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Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, crossover studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects. Methods We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI). Results All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects. Conclusions MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.

Lysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated.

The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25–200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as “Well-Being”, “Emotional Excitability”, and “Anxiety” were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait “Openness to Experiences” was positively correlated with elevated ratings in “Oceanic Boundlessness” and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with “Anxious Ego Dissolution”. Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience.

Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared. Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg), and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of amphetamine, subjective effects, and vital signs were repeatedly assessed. The pharmacokinetic parameters were determined using compartmental modeling. The increase in plasma concentrations of amphetamine had a 0.6 ± 0.6 h (mean ± SD) longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration, but no differences in maximal concentrations or total exposure (AUC) were found between the two treatments. Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with D-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence) were observed after lisdexamfetamine administration compared with D-amphetamine administration. Lisdexamfetamine and D-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects. The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to D-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as D-amphetamine. The study was registered at ClinicalTrials.gov (NCT02668926).

Rationale Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. Acute mystical-type experiences that are acutely induced by hallucinogens are thought to contribute to their potential therapeutic effects. However, no data have been reported on LSD-induced mystical experiences and their relationship to alterations of consciousness. Additionally, LSD dose- and concentration-response functions with regard to alterations of consciousness are lacking. Methods We conducted two placebo-controlled, double-blind, cross-over studies using oral administration of 100 and 200 μg LSD in 24 and 16 subjects, respectively. Acute effects of LSD were assessed using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale after both doses and the Mystical Experience Questionnaire (MEQ) after 200 μg. Results On the MEQ, 200 μg LSD induced mystical experiences that were comparable to those in patients who underwent LSD-assisted psychotherapy but were fewer than those reported for psilocybin in healthy subjects or patients. On the 5D-ASC scale, LSD produced higher ratings of blissful state, insightfulness, and changed meaning of percepts after 200 μg compared with 100 μg. Plasma levels of LSD were not positively correlated with its effects, with the exception of ego dissolution at 100 μg. Conclusions Mystical-type experiences were infrequent after LSD, possibly because of the set and setting used in the present study. LSD may produce greater or different alterations of consciousness at 200 μg (i.e., a dose that is currently used in psychotherapy in Switzerland) compared with 100 μg (i.e., a dose used in imaging studies). Ego dissolution may reflect plasma levels of LSD, whereas more robustly induced effects of LSD may not result in such associations.

Abstract Background Stimulants such as methylphenidate and modafinil are frequently used as cognitive enhancers in healthy people, whereas 3,4-methylenedioxymethamphetamine (ecstasy) is proposed to enhance mood and empathy in healthy subjects. However, comparative data on the effects of methylphenidate and modafinil on negative emotions in healthy subjects have been partially missing. The aim of this study was to compare the acute effects of methylphenidate and modafinil on the neural correlates of fearful face processing using 3,4-methylenedioxymethamphetamine as a positive control. Methods Using a double-blind, within-subject, placebo-controlled, cross-over design, 60 mg methylphenidate, 600 mg modafinil, and 125 mg 3,4-methylenedioxymethamphetamine were administrated to 22 healthy subjects while performing an event-related fMRI task to assess brain activation in response to fearful faces. Negative mood states were assessed with the State-Trait Anxiety Inventory and subjective ratings. Results Relative to placebo, modafinil, but not methylphenidate or 3,4-methylenedioxymethamphetamine, increased brain activation within a limbic-cortical-striatal-pallidal-thalamic circuit during fearful face processing. Modafinil but not methylphenidate also increased amygdala responses to fearful faces compared with 3,4-methylenedioxymethamphetamine. Furthermore, activation in the middle and inferior frontal gyrus in response to fearful faces correlated positively with subjective feelings of fearfulness and depressiveness after modafinil administration. Conclusions Despite the cognitive enhancement effects of 600 mg modafinil in healthy people, potential adverse effects on emotion processing should be considered.

Background and Objective Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure–response relationship of oral LSD. Methods We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Results Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2–1.9) and 3.1 (2.6–4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2–3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups. Conclusions The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance. Trial registration: NCT02308969, NCT01878942.

Microdosing with psychedelics has gained considerable media attention where it is portrayed as a performance enhancer, especially popular on the work floor. While reports are in general positive, scientific evidence about potential negative effects is lacking aside from the prevalence and motives for use. The present study addressed this gap by surveying psychedelic users about their experience with microdosing including their dosing schedule, motivation, and potential experienced negative effects. An online questionnaire was launched on several websites and fora between March and July 2018. Respondents who had consented, were 18 years of age or older, and had experience with microdosing were included in the analyses. In total, 1116 of the respondents were either currently microdosing (79.5%) or microdosed in the past (20.5%). Lysergic acid diethylamide (10 mcg) and psilocybin (0.5 g) were the most commonly used psychedelics with a microdosing frequency between 2 and 4 times per week. The majority of users, however, were oblivious about the consumed dose. Performance enhancement was the main motive to microdose (37%). The most reported negative effects were of psychological nature and occurred acutely while under the influence. In line with media reports and anecdotes, the majority of our respondents microdosed to enhance performance. Negative effects occurred mostly acutely after substance consumption. However, the main reason to have stopped microdosing was that it was not effective. Future experimental placebo-controlled studies are needed to test whether performance enhancement can be quantified and to assess potential negative effects after longer term microdosing.

Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes and in rat and mouse brains through 5-HT receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT receptor gene ( ) and genes. mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. LSD did not alter the expression of the or genes 1.5 and 24 h after administration compared with placebo. No changes were observed in the gene expression of LSD's primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.