The Ayahuasca Science Since Narby: What Twenty-Five Years of Research Has Found

“Narby published in 1998, when there was almost no controlled research on ayahuasca. There is now. The combinatorial problem he posed remains open. Everything else is better understood.”

When Jeremy Narby published The Cosmic Serpent in 1998, controlled clinical research on ayahuasca was essentially nonexistent in Western scientific literature. He was writing about a phenomenon, the pharmacological effects and cultural context of ayahuasca, that had been documented by ethnobotanists and anthropologists but not studied in clinical settings. The Hoasca Project (1993), a collaboration between Brazilian and American researchers studying União do Vegetal members, was the first controlled study of long-term ayahuasca use, and it had only recently been published.

Twenty-five years later the research landscape is substantially different. The mechanism is well characterized. The therapeutic applications are actively studied. The phenomenology has been measured in hundreds of subjects. The combinatorial problem Narby posed remains open. Everything else is better understood.

THE PHARMACOLOGY

Ayahuasca is a brew prepared from Banisteriopsis caapi (a vine containing β-carboline alkaloids, harmine, harmaline, tetrahydroharmine) and Psychotria viridis or Diplopterys cabrerana (leaves containing N,N-dimethyltryptamine). The β-carbolines are monoamine oxidase inhibitors that prevent the gut and liver from metabolizing DMT before it reaches the central nervous system. Without MAO inhibition, orally ingested DMT is pharmacologically inactive. The combination produces 4-6 hour psychedelic experiences with a characteristic phenomenology.

The specific 5-HT2A receptor binding that drives the psychedelic effects is now characterized at atomic resolution. The contribution of each alkaloid to the overall experience, harmine's mild stimulant effect, tetrahydroharmine's serotonin reuptake inhibition, DMT's primary hallucinogenic action, is reasonably well understood at the receptor level.

THERAPEUTIC RESEARCH

Rafael Guimarães dos Santos and colleagues at the University of São Paulo reviewed studies of ayahuasca, psilocybin and LSD for depression, anxiety and addiction (Therapeutic Advances in Psychopharmacology, 2016). They found promising antidepressant, anti-anxiety and anti-addictive effects, mostly from small or uncontrolled studies. The neuroplasticity mechanism, BDNF upregulation, dendritic spine growth, provides a pharmacological explanation for both the rapid onset and the lasting duration.

A 2019 review in Current Neuropharmacology by Hamill and colleagues summarized ayahuasca research in addiction and mental illness and reported generally positive but preliminary findings. The evidence base is substantially weaker than for psilocybin (fewer RCTs, smaller samples, more heterogeneous preparation) but points in the same direction.

THE ENTITY CONTACT QUESTION

Narby's specific focus, the consistency of serpentine imagery and entity contact across shamanic traditions, has been documented further in surveys, though not explained. Timmermann et al.'s 2023 PNAS paper, using simultaneous EEG-fMRI during IV DMT administration, mapped DMT's global brain effects, large increases in global functional connectivity, network disintegration and desegregation, and compression of the principal cortical gradient. It did not isolate entity contact as a distinct neural signature, and no published imaging study yet has: the phenomenology is well documented, the neural specificity is not. Similar reports are well documented in self-selected surveys. Neural correlates specific to entity contact have not been identified. The interpretation, whether entities are produced by the brain or perceived through the brain, is not settled by neuroscience.

THE COMBINATORIAL PROBLEM

Narby's core puzzle, how Amazonian peoples identified the specific combination of these two plants from 80,000 candidate species in the absence of any obvious single-session discovery mechanism, remains without an accepted scientific explanation. No controlled research has addressed the acquisition question. The pharmacological interaction is understood; its discovery by human beings without the tools of Western pharmacology is not. This remains the most genuinely open question Narby raised.

Sources

• Narby, The Cosmic Serpent (1998)
• Dos Santos et al., Ther Adv Psychopharmacol (2016)
• Frecska et al., Front Pharmacol (2016)
• Hamill et al., Curr Neuropharmacol (2019)
• Timmermann et al., PNAS 120(13) (2023)