient program) psychedelic model of quiet and pleasant Positive trends in reductions in trait psychotherapy room” anxiety (STAI) at 2 months STAI reductions sustained for 12 months if they did not complete the intended treatment program (72) or only representative at 12 and 18 months, not at 6 months. In the if received additional doses of LSD (62). other three trials (59, 69, 73), authors considered missing Four studies (59, 65, 69, 73) had substantial rates of missing participants as unimproved. participants at follow-up. However, retention rates were Three trials (69, 70, 73) were judged to have a high risk of bias generally high, and data missed in one of the trials (63) was because of possible selective outcome reporting, presenting lack Frontiers in Psychiatry | www.frontiersin.org 6 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD TABLE 3 | Quality assessment of all included studies based on the risk of bias. Clinical trial Random Allocation con- Blinding for partici- Blinding of Incomplete outcome Selective Other sequence cealment pants and outcome data reporting sources generation personnel assessment of bias Smart et al. (68) Low Low Unclear Low Low Low Low Hollister et al. (69) Low Unclear Low Low Low High Low Ludwig et al. (70) Low Unclear High Low Low High Low Hollister et al. (69) Low Unclear High Low Unclear Unclear High Bowen et al. (72) Low Low Low Unclear High Low Low Johnson (71) Low Unclear High Unclear Unclear High Unclear Pahnke et al. (62) Low Unclear Low Low High Low High Tomsovic and Low Low High Unclear Low Low Low Edwards (59) Savage and McCabe Low Low High Low Low Low High (74) Savage et al. (70) Low Unclear Low Low Low Low High Gasser et al. (75) Low Low Low Low Low Low Unclear of clarity at short-term follow-up clinical outcome and giving under study (life-threatening diseases). Two of the studies (67, more detailed data at medium or late-term follow-up. Another 75) also excluded those patients with a history of severe affective trial (71) was judged to have an unclear risk because some disorder. Most clinical trials (65, 68–71, 74, 75) discarded those measures were not strictly reported. patients with active psychosis for the study, but some of them Finally, four trials (62, 65, 71, 74) were judged to have a high (65, 68, 70, 74) did not rule out patients with a history of risk of other sources of bias. In one of them (62), due to baseline psychosis in the past. It is noteworthy that in the study of imbalance (full-dose LSD participants were less likely to be Tomsovic and Edwards (59), LSD was administered to a divorced and more likely to have prior admissions for alcohol subgroup of 12 patients diagnosed with schizophrenia treatment), other trial (65) due to treatment time (full-dose LSD (withdrawn from Table 1, due to modern exclusion criteria), participants were more likely to have more psychotherapy hours) to which they applied a separate statistical analysis that showed and the rest of them (71, 74) due to a shorter time of better results for the subgroup of non- schizophrenics who had hospitalization [from one day (71) to a few days (74)] for the received a single LSD dose. LSD treatment group and not the control group. Two last trials Two cases of serious adverse effects were reported. In one of (73, 75) presented unclear risk of bias due to uneven concurrent the studies (69), authors described a tonic–clonic seizure, use of other pharmacological treatments during study without subsequent complications, in a patient with a previous between participants. history of seizures in a context of abstinent clinical symptoms. In another one (74), a case of prolonged psychosis was reported in a LSD Dosage and Method 21-year-old patient with a previous history of recurrent LSD was administered to 567 patients in a dose range from 20 to psychotic episodes in the context of hospitalization during 800 mcg. The oral route was significantly the most used one, adolescence. This patient received psychotherapy and while one study (71) used the intravenous route and another one antipsychotic medication, recovering without later (68) did not describe the route used. A single dose of LSD was the complications. No other serious adverse effects were described procedure of choice for most selected clinical trials. Other studies in the remaining 565 subjects. (71, 73) opted for a dosage-escalation approach, and some (73, 75) offered the possibility of repeating LSD doses at 2–3 Control Group and Active Placebo week intervals. Five studies within our review (68, 70–73) designed a control The concomitant use in some of the studies of other group for which no drug was administered, and three others pharmacological principles, such as dextroamphetamine (73) (59, 65, 76) had a control group in which the usual treatment prior to the dose of LSD, or chlorpromazine or promazine (71, was applied to patients during hospitalization. In “Savage et al.” 73) after LSD treatment is worth mentioning. Since the the control group had the added benefit of participating therapeutic potential of LSD may be underestimated or in one hour and a half group therapy sessions three times a masked by such treatments. week, which were defined as eclectic (focused on the solution of specific problems through group interaction). Most studies Safety and Adverse Effects (see Table 1) had a control group in which active placebo Most studies describe exclusion criteria for patients to be treated was used, and four of them (62, 65, 72, 75) used LSD itself at a with LSD. Severe organic disease (mainly at neurological and lower dose. The difficulty in maintaining patient and therapist cardiovascular levels) was a common exclusion criteria (63, uncertainty, even with active placebo, is underlined by authors. 66–69). With ephedrine sulfate (68), in 19 of 20 cases the therapist “Gasser et al.” do not rule out those patients with correctly guessed which type of drug was administered to the cardiovascular disease, due to the idiosyncrasy of subjects patient, and 20 mcg of LSD (75) was considered too low a dose Frontiers in Psychiatry | www.frontiersin.org 7 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD to avoid unmasking the control group, both for patient “silent observation”, to study possible differences in their and therapist. therapeutic potential. The author described “an active, dynamically oriented psychotherapy, with the primary focus Treatment Program and “Set” on major problem areas”, which contrast with the description There was great heterogeneity among the clinical trials chosen of “psychedelic therapy” considered above. The most common for this review in terms of patient preparation and the general approach among these studies (62, 65, 74, 75) was to use therapeutic program to which LSD treatment was added. Table 2 psychedelic therapy, defined as 12-14 h after one relatively shows the type of treatment program used in each study, ranging high LSD dose (200-500 mcg), during which a nurse and a from 24 h to 90 days from the start of treatment to patient therapist provide constant attention (65) with the aim of the discharge. The treatment program between different studies also subject achieving a “peak or transcendental experience” (62). differed in structure, varying between highly structured intensive programs (70) (with five weekly meetings, seminars, group and Setting individual therapy, occupational therapy and rehabilitation Regarding the physical (sensory stimuli) and interpersonal program) and the absence (73) of a specific program. environment of subjects during the LSD treatment (see Table Preparation of the subject for LSD treatment ranged from 2), in five trials (59, 62, 69, 72, 75), musical stimulation during very brief orientation (68–71 to extensive preparation (62, 65, 74, the session was offered. Descriptions of environment were varied, 75) with the aim of promoting the therapeutic experience. finding “comfortable or tastefull furniture” (62, 69, 72) or Preparation time (pre-LSD session, Table 2), ranged from a “flowers and pictures” (59, 62) as examples. In four of the few hours to 5 weeks. The only information provided to subjects studies (65, 70, 73, 74), the physical environment was not in some cases was the great variation in the individual response described. Likewise, in two studies (66, 69), the use of waist of the drug (68), or very brief data on the nature of response (69), belt to bed method was mentioned to prevent subjects from with no intention to perform previous therapy. One of these leaving their position. Regarding the interpersonal environment, authors (70) points out that the previous preparation of patients the fact that in the earliest study (68) subjects were to LSD administration was possibly insufficient for achieving unaccompanied for an indefinite period of time during the therapeutic objectives. treatment is noteworthy. Despite heterogeneity, there was a trend among most modern trials within our review to emphasize the importance of the “set” Efficacy of the subjects to be studied, devoting more time and providing The efficacy of the intervention with LSD was presented by the them with a structure. In the earliest study meeting these main diagnosis where the substance was administered. characteristics (72), patients were previously informed of the nature of the drug, stating whether they would receive a small or Alcohol Use Disorder a large dose. Within the LSD group of treatment (full-dose or Most clinical trials in this review (59, 62, 68–73) evaluated the active placebo), approximately half of the patients performed the therapeutic potential of LSD in the treatment of alcohol use session during the first 3 weeks, with the remaining subjects disorder. The main outcomes of these studies and their main receiving LSD treatment during the last 3 weeks. There was a statistical analysis were summarized below, by order non-significant trend towards better results among those who of publication. received treatment during the last 3 weeks, which was In the study by “Smart et al.” there was a substantial highlighted by the authors as a positive association between improvement in abstinence (total abstinence and longest “set” and therapeutic outcomes. period of abstinence) in all three groups [LSD group (800 mcg), active placebo group (60 mg ephedrine sulfate) and “no Therapeutic Approach and “Setting” drug” group], but no significant differences were found between Therapeutic Approach them (ANOVA, p > 0.05). There were no significant differences Again, great heterogeneity was observed among studies between groups either in the Drinking History Questionnaire regarding the therapeutic approach during the treatment with nor in number of voluntary contacts with the clinic afterwards. LSD. Two studies (68, 71) applied an approach based on active The second study (69) showed a significant improvement (t- and directed interviews focused on problems derived from test, p < 0.01) in the 2-month follow-up in the LSD group with alcohol dependence. In one of these trials (68), these interviews respect to dextroamphetamine, based on the Drinking Behavior were described as an attempt to discover alternatives to alcohol Scale score. No significant differences were found at 6 months use, and to define patient attitudes regarding the transfer with the follow-up, except for two specific symptoms of this scale (related therapist, the act of moving towards drinking, parental to work performance), in which LSD was shown to be superior to relationships, suicidal ideation or sexual behavior. dextroamphetamine (chi-square, p < 0.05). In three of the studies (59, 69, 72), no psychotherapy attempts Conversely, in the study by “Ludwig et al.”, results showed a were made during the treatment session. In one of them (69), an significant improvement at two weeks of treatment (t-test for effort was made to maintain a supportive environment, which correlated means, p < 0.05) for all four groups (three different included non-verbal communication. In another study (70), approaches in LSD group (Hypnodelic therapy group, three different approaches were used during the LSD session, Psychedelic therapy group and Silent Observation group) and defined as “psychedelic therapy”, “hypnodelic therapy” and control group). However, no significant differences were found Frontiers in Psychiatry | www.frontiersin.org 8 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD between them (ANCOVA, no alpha value reported). In the same improvement (mainly focused on symptomatology and self- way, a significant improvement (t-test for correlated means, actualization) was significantly greater as an average for the p < 0.05) was observed in the Behavior Rating Scale values for LSD treatment group compared to the “usual treatment” control each period (6, 12 months) in all groups, without finding group, as well as for some measurements used for the active significant differences (ANCOVA, no alpha value reported) placebo (LSD) control group compared to the “usual treatment” between them. control group. The LSD treatment group showed superiority In the next study (71), a significant improvement was found (chi-square, p < 0.05) with respect to both control groups in a in terms of abstinence (ANOVA, p < 0.01), drinking behavior sub-scale of the Minnesota Multiphasic Personality Inventory (ANOVA, p < 0.01) and employment rate (ANOVA, p < 0.05) (F scale, focused on general psychopathology). Regarding after treatment in all groups (LSD treatment group, active subsequent evaluation (6 months), all groups showed placebo (Sodium Amytal and Methedrine) control group, and significant differences in a large number of variables, but in “no drug” control group). However, no significant differences this case the results of the statistical analysis failed to reach the (chi-square, p > 0.05) were found between them. In the same defined significance level (ANCOVA, p > 0.05) between direction, in the study by “Bowen et al.”, no significant the groups. differences were found between groups (chi-square, p > 0.05). In the study by “Denson et al.”, no significant differences (chi- square, p > 0.05) were observed between groups (LSD group and Heroin Use Disorder control group) at follow-up, except in the Background and Only one study (74) met the inclusion criteria in our review. Follow-up Questionnaire for Non-Schizophrenic Patients Significant differences were observed (chi square, p < 0.05) in (BFQNSP) data, in which the LSD treatment group showed total abstinence rates in favor of the LSD treatment group at better results in terms of general health (chi-square, p < 0.05). 12 months. A trend, not statistically significant (chi-square, p < In the next study (62), significant improvements were 0.02), was observed in favor of the LSD treatment group in observed in Global Adjustment (ANCOVA, p < 0.05) and Global Adjustment Rating Scale. Drinking Behavior (ANCOVA, p < 0.025) for the LSD treatment group compared to the control group at 6 months. Anxiety Associated With Life-Threatening Diseases Finally, in the last trial (59), a higher percentage of abstinence A modern study (75) assessed anxiety associated with chronic was observed among the LSD treatment group compared to inflammatory disease, chronic motor disease and cancer. All the remaining groups (control group 1: no treatment, only patients had a score of 40 and above in the State-Trait Anxiety ongoing follow-up evaluation; control group 2: usual Inventory (STAI). A positive tendency in trait anxiety reduction treatment, “Regular Alcoholic Rehabilitation Program”) at (ANOVA, p = 0.033) in the STAI was observed at two months three months, maintaining this superiority at one year in post ingestion, as well as a significant reduction (ANOVA, p = several grades. A statistical difference (chi-square p < 0.01) was 0.021) in state anxiety in the STAI. Reduction trends in the STAI observed between the LSD group and the control group 1, but were maintained after 12 months in the LSD group, however authors emphasized that the control group 1 was not with no significant difference (ANOVA, p > 0.05). representative of the best results observed in the control group 2. In summary, it was observed a significant effect of LSD in four studies performed. However, this effect was related to quality of Aftercare Related to Experimental (LSD) life and general health in some of the studies, with no clear Sessions improvements in alcohol abstinence. In some studies (69, 73) patients could be discharged after 24 h or in less time (73) if they were able to be assisted by friends or relatives. Other studies did not specify which patients Neurotic Symptoms (Anxiety, Depression, and maintained subsequent therapy (70), or did not examine Psychosomatic Diseases) session results unless patients actively requested it (68). In one Two trials (65, 73) evaluated LSD as a treatment of neurotic of these studies (70), a possibly inadequate follow-up of subjects symptoms. This diagnosis was referred to as depressive neurosis, was mentioned, without giving them the opportunity to receive obsessive-compulsive reaction, phobic reaction, anxiety state, further treatment. hysteria, psychoneurosis with somatic symptoms, character One of the authors (72) suggested that short-term changes disorder and sexual neurosis. The presence of all that occurred frequently in subjects' personality could be symptomatology was not required, and a subset of neurotic integrated and applied to their daily-life insight with greater symptoms was adequate. “Denson et al.” found significant support and additional help after hospital discharge. In one study differences (chi-square, p < 0.05) in Questionnaire data (65), patients remained hospitalized at least one week after the (BFQNSP), in which the LSD treatment group showed better LSD session, being visited by their therapists repeatedly. In this results in terms of general health at 6 and 12 months. Also, in the study, a second session with LSD was offered to those patients study by “Savage et al.”, a significant improvement (chi-square, who were considered suitable for second exposure p < 0.05) was observed at 6-8 weeks in most of measurements (approximately 25% out of both LSD groups (full-dose and used for all three groups (LSD treatment group, active placebo active placebo) received an equal second dose). In another (LSD) control group and “usual treatment” control group). This study (75), a second dose was also offered to subjects in the Frontiers in Psychiatry | www.frontiersin.org 9 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD active placebo group at months of follow-up (open- label cross- maintained at 6–12 months after treatment. Moreover, in a over design). Finally, in one of trials (70), half of each group was follow-up study (78) beneficial changes were found at one year also treated with disulfiram (daily dose of 500 mg) after hospital of follow-up for hallucinogen therapy compared with discharge. Patients were strongly encouraged to take a fixed, conventional psychotherapy in adolescent behavior disorders. prescribed dosage every day, instructed on the dangers of Numerous studies in healthy volunteers have been carried out imbibing alcohol while on disulfiram, and started on the drug within the last decade, and some of them have showed positive four days prior to hospital discharge. They were given a six- effects more than a year after a LSD or psilocybin single dose month supply of disulfiram and instructed to take one 500 mg (79, 80). tablet per day. Baseline to post-treatment t-tests revealed The results of this review could conclude that alcohol use significant improvement (t-test for correlated means, p < 0.05) disorder patients may benefit from LSD treatment. Other studies in Behavior Rating Scale for every group at every period, while with a lower quality control group (patients did not receive a two-way analysis of covariance revealed no significant differences treatment comparable to the treatment group) also found (ANCOVA, no alpha value reported) between groups that significant differences in favor of LSD treatment in alcoholism received disulfiram and those that did not after hospital (60, 81). Likewise, according to a retrospective analysis of studies discharge, for any of the measurements studied. published in the late 1960s, LSD is a potential therapeutic agent for the treatment of chronic alcoholism (82). A recent meta- analysis (83) of six of the clinical trials chosen for this review Variables in Therapeutic Response showed the superiority of LSD over placebo in the treatment of Some studies (59, 62, 74) described efforts to predict therapeutic alcoholism with an odds ratio (OR) of 1.96 (95% confidence outcomes in relation to an acute hallucinogen experience. In one interval 1.36–2.84 OR, p = 0.0003). This study found that a LSD of them (59), it was emphasized that the methodology used did single dose was comparable in terms of effectiveness with the not manage to measure crucial aspects of the experience that daily intake of naltrexone, acamprosate, or disulfiram in foresee subsequent benefits. In two others, a significant link was alcoholism treatment (84–86). Other studies in our review also observed between values in the Global Adjustment Scale (62) and found promising results regarding LSD use for the treatment of the probability of optimal adjustment in the community (74) in heroin use disorder, anxiety, depression, psychosomatic illnesses, relation to the achievement of a “mystical or peak experience” and anxiety in relation to life-threatening diseases. Regarding the during the LSD session. One of these authors (62) identified the latter, several authors (56, 57) emphasize the difficulty of LSD dose as a better predictor than the type of experience in his designing placebo-controlled and double-blind trials, due to study; although he also pointed out that there was a close link ethical reasons and the nature of the psychoactive intervention. between “peak-experiences” and a higher drug dose. Regarding the disparity between some results in our review, On the other hand, in two studies (59, 74) it was observed that and as noted by Pahnke et al. (62) “it is essential to keep in mind patients who seemed to benefit from the treatment with LSD did the differences in procedure among the various methods, not so optimally with more probability. A greater likelihood of only because of different kinds of experiences being facilitated, complete abstinence from alcohol (59) or optimal adjustment but also because of conflicting results that can be correlated with in the community (74) was observed after the LSD treatment. the method used”. LSD invariably involves a complex interaction Finally, one of the authors (65) highlighted that male patients between drug dosage, set and setting. This link is also objectified showed a clear improvement in Global Adjustment with as full in different studies, showing the significant relationship between dose (350 mcg) of LSD at six months post ingestion, while in the therapeutic efficacy of hallucinogens and an adequate set, females, a greater improvement was observed with low doses of setting and integration of later experience (62, 87–90). This could 50 mcg (ANCOVA, p < 0.1). explain some differences between the results of these reviewed trials, in which there was a great variation between the approach of “Smart et al.”, (Psychedelic–chemotherapy: no attempt of DISCUSSION psychotherapy, waist belt) and that of “Savage et al.” (psychedelic therapy: set, setting and aftercare related to the Despite design heterogeneity among the clinical trials in this LSD session). Some authors (91) argued that the accepted review, some positive results were observed, revealing the methods proven to generate some beneficial experience with therapeutic potential of LSD in the reduction of psychiatric LSD are far from those used by Smart at the 1960s. Therefore, the symptomatology. The vast majority of authors described inherent difficulty in conducting a double blind controlled important positive short-term changes in patients, although in clinical trials with LSD should be mentioned. In 1964, some studies (59, 65, 69) an important homogenization was Whitaker (92) stated his opposition to the design of a control observed between the LSD treatment group and the control group with this type of substance, due to the promising responses group at long-term follow-up. Some previous studies of lower of first patients as opposed to the control group. Due to this quality (77) also exemplified a clear improvement in short-term difficulty, widely discussed at the time, many studies previous to adjustment, with a later tendency to balance results with the that carried out by “Smart et al.”, did not apply adequate control group. However, this is in contrast with the results shown measures or assessments, without a control group or properly by some authors (62, 74, 75), in which therapeutic changes were designed statistical analysis. In this regard, Tomsovic and Frontiers in Psychiatry | www.frontiersin.org 10 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD Edwards (59) mentioned “the complexities and difficulties of during the acute effects of hallucinogens have been associated achieving control over the placebo effect of a drug that has with the aforementioned subjective effects “ego dissolution” and spectacular mind-altering properties, and where research is “mystical-type”, and could be related to the wide therapeutic contaminated by expectations of benefit”. value of these substances (101, 102, 105, 110). Also, modern clinical trials are currently facing a series of Likewise, multiple modern clinical trials involving other problems, which could be summarized as follows (93). Firstly, hallucinogens have been carried out in the last decade, mainly subjective and objective changes experienced with LSD and the rest with psilocybin. Hopeful results have been found for the of hallucinogens, apparent for both the subject and observer, make treatment of alcohol (111) or tobacco (112) addiction, performing double-blind tests virtually impossible. Likewise, anxiety in relation to advanced cancer (113) or obsessive- adequate placebo control becomes extremely difficult due to the compulsive disorder (114). Moderate doses of psilocybin (200 absence of such changes in the control group. Strict control of the µg/kg) have been used in some modern studies, either with dose variables related to the therapeutic benefits of LSD is also necessary. escalation (114) or the same dose in various sessions (113), Finally, research with these substances must overcome a series of something reminiscent of the psycholithic therapy used in strict ethical committees and restrictions at the legal level. Europe in the past century. Some possible reasons for the When attempting to solve difficulties in terms of blinding and greater use of psilocybin over LSD in modern trials were the adequate placebo control, a valid approach is an active placebo, shorter duration of one effects of the former (thus avoiding using LSD at lower doses (94), an approach already suggested hospitalization) or the greater stigma that prevailed regarding within some of clinical trials in our review (62, 65). This the latter (making it difficult to get economic funds and the methodology, despite possibly minimizing the effects of LSD approval by ethical committees). Beyond psychiatry, the when compared to its sole administration, is based on results by therapeutic potential of LSD in other medicine fields has numerous researchers who have observed the link between dose recently become evident, as in the treatment of cluster and quality and intensity of the hallucinogen response (95–98). headaches in neurology (115). Dosage and form of administration, as well as the context in As it has been previously pointed out, the homogenization of which it is carried out, can be strictly controlled within a hospital the therapeutic approach is strictly necessary, and training setting. The possible effects of microdoses of LSD must be takin programs related to research and psychotherapy with into account, possibly limiting its use. hallucinogens have recently been developed (116). Also, there Despite the known unpredictability of hallucinogens, great are modern guidelines available for the correct use of efforts have been made in recent years to know which variables hallucinogens in clinical research (31). Therefore, the reborn are associated with the therapeutic value of these substances, interest of the therapeutic potential of hallucinogens in modern finding mystical-type experiences as one of the objectives to be clinical trials is evident, something proven by the remarkable achieved (97, 99, 100). Results of recent investigations show that increase in the number of studies carried out with these mystical-type experiences are associated with positive long-term substances over the last decade (117). changes after a dose of hallucinogens (33, 79, 99–102). The The present review has limitations. Firstly, only articles musical stimuli variable has also been observed as a predictor of written in English were selected; this could imply that articles mystical-type experiences and positive therapy outcomes (103). in other languages were excluded despite the fact that these As noted by Gasser (76), designing qualitative studies, might have provided valuable information. Furthermore, as not only based on pathology-oriented measurements, mentioned above, most studies were carried out during the is also important to detect variables related to other past century. Moreover and as previously discussed, there was psychopathological symptoms that can potentially be considerable heterogeneity in their design. Also, differences improved by LSD use (e.g. equanimity, self- assurance and regarding patient populations, features, and diagnostic mental strength). Currently, there are validated scales available methods were noticed. Therefore, due to the lack of studies to measure the quality of the hallucinogen experience, such as and the features exhibited by selected research, this review can the Mystical Experience Questionnaire (MEQ-30) (104) and contribute limited evidence on the topic of interest. the Ego-Dissolution Inventory (EDI) (96). The apparently This study comes with its own set of strengths. On the one unpredictable nature of these experiences makes studying hand, to our knowledge this is the first systematic review of them in empirical research equally difficult and necessary randomized-controlled trials to assess the therapeutic potential (14, 104, 105). of LSD in psychiatry. On the other, a strict selection of studies Moreover, numerous recent studies with LSD regarding was carried out, considering inclusion and exclusion criteria as changes in neural networks have been carried out. Modularity well as confounding factors. With regards to this and in spite of and integration networks (as observed in resting- state functional the heterogeneity mentioned above, the important therapeutic connectivity) have been shown to decrease due to effects of LSD value of LSD is revealed and it is observed to be related to (106, 107). Patterns compared to normal waking consciousness variables controlled by the researcher, such as: set, setting and have been demonstrated with LSD (108), and a correlation aftercare related to the LSD session. Another positive aspect of between subjective reports of “ego dissolution” during LSD and this review is that our results highlight the need for randomized- an increment of the overall connectivity and global integration of controlled clinical trials with standardized methods to accurately the brain was found (109). These changes at the cerebral level assess the quality of an acute hallucinogen experience. Finally, Frontiers in Psychiatry | www.frontiersin.org 11 January 2020 | Volume 10 | Article 943 Fuentes et al. Therapeutic Use of LSD this review could serve as a guide for further research involving the selected articles. JF, FF, ME, MF, and MT wrote and reviewed LSD as a therapeutic agent. the manuscript. CONCLUSIONS In conclusion, and despite some controversial results mentioned FUNDING above, LSD is revealed as a potential therapeutic agent in This work was supported in part by grants from Instituto de psychiatry; the evidence to date is strongest for the use of LSD Salud Carlos III (ISCIII, FIS-FEDER, FIS PI11/01961, FISPI17/ in the treatment of alcoholism. Despite the difficulty of designing 01962), ISCIII-Red de Trastornos Adictivos (RTA RD16/0017/ double-blind clinical trials with this substance, new studies 0003 and RD16/0017/0010) and The European Commission performed under modern standards are necessary in order to (HOME/2014/JDRU/AG/DRUG/7082, Predicting Risk of strengthen our knowledge, help erase the stigma that still prevails Emerging drugs with in silico and Clinical Toxicology around these substances and open new doors in the future. (PREDICT)). Also, Suport Grups de Recerca AGAUR-Gencat (2017 SGR 316 and 2017 SGR 530); Acció instrumental AUTHOR CONTRIBUTIONS d'Intensificació de Professionals de la Salut - Facultatius especialistes (PERIS: SLT006/17/00014); ME has a Juan de la JF, FF, ME, MF, and MT designed the review. JF and FF reviewed Cierva research contract awarded by the ISCIII (FJCI- the abstracts and the papers. JF and ME obtained the data from 2017-31738). REFERENCES 17. Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci (1984) 35:2505–1. 1. Stoll A, Hofmann A. Partialsynthese von Alkaloiden vom Typus des 18. Glennon RA, Young R, Rosecrans JA. Antagonism of the effects of the Ergobasins. (6. Mitteilung über Mutterkornalkaloide). Helv Chim Acta hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 (1943) 26:944–5. doi: 10.1002/hlca.19430260326 antagonists. Eur J Pharmacol (1983) 91:189–6. 2. Hofmann A, Feilding A, eds. 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This is an open- sustained symptom reduction following psilocybin treatment for anxiety and access article distributed under the terms of the Creative Commons Attribution depression in patients with life-threatening cancer: a randomized controlled License (CC BY). The use, distribution or reproduction in other forums is permitted, trial. J Psychopharmacol (2016) 30:1165–0. provided the original author(s) and the copyright owner(s) are credited and that the 103. Kaelen M, Giribaldi B, Raine J, Evans L, Timmerman C, Rodriguez N, et al. original publication in this journal is cited, in accordance with accepted academic The hidden therapist: evidence for a central role of music in psychedelic practice. No use, distribution or reproduction is permitted which does not comply with therapy. Psychopharmacol (2018) 235:505–9. these terms. Frontiers in Psychiatry | www.frontiersin.org 14 January 2020 | Volume 10 | Article 943