Neuropsychological Functioning in Users of Serotonergic Psychedelics – A Systematic Review and Meta-Analysis

This review paper (2021) investigated the persisting effects of psychedelics on neuropsychological function. There is relatively little reliable data on neuropsychological consequences of psychedelics, especially studies with psilocybin (now most commonly used in trials) are lacking.

Abstract

“Background: Serotonergic psychedelics (SPs) like LSD, psilocybin, DMT, and mescaline are a heterogeneous group of substances that share agonism at 5-HT_2a receptors. Besides the ability of these substances to facilitate profoundly altered states of consciousness, persisting psychological effects have been reported after single administrations, which outlast the acute psychedelic effects. In this review and meta-analysis, we investigated if repeated SP use associates with a characteristic neuropsychological profile indicating persisting effects on neuropsychological function.

Methods: We conducted a systematic review of studies investigating the neuropsychological performance in SP users, searching studies in Medline, Web of Science, embase, ClinicalTrials.gov, and EudraCT. Studies were included if they reported at least one neuropsychological measurement in users of SPs. Studies comparing SP users and non-users that reported mean scores and standard deviations were included in an exploratory meta-analysis.

Results: 13 studies (N = 539) published between 1969 and 2020 were included in this systematic review. Overall, we found that only three SPs were specifically investigated: ayahuasca (6 studies, n = 343), LSD (5 studies, n = 135), and peyote (1 study, n = 61). However, heterogeneity of the methodological quality was high across studies, with matching problems representing the most important limitation. Across all SPs, no uniform pattern of neuropsychological impairment was identified. Rather, the individual SPs seemed to be associated with distinct neuropsychological profiles. For instance, one study (n = 42) found LSD users to perform worse in trials A and B of the Trail-Making task, whereas meta-analytic assessment (5 studies, n = 352) of eleven individual neuropsychological measures indicated a better performance of ayahuasca users in the Stroop incongruent task (p = 0.03) and no differences in the others (all p > 0.05).

Conclusion: The majority of the included studies were not completely successful in controlling for confounders such as differences in non-psychedelic substance use between SP-users and non-users. Our analysis suggests that LSD, ayahuasca and peyote may have different neuropsychological consequences associated with their use. While LSD users showed reduced executive functioning and peyote users showed no differences across domains, there is some evidence that ayahuasca use is associated with increased executive functioning.“

Authors: Lukas A. Basedow, Thomas G. Riemer, Simon Reiche, Reinhold Kreutz & Tomislav Majić

Summary

INTRODUCTION

In the past 25 years, there has been a surge of new research on serotonergic psychedelics (SPs), such as LSD, psilocybin, and DMT, and their therapeutic potential in different psychiatric indications. SPs can be divided into three subgroups: tryptamines, ergoline derivatives, and phenethylamines.

All SPs seem to induce similar ASCs, including changes in perception, cognition, mood, and sense of self. However, there are some pharmacological differences between SPs, including the existence of non-psychedelic 5-HT2aR agonists like lisuride.

SPs are unique with regard to the temporal dynamics of their effects, including acute (psychedelic states), subacute (“afterglow”) phenomena, and long-term effects. However, SP use has also been reported to exhibit prolonged negative consequences, including an enduring psychotic reaction and hallucinogen persisting perception disorder.

While many persisting psychological effects of SP use have been investigated, neuropsychological consequences remain underexplored. Based on the evidence that SPs can facilitate different subacute and persisting psychological changes, we aim to investigate if repeated SP use is associated with changes in neuropsychological performance.

Search Strategy

This review was conducted using an algorithm connecting a selection of SPs and terms associated with neuropsychological testing or domains. The search was extended to all SPs across chemical sub-groups, and references were retrieved through the electronic searches and by manual searches.

Data Extraction

Two researchers screened the search results and a third provided input on whether an article should be included or excluded. The studies were divided into four groups according to substance and the neuropsychological tests used were categorized into six domains.

Study Quality

We used the Newcastle-Ottowa-Scale to estimate study quality and risk of bias. A study was considered high quality if it fulfilled both comparability criteria and reached a total score of seven or higher.

Meta-Analysis

We included studies that reported results as mean scores with standard deviations and calculated the overall effect for each neuropsychological test and subtest. We performed four a-priori planned sensitivity analyses and assessed heterogeneity in effect sizes using the I2 statistic.

Study Selection

After excluding duplicates, 5,401 articles were found, of which 4,980 were rejected for not dealing with the effects of SPs on neuropsychological functioning. 13 articles were left for full-text screening, of which 5 met the criteria for inclusion in the meta-analysis.

Study Quality

A median NOS score of 5 was obtained across all studies, with no included study rated as having high quality.

Memory

Working memory was assessed in 157 users of SPs and 175 non-using controls. Ayahuasca users had a higher number of hits, a lower number of misses, and faster reaction times on hit trials than the non-using group.

In three studies, ayahuasca users were able to recall more words on the fifth learning trial, but not on the other trials. There was no difference in total number of words recalled, in number of false positives, in words recalled after interference, or in words recalled after a delay.

No studies have assessed whether SP users differ from the non-using population in their long-term memory. Users of SPs performed better on some trials, but not on all trials.

Executive Functions

In nine studies, 339 SP users were included (198 ayahuasca, 14 LSD or mescaline, 61 peyote, 66 LSD) and their executive functions were assessed by seven different tasks. Three studies reported significant differences in executive functioning, whereas no difference was reported in the other studies.

LSD users performed worse on a letter-number sequencing task, while ayahuasca users performed better on the congruent word and color lists and the incongruent list in the Stroop task.

One study reported lower performance in users of SPs on the TMT-B, while another study reported the opposite pattern. No other study detected any difference in performance between users and non-users.

Attention

Seven studies examined the effect of ayahuasca, peyote, and LSD on attention. Two studies found that LSD users performed worse than non-users in the Trail Making Test, and one study found that SP users performed faster on a self-designed reaction time task.

Visuospatial Abilities

In eight studies, 232 SP users were included and their visual and perceptual abilities were evaluated using eleven different tests. Cohen and Edwards (1969) found reduced performance for LSD users in the Halstead-Reitan battery spatial orientation task.

Intelligence

Three measures of intelligence were used to compare 178 SP users to 196 nonusers. No significant differences were observed.

Other Measures

In five studies, 120 SP users were included (40 ayahuasca, 80 LSD) and compared to 120 nonusers. In three of the subtests, significant differences were found, but in none of the tests did researchers detect any difference.

DISCUSSION

We will discuss studies on LSD and ayahuasca, two plant-derived SPs, that were conducted from 1969 to 2020. The first group includes recreational users also prone to using other psychoactive substances.

Studies From 1969 to 1983: Lysergic Acid Diethylamide

In the first identified period of research, LSD was by far the most intensively used SP, and most studies focused on LSD. However, the majority of studies were of insufficient quality and did not adequately control for other, non-psychedelic substances. Based on the results of this study, McGlothlin et al. (1969) reported that LSD users had reduced performance in a categorical task compared to 16 controls matched on age, gender, education, occupation, and the number of people who had received psychotherapy (without LSD).

LSD use has an apparent negative association with neuropsychological functioning, and is also associated with Hallucinogen Persisting Perception Disorder. Matefy et al. (1979) found that SP users with flashbacks had an increased reaction time on a simple reaction-time task compared to SP users without flashbacks and 23 controls without any substance use. However, Vardy and Kay (1983) found no differences in neuropsychological performance between patients with and without LSD use.

Studies From 1996 to 2020: Ayahuasca and Peyote

After this early period of LSD research, no further studies have been published dealing with the neuropsychological consequences of regular LSD use. However, a study from the 1990s compared religious users of peyote with former patients suffering from alcohol use disorder and 79 controls with minimal substance use.

In studies of religious SP use, members of syncretic Brazilian churches that regularly use ayahuasca as a sacrament showed very high lifetime use of ayahuasca and comparably low use of other substances. In one study, 15 male UDV members performed better on one measure of verbal memory than 15 male controls. The control group had a history of moderate to severe alcohol use and five reported a history of cocaine and amphetamine use before their engagement with the church.

A study with 30 members of the UDV church found that they had a higher verbal learning performance compared to a control group without a history of ayahuasca use. However, the control group had used significantly more alcohol in the past month.

A single study found that 22 ayahuasca users outperformed 22 controls on tasks related to working memory and executive functioning.

Ayahuasca and Improved Neuropsychological Performance

Ayahuasca users performed better on the inhibitory control section of the Stroop task than non-users, which suggests a beneficial effect of ayahuasca use on executive functioning. Ayahuasca use may improve executive functioning in humans and animals due to its pharmacological mechanism. This mechanism may also explain why a similar effect was not found in well-controlled studies with users of LSD or peyote. The improved performance in the Stroop task in ayahuasca users might be related to the involvement of specific brain structures, or to the improvement of neuronal plasticity, however, further research is required to confirm these hypotheses.

Most research in this field is cross-sectional, not allowing any conclusions on causality. Despite this, we could not find any studies assessing the neuropsychological consequences of psilocybin use.

We speculate that the neuropsychological consequences of repeated use of psilocybin could be of a similar nature, but more studies with well-matched control groups are necessary before any conclusions can be drawn. Future research should include users of psilocybin, as this substance is frequently used in recreational settings and has been most extensively investigated in clinical studies. However, the relevance of our findings regarding SP-assisted therapy remains limited, as participants in our studies used SPs repeatedly.

Limitations

Although the majority of SP users report use of additional psychoactive substances, some studies recruited participants in groups of a specific religious background who use SPs as part of their religious practice.

Although ayahuasca may have beneficial effects on performance in tasks dealing with executive functioning and attention, it is not clear whether this effect is shared by other substances or due to other non-substance related differences.

CONCLUSION

While studies on the neuropsychological consequences of repeated SP use are scarce, it appears that LSD use is associated with lower task-switching performance and ayahuasca use is associated with a higher performance in inhibitory control.

AUTHOR CONTRIBUTIONS

LB, TR, TM, SR, and RK conceptualized the study, LB acquired, curated, and analysed the data, and RK wrote the manuscript.