Anxiety disorders are a major public health burden with limited treatment options.

We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness.

This study was an a priori-planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 μg) or placebo per period. Participants (n = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger's State-Trait Anxiety Inventory–Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO-Five-Factor Inventory.

Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = −21.6 (−32.7, −10.4), d = 1.04, P < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and −16.5 (−26.2, −6.8), d = 1.02, P < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of −8.1 (−13.2, −3.1), d = 0.71, P < 0.01, and −8.9 (−12.9, −4.9), d = 1.21, P < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased (P < 0.0001) and trait extraversion increased (P < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience.

Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.

The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans.

Healthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating (‘learning rates’) and deployment of value representations (‘reinforcement sensitivity’) during choice, as well as ‘stimulus stickiness’ (choice repetition irrespective of reinforcement history).

Raw data measures assessing sensitivity to immediate feedback (‘win-stay’ and ‘lose-shift’ probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase.

Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

Lysergic acid diethylamide (LSD) a semi synthetic hallucinogen, was first synthetized by Albert Hofmann in 1938 and its psychological properties were not discovered until 1943. There was a brief renaissance of its use in psychiatry, specifically in assisted psychotherapy for the treatment of alcoholism, neurosis and psychosomatic disorders. However, research with LSD and others psychedelics substances rapidly came to an end with its broad international prohibition in the 1970´s.

This work aims to provide an understanding on the potential benefits of LSD in mental disorders, as well as its mechanism of action and effects on human brain.

A non-systematic review was performed on PubMed database, using the key words “LSD, mental disorder, neuroimaging, cerebral plasticity, psychedelics, substance use disorder”. Websites of the Berkley Foundation and Multidisciplinary Association For Psychedelic Studies (MAPS) were also searched.

Significant evidence has emerged that LSD may have a role in the treatment for some mental disorder, including drug and alcohol dependence and anxiety associated with life threatening diseases. Evidence based on modern neuroimaging technique suggest that LSD alters the brain blood flow, electrical activity, and network communication patterns. Preclinical evidence also demonstrated that psychedelics affect neuroplasticity after acute and chronic administration.

Based on the available evidence LSD when administered safely in a methodologically supervised psychotherapeutic setting can have a potential use for certain psychiatric conditions, suggesting that larger controlled studies are warranted

No significant relationships.

Depression is one of the most prevalent mental illnesses, leading to important personal distress and economic consequences. Treatment is long, often involving psychotherapy and pharmacological treatment, and relapses are frequent. Used mostly for treatment of mood disorders and alcohol dependence, drugs such as lysergic acid diethylamide (LSD) were studied in the 1950’s and showed therapeutic promise in attenuating depressive symptoms. However, in the 1960s all major psychedelic research programs were ended. Recently, there is a renewed research interest in these drugs, considering its antidepressant potential.

To review current knowledge on the therapeutic uses of psychedelic drugs such as LSD in depression disorders.

Review of the most recent literature regarding the therapeutical potential of psychedelic drugs such as LSD in depression disorders. The research was carried out through the UptoDate, PubMed, MedLine, ScienceDirect and SpringerLink databases, using the terms “LSD”, “psychedelic drugs” and “depression disorders”, until December 2020.

As in past scientific studies, data of recent clinical research shows that the use of LSD relieves distress concerning death, particularly in terminally ill oncologic patients, and addictions including alcoholism and nicotine. There is more limited data concerning the use of classic hallucinogens to treat depression and anxiety disorders.

Although research has shown many of the neurobiological and psychological effects of classic hallucinogens on humans, the studies that have been completed to date are not sufficient to establish clinically relevant effects. Despite further research is needed, the outcomes are encouraging, and larger, well-designed, placebo-controlled trials are now underway or being planned.

No significant relationships.

Recently there has been renewal in interest of psychedelic research. Classic psychedelics such as lysergic acid diethylamide (LSD), psilocybin and mescaline act pharmacologically as agonists at the 5-HT2A receptor. The entactogens like methylenedioxymethamphetamine (MDMA), acts as a serotonin, dopamine and noradrenaline agonist. All of these drugs are potential candidates in the treatment of multiple psychiatric illnesses.

The authors intend to review the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Non-systematic review of the literature.

In recent clinical trial the psychedelic is given with psychotherapeutic input. In a supportive setting, psychedelics produced immediate and significant anti-depressant and anxiolytic effects that were endured for several months. Randomized clinical trials support the efficace of psilocybin in the treatment of depression and those with anxiety and depression symptoms provoked by life-threatening cancer. There have also been studies showing efficacy in both alcohol and tobacco dependence. When administered safely LSD can reduce anxiety and have anti-addictive property. Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD. Psychedelics were well-tolerated, few adverse effects have been reported. The most common adverse effects were transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure, with no persisting adverse effects. Serious adverse events, such as persistent psychosis and suicidality, have not been demonstrated.

Psychedelics appear to be effective in multiple psychiatric disorders and are well-tolerated, although further evidence is required, to better see they therapeutic potential.

No significant relationships.

Autism Spectrum Disorder and Social Anxiety Disorder are mental illnesses characterized by a dysfunction in social behavior (SB); a phenomenon largely mediated by the medial prefrontal cortex (mPFC). Clinical studies have demonstrated that lysergic acid diethylamide (LSD), a partial agonist of the 5-HT2A receptor, can promote SB. However, its mechanism of action on SB is unknown.

To assess the effects of repeated LSD administration on social behavior in mice and to identify which mPFC receptors mediate LSD’s behavioral effects.

Eight-week-old C57BL/6J male mice received vehicle or repeated LSD (30 μg/kg/day i.p. for 7 days) as well the selective 5-HT2A receptor antagonist MDL, or the AMPA receptor antagonist NBQX. Twenty-four hours following the last injection, mice underwent the Direct Social Interaction Test and the Three-Chamber Test (TCT) to assess sociability and preference for social novelty. in vivo electrophysiological recordings were performed in mice treated with vehicle or LSD using multi-barrelled electrodes for microiontophoretic ejections of the selective 5-HT2A receptor agonist DOI or the selective AMPA receptor agonist quisqualate on mPFC pyramidal neurons.

Repeated treatment with low doses of LSD increased the interaction time in the DSI as well as sociability and social novelty indices in the TCT. These pro-social effects were blocked by the intra-PFC administration of both 5-HT2A and AMPA antagonists. LSD also potentiated, in a current-dependent manner, the excitatory response of mPFC neurons to 5-HT2Aand AMPA agonists.

Repeated, low doses of LSD increases social behavior via a mechanism of action that is mediated by 5-HT2A and AMPA in the mPFC.

For a century, psychedelics have been investigated as models of psychosis for demonstrating phenomenological similarities with psychotic experiences and as therapeutic models for treating depression, anxiety, and substance use disorders. This study sought to explore this paradoxical relationship connecting key parameters of the psychotic experience, psychotherapy, and psychedelic experience.

In a randomized, double-blind, placebo-controlled, crossover design, 24 healthy volunteers received 50 μg d-lysergic acid diethylamide (LSD) or inactive placebo. Psychotic experience was assessed by aberrant salience (Aberrant Salience Inventory, ASI), therapeutic potential by suggestibility (Creative Imagination Scale, CIS) and mindfulness (Five Facet Mindfulness Questionnaire, FFMQ; Mindful Attention Awareness Scale, MAAS; Experiences Questionnaire, EQ), and psychedelic experience by four questionnaires (Altered State of Consciousness Questionnaire, ASC; Mystical Experiences Questionnaire, MEQ; Challenging Experiences Questionnaire, CEQ; Ego-Dissolution Inventory, EDI). Relationships between LSD-induced effects were examined.

LSD induced psychedelic experiences, including alteration of consciousness, mystical experiences, ego-dissolution, and mildly challenging experiences, increased aberrant salience and suggestibility, but not mindfulness. LSD-induced aberrant salience correlated highly with complex imagery, mystical experiences, and ego-dissolution. LSD-induced suggestibility correlated with no other effects. Individual mindfulness changes correlated with aspects of aberrant salience and psychedelic experience.

The LSD state resembles a psychotic experience and offers a tool for healing. The link between psychosis model and therapeutic model seems to lie in mystical experiences. The results point to the importance of meaning attribution for the LSD psychosis model and indicate that psychedelic-assisted therapy might benefit from therapeutic suggestions fostering mystical experiences.

Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.

We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.

A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges' gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.

High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.

Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision-making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied.

We examined the acute effects of LSD (100 µg) alone and in combination with the 5-HT2A antagonist ketanserin (40 mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery.

Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence the quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits.

The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.

Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.

In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.

Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.

Our findings show that 5-HT2AR activation by LSD leads to a hippocampal–prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.

A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session.

LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.

The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of ‘loosened cognition’ in the mid to long term that is conducive to improved psychological wellbeing.