Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

This fourth publication on the administration of a microdose of LSD (5, 10, or 20 µg) found enhanced attention, slower information processing, more positive mood, and increased anxiety and confusion. Again, the results are small and quite ambiguous.

Abstract

“There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.”

Authors: Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Amanda Feilding, Johannes G. Ramaekers & Kim P. C. Kuypers

Notes

This paper uses the same participants (possibly now burdened with RSI) as Holze et al. (2020), Hutten et al. (2020), and Ramaekers et al. (2020). The other studies respectively looked at pharmacodynamics and felt effect (only really at 20 µg), blood plasma levels (ambiguous results), and increased pain tolerance.

This study is quite similar to Yanakieva et al. (2019), which found only small effects on mood (more vigour, lower rating of positive images).

The study is supported in part by the Beckley Foundation.

It was (lazily) reported on in Futurism (October 2020).

Although the conclusions presented in the abstract are valid. Please do consult Figure 1 in the paper to see how small and relatively ‘random’ these results are (i.e. noise). Also:

“Binomial tests indicated that the proportion of observations containing fewer attentional lapses after administration of 5 and 20 mcg LSD was respectively 76% ( p < 0.01) and 74% ( p < 0.01), while this was 38% ( p = 0.19) after 10 mcg LS.” (this is represented in the top-left bar graph in figure 1)

The same can be said of Table 3, which displays mood and cognition scores that move only ever so slightly.

Summary

A placebo-controlled within-subject study was conducted to assess the acute effects of three LSD doses on measures of cognition, mood, and subjective experience. The results demonstrated that low doses of LSD have selective, beneficial effects on mood and cognition.

2.1. Design

This study was conducted with 24 participants and involved four doses of LSD hydrate. The treatment days were separated by a minimum washout period of 5 days to avoid potential carry-over effects.

2.2. Participants

Participants were 24 healthy recreational psychedelic drug users aged 22.8 years on average. They had used at least one psychedelic substance, and reported previous use of cannabis, amphetamines, cocaine, nicotine, and alcohol.

2.3. Procedures

Participants were recruited through advertisements, social media and word of mouth. They underwent a medical screening by a physician and blood and urine samples were taken.

Inclusion criteria were written informed consent, proficient knowledge of the English language, and a BMI between 18 and 28 kg/m 2.

Exclusion criteria were history of drug abuse, psychiatric disorders, cardiovascular abnormalities, hypertension, psychotic disorder in first-degree relatives, tobacco smoking, excessive alcohol consumption, and pregnancy.

Participants were trained to perform with 100% accuracy on a rule-based cognitive control task (CCT) before the test days. They were also asked to refrain from consuming caffeinated or alcoholic beverages after midnight of the evening before the test days.

Participants spent the whole day in a quiet room with a window, were screened for the presence of alcohol in breath, drugs of abuse in urine, and women were tested for pregnancy. After drug administration, a test battery was conducted, including subjective measures and blood samples.

This study was conducted according to the code of ethics on human experimentation established by the declaration of Helsinki and subsequent amendments, and participants received monetary compensation per hour invested.

2.4.1. Psychomotor vigilance task

The Psychomotor Vigilance Task (PVT) is a sustained attention task in which participants have to react as quickly as possible to visual stimuli.

2.4.2. Digit symbol substitution test

The Digit Symbol Substitution Test (DSST) is a computerized version of the original paper and pencil test that measures information processing, motor speed, attention, working memory, and visual processing.

2.4.3. Cognitive control task

The Cognitive Control Task (CCT) was used to assess participants’ level of cognitive control. Participants learned to respond to squared patterns on a computer screen by either pressing left or right key to open a box, and to reveal a food item inside, which was the reward.

A refresher of the rules was given each test day before dose administration, and the accuracy level was tested with the questionnaire (100% correct). Two and a half hours after drug administration, the participants were tested for goal-directed responding (cognitive control).

2.5.1. Profile of mood states

The Profile of Mood States is a self-assessment mood questionnaire with 72 adjectives describing specific mood states. Two composite scales were derived, arousal and positive mood.

2.5.2. Visual analogue scales

Participants indicated on nine Visual Analogue Scales (VAS) how they felt by putting a mark on each 10-cm long horizontal scale. There were five statements and four adjectives presented.

2.5.3. 5-Dimensional altered states of consciousness rating scale

The 5-Dimensional Altered States of Consciousness Rating Scale is a 94-item self-report scale that assesses participants’ alterations from normal waking consciousness.

The 5D-ASC consists of five key dimensions and eleven associated subscales: Oceanic boundlessness, Anxious ego dissolution, Visionary restructuralization, Auditory alterations, and Reduction of vigilance.

2.5.4. Ego dissolution inventory

The Ego Dissolution Inventory (EDI) is an eight-item self-report scale that asks participants to indicate to what extent they have experienced a dissolution of their “self” or ego.

2.6.1. The Groninger sleep scale

The Groninger Sleep Scale consists of 15 questions about sleep complaints and 1 question about sleep quantity. The resulting score indicates sleep quality.

2.6.2. LSD plasma concentrations

Blood samples were centrifuged, and pipetted plasma was frozen at -20 °C until analysis for pharmacokinetic analyses. LSD concentrations were determined using ultra high-performance liquid chromatography-tandem mass spectrometry.

2.7. Data and statistical analysis

The data and statistical analysis comply with the recommendations on experimental design and analysis in pharmacology. A General Linear Model (GLM) Univariate Analysis of Variance (ANOVA) was performed with Dose and Time as fixed factors, and Participant as a random factor.

For each participant, a different dose of LSD was administered, and a different outcome measure was recorded. Binomial tests were conducted to determine the proportion of observations showing improvement versus impairment.

We used GLM repeated measures (RM) ANOVA with Dose as within-subjects factor to analyze the effects of the 5D-ASC, EDI, and CCT on general health and cognitive function.