OPEN Foundation

S. Ribeiro

Whole Organisms or Pure Compounds? Entourage Effect Versus Drug Specificity

Abstract

As the therapeutic use of sacred plants and fungi becomes increasingly accepted by Western medicine, a tug of war has been taking place between those who advocate the traditional consumption of whole organisms and those who defend exclusively the utilization of purified compounds. The attempt to reduce organisms to single active principles is challenged by the sheer complexity of traditional medicine. Ayahuasca, for example, is a concoction of at least two plant species containing multiple psychoactive substances with complex interactions. Similarly, cannabis contains dozens of psychoactive substances whose specific combinations in different strains correspond to different types of therapeutic and cognitive effects. The “entourage effect” refers to the synergistic effects of the multiple compounds present in whole organisms, which may potentiate clinical efficacy while attenuating side effects. In opposition to this view, mainstream pharmacology is adamant about the need to use purified substances, presumably more specific and safe. In this chapter, I will review the evidence on both sides to discuss the scientific, economic, and political implications of this controversy. The evidence indicates that it is time to embrace the therapeutic complexity of psychedelics.

Ribeiro, S. (2018). Whole organisms or pure compounds? entourage effect versus drug specificity. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 133-149. 10.1007/978-3-319-76720-8_8
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Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT

Abstract

Dimethyltryptamines are entheogenic serotonin-like molecules present in traditional Amerindian medicine recently associated with cognitive gains, antidepressant effects, and changes in brain areas related to attention. Legal restrictions and the lack of adequate experimental models have limited the understanding of how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico analysis reinforced previously reported anti-inflammatory actions of 5-MeO-DMT and revealed modulatory effects on proteins associated with long-term potentiation, the formation of dendritic spines, including those involved in cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization. Our data offer the first insight about molecular alterations caused by 5-MeO-DMT in human cerebral organoids.
Dakic, V., Nascimento, J. M., Sartore, R. C., de Moraes Maciel, R., Araujo, D. B., Ribeiro, S., … & Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific Reports7(1), 12863. 10.1038/s41598-017-12779-5
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Short term changes in the proteome of human cerebral organoids induced by 5-methoxy-N,N-dimethyltryptamine

Abstract

Dimethyltryptamines are hallucinogenic serotonin-like molecules present in traditional Amerindian medicine (e.g. Ayahuasca, Virola) recently associated with cognitive gains, antidepressant effects and changes in brain areas related to attention, self-referential thought, and internal mentation. Historical and technical restrictions impaired understanding how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by dimethyltryptamine (5-methoxy-N,N-dimethyltryptamine, 5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico systems biology analyses support 5-MeO-DMT’s anti-inflammatory effects and reveal a modulation of proteins associated with the formation of dendritic spines, including proteins involved in cellular protrusion formation, microtubule dynamics and cytoskeletal reorganization. Proteins involved in long-term potentiation were modulated in a complex manner, with significant increases in the levels of NMDAR, CaMKII and CREB, but a reduction of PKA and PKC levels. These results offer possible mechanistic insights into the neuropsychological changes caused by the ingestion of substances rich in dimethyltryptamines.

Dakic, V., Nascimento, J. M., Sartore, R. C., de Moraes Maciel, R., de Araujo, D. B., Ribeiro, S., … & Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-methoxy-N, N-dimethyltryptamine. bioRxiv, 108159.
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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 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.

Bouso, J. C., Palhano-Fontes, F., Rodríguez-Fornells, A., Ribeiro, S., Sanches, R., Crippa, J. A. S., … & Riba, J. (2015). Long-term use of psychedelic drugs Is associated with differences in brain structure and personality in humans. European Neuropsychopharmacology. http://dx.doi.org/10.1016/j.euroneuro.2015.01.008
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Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion

Abstract

The hallucinogenic brew Ayahuasca, a rich source of serotonergic agonists and reuptake inhibitors, has been used for ages by Amazonian populations during religious ceremonies. Among all perceptual changes induced by Ayahuasca, the most remarkable are vivid “seeings.” During such seeings, users report potent imagery. Using functional magnetic resonance imaging during a closed-eyes imagery task, we found that Ayahuasca produces a robust increase in the activation of several occipital, temporal, and frontal areas. In the primary visual area, the effect was comparable in magnitude to the activation levels of natural image with the eyes open. Importantly, this effect was specifically correlated with the occurrence of individual perceptual changes measured by psychiatric scales. The activity of cortical areas BA30 and BA37, known to be involved with episodic memory and the processing of contextual associations, was also potentiated by Ayahuasca intake during imagery. Finally, we detected a positive modulation by Ayahuasca of BA 10, a frontal area involved with intentional prospective imagination, working memory and the processing of information from internal sources. Therefore, our results indicate that Ayahuasca seeings stem from the activation of an extensive network generally involved with vision, memory, and intention. By boosting the intensity of recalled images to the same level of natural image, Ayahuasca lends a status of reality to inner experiences. It is therefore understandable why Ayahuasca was culturally selected over many centuries by rain forest shamans to facilitate mystical revelations of visual nature.

de Aurojo, D. B., Ribeiro, S., Cecchi, G. A., Carvalho, F. M., Sanchez, T. A., Pinto, J. P., … Santos, A. C. (2011). Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion. Human Brain Mapping, 33(11), 2550-2560. http://dx.doi.org/10.1002/hbm.21381
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