Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities, Frederic Sampedro et al., 2017

Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Ayahuasca post-acute effects

Regular Research Article

Frederic Sampedro, Mario de la Fuente Revenga, Marta Valle, Natalia Roberto, Elisabet Domínguez-Clavé, Matilde Elices, Luís Eduardo Luna, José Alexandre S. Crippa, Jaime E. C. Hallak, Draulio B. de Araujo, Pablo Friedlander, Steven A. Barker, Enrique Álvarez, Joaquim Soler, Juan C. Pascual, Amanda Feilding and Jordi Riba

© The Author 2017. Published by Oxford University Press on behalf of CINP.

The International Journal of Neuropsychopharmacology, 2017, 20, 9

DOI : 10.1093/ijnp/pyx036

Significance Statement

Psychedelics are intriguing drugs that induce transient but intense modifications in perception, emotion and cognition. Despite human use dating back millennia, their mechanism of action is still poorly understood. Recent research in patients has shown that ayahuasca, a plant psychedelic used traditionally in the Amazon for religious and medicinal purposes, exerts rapid and potent anti-depressant effects in treatment-resistant patients. These beneficial effects are observed after a single dose and intriguingly persist for weeks, long after the immediate acute effects have disappeared. Here we demonstrate using two neuroimaging techniques that during the post-acute phase, that is within 24 hours after intake, ayahuasca leads to metabolic and connectivity changes in the brain. These changes are associated with enhanced psychological capacities that are beneficial in the therapeutic context. These findings provide a biological basis for the post-acute or “after-glow” stage of psychedelic effects, and contribute to elucidate the therapeutic mechanisms of these substances.



Background : Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyl-tryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here we investigated in an open-label uncontrolled study in sixteen healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications, and their association with mindfulness measures.

Methods : Using 1H-magnetic resonance spectroscopy (MRS) and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior (PCC) and anterior (ACC) cingulate cortex after a single ayahuasca dose.

Results : MRS showed post-acute reductions in Glx (glutamate+glutamine), creatine and NAA-NAAG (N-acetylaspartate+N-acetyl-aspartylglutamate) in the PCC. Connectivity was increased between the PCC and the ACC, and between the ACC and limbic structures in the right medial temporal lobe (MTL). Glx reductions correlated with increases in the “Non-Judging” subscale of the Five Facets Mindfulness Questionnaire. Increased ACC-MTL connectivity correlated with increased scores on the Self-Compassion questionnaire. Post-acute neural changes predicted sustained elevations in “Non-Judging” two months later.

Conclusions : These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the PCC, a key region within the DMN, and increased connectivity between the ACC and MTL structures involved in emotion and memory, potentially underlie the post-acute psychological effects of ayahuasca.

Key words : ayahuasca, psychedelic after-effects, magnetic resonance imaging, mindfulness, human



Psychedelics are the object of renewed interest as potential therapeutic tools in psychiatry (Sessa, 2005; Vollenweider and Kometer, 2010; Grob et al., 2011). Among these substances is ayahuasca, an Amazonian psychoactive beverage typically obtained from the plants Banisteriopsis caapi and Psychotria viridis. The ayahuasca tea contains a combination of the psychedelic indole N,N-dimethyltryptamine (DMT) from P. viridis, and β-carboline (harmala) alkaloids with monoamine-oxidase (MAO)-inhibiting properties from B. caapi (McKenna et al., 1984). DMT is a classical serotonergic psychedelic that stimulates the 5-HT2A receptor (Carbonaro et al., 2015). Agonism at this level by DMT and other psychedelics recruits glutamatergic neurotransmission (Carbonaro et al., 2015), induces neuronal excitatory effects (Kłodzinska et al., 2002) and increases glutamate release (Scruggs et al., 2003; Muschamp et al., 2004). However, unlike psilocybin or LSD, DMT is orally inactive due to extensive degradation by MAO (Riba et al., 2015). Interestingly, the presence of β-carbolines in the ayahuasca tea inhibits DMT metabolism, allowing for psychoactive effects after oral intake (Riba et al., 2003). Additionally, DMT shows neuroprotective effects mediated through interaction with the sigma-1 receptor (Szabo et al., 2016).

Interest in the general pharmacology and therapeutic properties of ayahuasca has greatly increased in recent years (Domínguez-Clavé et al., 2016). Acute administration to healthy volunteers induces a transient introspective state characterized by dream-like visions with eyes closed, recollection of personal memories and intense emotion (Riba et al., 2001, 2003). Neurophysiological studies show a suppression of the inhibitory alpha rhythm in the occipital and parietal cortex, including the posterior cingulate cortex (PCC) (Schenberg et al., 2015; Valle et al., 2016), a key node of the default mode network (DMN) with a prominent role in self-reflection and consciousness (Vogt and Laureys, 2005). Furthermore, decreased activity for the most part of the DMN and reduced connectivity of the PCC have been observed during the acute effects of Ayahuasca (Palhano-Fontes et al., 2015). On the other hand, radiotracer data shows increased blood flow in the anterior cingulate cortex (ACC) and in the insula, amygdala and hippocampus, brain areas involved in cognitive control, emotion and memory (Riba et al., 2006). Recently, ayahuasca was found to induce post-acute increases in “decentering” ability, i.e., the capacity to observe one’s thoughts and emotions in a detached manner, and to reduce automatic negative judgmental attitudes and inner reactivity (Soler et al., 2015). It thus enhanced a series of “mindfulness” capacities traditionally cultivated by meditation schools and that are known to be impaired in many forms of psychopathology (Soler et al., 2014b). In a subsequent review, the authors postulated that the mindfulness-enhancing properties of ayahuasca could be used in a therapeutic context to facilitate emotional reprocessing in patients with depression, addiction and personality disorders (Domínguez-Clavé et al., 2016).

In line with the above, two recent open-label uncontrolled clinical studies have found rapid reductions in psychopathology after administration of single ayahuasca doses to depressed patients. Remarkably, antidepressant effects appeared within hours after dosing and were maintained for three weeks (Osório et al., 2015; Sanches et al., 2016). Analogous improvements have also been observed after psilocybin (Carhart-Harris et al., 2016b). In all cases, sustained antidepressant effects were in sharp contrast with the much shorter duration of the acute psychedelic state. This disparity of time courses suggests that 5-HT2A stimulation leads to persistent effects beyond the time frame of the acute inebriation. In fact, early researchers coined the term “after-glow” to designate a positive post-acute phase of psychedelic drug effects characterized by elevated mood and openness (Pahnke et al., 1970). This post-acute phase has been reported to extend between six and eight weeks after the acute psychedelic effects, and characterized as a window of opportunity for therapeutic intervention (Halpern, 1996; Winkelman, 2014). Recent clinical studies have described persisting positive after-effects following psilocybin and LSD (Griffiths et al., 2008; Lebedev et al., 2016).

Here, we investigated the neural correlates of the psychedelic “after-glow” in healthy volunteers, in order to improve our understanding of the neural mechanisms potentially involved in the rapid and sustained therapeutic effects observed in patients. Using two different neuroimaging techniques we assessed post-acute neurometabolic and connectivity changes induced by ayahuasca in healthy volunteers. Our study focused on the PCC and the ACC, two brain regions that have consistently been identified as targets of psychedelics (Carhart-Harris et al., 2012, 2016a; Palhano-Fontes et al., 2015; Valle et al., 2016). We postulated three hypotheses; First, that excitatory effects in PCC and ACC during acute ayahuasca would lead to measurable decreases of glutamate-glutamine and energy metabolites in the post-acute phase. Second, that neurometabolic changes would parallel enhanced connectivity between the PCC and the ACC, by decreasing the normal pattern of anti-correlated brain activity existing between these brain regions. Third, that the measured neurometabolic and connectivity changes would correlate with increased mindfulness capacities in the immediate post-acute phase and at follow-up two months later.