Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans

This study (n=44) investigated the long-term effects of regular ayahuasca use on the human brain. Structural MRI showed that regular ayahuasca users had significantly different cortical thickness (with thinning in the posterior cingulate cortex) when compared to non-users. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation.

Abstract

“Psychedelic agents have a long history of use by humans for their capacity to induce profound modifications in perception, emotion and cognitive processes. Despite increasing knowledge of the neural mechanisms involved in the acute effects of these drugs, the impact of sustained psychedelic use on the human brain remains largely unknown. Molecular pharmacology studies have shown that psychedelic 5-hydroxytryptamine (5HT)2A agonists stimulate neurotrophic and transcription factors associated with synaptic plasticity. These data suggest that psychedelics could potentially induce structural changes in brain tissue. Here we looked for differences in cortical thickness (CT) in regular users of psychedelics. We obtained magnetic resonance imaging (MRI) images of the brains of 22 regular users of ayahuasca (a preparation whose active principle is the psychedelic 5HT2A agonist N,N-dimethyltryptamine (DMT)) and 22 controls matched for age, sex, years of education, verbal IQ and fluid IQ. Ayahuasca users showed significant CT differences in midline structures of the brain, with thinning in the posterior cingulate cortex (PCC), a key node of the default mode network. CT values in the PCC were inversely correlated with the intensity and duration of prior use of ayahuasca and with scores on self-transcendence, a personality trait measuring religiousness, transpersonal feelings and spirituality. Although direct causation cannot be established, these data suggest that regular use of psychedelic drugs could potentially lead to structural changes in brain areas supporting attentional processes, self-referential thought, and internal mentation. These changes could underlie the previously reported personality changes in long-term users and highlight the involvement of the PCC in the effects of psychedelics.”

Authors: José C. Bouso, Fernanda Palhano-Fontes, Antoni Rodríguez-Fornells, Sidarta Ribeiro, Rafael F. Sanches, José A. S. Crippa, Jaime E.C. Hallak, Draulio B. de Araujo & Jordi Riba

Summary

Abstract

Psychedelic agents induce profound modifications in perception, emotion and cognitive processes. The impact of sustained psychedelic use on the human brain remains largely unknown.

1. Introduction

Psychedelics have been used since ancient times by geographically distant human groups to induce profound modifications in the ordinary state of consciousness.

Brazilian religious groups that consume ayahuasca have adapted psychedelic use to their rituals, and around 20,000 people attend rituals once every other week for many years.

DMT, a 5-HT2A receptor agonist, is found in P. viridis and B. caapi and is rendered orally active by -carboline alkaloids.

Molecular pharmacology studies have shown that psychedelic 5-HT2A agonists increase the expression of genes that encode transcription factors, and are associated with synaptic plasticity, memory, and attention.

Despite increasing research into the acute effects of psychedelics and growing interest in their potential use as therapeutic agents, little is known about the impact of sustained psychedelic use on the human brain.

2.2. Participants

A group of 22 Spanish ayahuasca users and 22 controls were selected for the study. The participants were interviewed by a clinical psychologist and had their structural MRI images assessed by a neuroradiologist to rule out any CNS anomalies. The two participant groups were matched for sex, age, years of education, and verbal and fluid intelligence quotient (IQ). The IQ tests used were the NART and the Matrix Reasoning.

Table 1 shows that there were no significant differences between groups regarding employment, marital status, or tobacco use. However, the control group showed a higher frequency of use.

Ayahuasca users had taken ayahuasca an average of 123 times in their lifetime, and had been using it for an average of 5.3 years. None of the participants had ever used cannabis, and some had used psychedelics other than ayahuasca once in their lifetime.

2.3. Acquisition and analyses of images

A general linear model was applied to estimate statistical differences at each voxel across the entire cortical surface. Results were mapped onto the inflated white-matter surface of the average reconstruction of the brain and colored-coded to show regions with significant differences.

2.4. Assessment of personality, psychopathology and neuropsychology

The Temperament and Character Inventory-Revised (TCI-R) is a 240-item questionnaire that assesses four dimensions of personality: harm avoidance, novelty seeking, reward dependence, and persistence.

Psychopathological assessment was carried out using the Symptom Check-List-90-Revised (SCL-90-R) questionnaire. It provides three global psychopathological indices: General Severity Index, Positive Symptoms Distress Index and Positive Symptoms Total.

Three classic neuropsychological tests were administered by computer: the two-back test, Wisconsin Card-sorting Test and switching task. The variables assessed were total number of correct responses, total number of errors, total number of perseverances and reaction time for correct responses.

A switching task was performed in which participants had to indicate by button press where on the screen the target item was located. The switch of the attention focus from letter to digit and vice versa was associated with shorter reaction times.

The Kolmogorov-Smirnov test showed that personality scores were normally distributed, whereas psychopathology and neuropsychological performance scores were not. Therefore, the Student’s t-test was used to compare groups, and correlations were calculated.

3.1. Structural MRI and CT

Ayahuasca users showed thinner cortical areas in six areas compared to their matched controls, while thickening was observed in the precentral gyrus and the anterior cingulate cortex.

3.2. Personality, psychopathology and neuropsychology

Results from the psychopathology assessment and neuropsychological tests show that ayahuasca users showed significantly better performance than controls in several variables. In the two-back test, only the percentage of false alarms and correct rejections did not differ, and in the WCST, ayahuasca users showed a trend to higher number of correct responses and lower errors.

4. Discussion

We compared brain structure, personality, psychopathology and neuropsychological function between regular users of psychedelic drugs and controls. We found that regular users had a larger anterior cingulate cortex.

The correlation between lifetime use of ayahuasca and CT in the PCC is supported by the results of this study. However, we did not observe increased psychopathology or worse neuropsychological performance in the ayahuasca-using group.

Ayahuasca and other psychedelic agents have been found to increase blood flow in the medial prefrontal cortex, including the ACC. This has been replicated in studies on psilocybin use.

Psilocybin effects were found in the anterior and posterior cingulate cortices and in the functional coupling of these two regions. The structural differences observed could reflect a direct drug-induced modulatory action or an adaptive response.

5-HT2A agonists induce expression of the transcription factors egr-1 and egr-2, which modulate synaptic plasticity, short- and long-term memory, and attention.

The greater CT observed in anterior brain regions involved with attention and executive control could explain intriguing findings from long-term users of psychedelic agents, including the fact that long-term users scored significantly better on several neuropsychological tests. The present study identified anti-correlated structural differences in the default mode network and attention/cognitive control networks in psychedelic users, which could explain the preservation of neuropsychological function in ayahuasca users.

Ayahuasca users scored higher on ST than non-users, and greater scores on ST were associated with increased thinning of the PCC. This finding is consistent with previous research that shows that psychedelic use can lead to personality changes.

The present study found a relationship between spirituality and the posterior cingulate cortex, which is an important brain region in the DMN and is associated with the inner world, i.e., endogenous thoughts and feelings.

Regular use of psychedelic drugs was associated with changes in the medial aspects of the frontal and parietal cortices, which may contribute to personality changes.

Funding

This work was funded by the Spanish government’s “Plan Nacional Sobre Drogas” (PNSD).