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

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 5HT_2A 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.

Introduction

Psychedelics, have been used since ancient times by geographically distant human groups for their capacity to induce profound modifications in the ordinary state of consciousness and to generate spiritually meaningful experiences (Schultes, 1979). The ancient practice of ritual psychedelic use not only survived well into the twentieth century, but has expanded beyond indigenous use following contact of previously isolated groups with foreigners (Tupper, 2008).

One of the most interesting contemporary adaptations of psychedelic use is the syncretism observed in Brazilian religious groups that consume ayahuasca, an infusion of the plants Banisteriopsis caapi and Psychotria viridis. These ayahuasca religions have expanded in the last decades, and it is estimated that around 20,000 people in 23 countries currently take ayahuasca regularly within a ritual context. Typically, participants attend ayahuasca-using rituals once every other week for many years (Grob et al., 1996).

Regarding the active principles present in ayahuasca, one of the plants, P. viridis, contains N,N-dimethyltryptamine (DMT). DMT is structurally related to serotonin and acts as a 5-HT_2A receptor agonist (González-Maeso and Sealfon, 2009). DMT elicits intense, short-acting psychedelic effects when administered intravenously (Strassman et al., 1994) but is rapidly degraded by monoamine-oxidase (MAO) when orally ingested. Interestingly, DMT is rendered orally active by the MAO-inhibiting β-carboline alkaloids found in the other plant, B. caapi, used in ayahuasca (Riba et al., 2001).

Molecular pharmacology studies have shown that psychedelic 5-HT_2A agonists stimulate expression of immediate early genes that encode transcription factors, such as c-fos (Frankel and Cunningham, 2002), egr-1 and egr-2 (González-Maeso et al., 2007). They also increase the expression of the brain-derived neurotrophic factor (Gewirtz et al., 2002). Activation of these transcription factors has been associated with synaptic plasticity (O’Donovan et al., 1999), and cognitive processes such as memory (Jones et al., 2001) and attention (DeSteno and Schmauss, 2008).

Despite increasing research into the acute effects of psychedelics and the growing interest for their potential use as therapeutic agents (Grob et al., 2011), little is known about the impact of sustained psychedelic use on the human brain. Based on the available molecular data mentioned above, we postulated that repeated exposure to psychedelics would correlate with changes in brain structure. To test this hypothesis we investigated brain cortical thickness (CT) in chronic psychedelic drug users who had minimal exposure to other drugs and their matched controls.