One of the most consequential shifts in psychedelic science over the past decade has been the reframing of these compounds as psychoplastogens — molecules that, in preclinical models, rapidly and durably promote structural neural plasticity. DMT, the active alkaloid in ayahuasca, sits at the center of that reframing.

Medically supervised ayahuasca ceremony and neuroplasticity research at Sanctuary Tulum

The Ly 2018 Paper

The most-cited paper in this area is Ly et al., "Psychedelics Promote Structural and Functional Neural Plasticity," published in Cell Reports in 2018. Using cultured rat cortical neurons and in vivo work in flies and rodents, the authors reported that a range of classic serotonergic psychedelics — including DMT, psilocin, and LSD — increased dendritic spine density, dendritic arbor complexity, and synapse number, with effects comparable to ketamine.

The mechanism they proposed centered on activation of 5-HT2A receptors and downstream TrkB/mTOR signaling — the same pathway implicated in ketamine's rapid antidepressant effects. The authors coined the term psychoplastogen to describe this compound class.

Ayahuasca and BDNF in Humans

In human work, de Almeida et al. (2019) measured serum brain-derived neurotrophic factor (BDNF) before and after a single ayahuasca session in healthy volunteers and patients with treatment-resistant depression. BDNF is a key growth factor supporting neuronal survival and synaptic plasticity, and low BDNF has been associated with depression. They reported a significant increase in serum BDNF at 48 hours post-ayahuasca in both groups. The sample was small and BDNF in serum is a peripheral proxy, not a direct measure of what is happening in the brain, but the direction of the finding is consistent with the psychoplastogen framework.

Ayahuasca in a Randomized Trial

Palhano-Fontes et al., "Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial," published in Psychological Medicine in 2019, remains the reference clinical trial. In 29 patients with treatment-resistant depression randomized to ayahuasca or placebo, response rates at day 7 were significantly higher in the ayahuasca arm. The trial was small and single-session, and larger trials are needed, but it is the first controlled clinical demonstration that ayahuasca can produce a rapid antidepressant effect.

The Non-Hallucinogenic Analog Question

Cameron and colleagues (Nature, 2021) reported that a novel ibogaine-derived compound, tabernanthalog, promoted structural neural plasticity in rodent cortical neurons and produced antidepressant-like and anti-addiction behavioral effects — without the acute psychoactive profile of the parent compound. If replicated in humans, this would separate the plasticity mechanism from the subjective experience, and would represent a genuinely new drug-development strategy: keep the biology, drop the trip. Whether the subjective experience is dispensable to therapeutic effect in humans is not yet answered.

What This Doesn't Tell Us

Preclinical plasticity is not clinical cure. A compound can grow dendritic spines in a dish and still fail a Phase 3 trial. A serum BDNF bump at 48 hours does not, on its own, demonstrate durable brain change or symptom relief. And ayahuasca is a complex botanical preparation — DMT plus MAOI harmala alkaloids — whose pharmacology is not identical to isolated DMT.

The honest summary: the mechanistic case that ayahuasca and related tryptamines promote neural plasticity is well-supported preclinically and has some early human corroboration. The clinical case that this translates into durable relief for specific psychiatric conditions is promising but still under-powered. The field is now doing the harder work of designing controlled trials that can separate real drug effect from expectation, and confirm — or refute — the mechanistic story in humans.

Ayahuasca Is Not the Same as Isolated DMT

A methodological point often lost in enthusiastic coverage: the neuroplasticity work in cell culture and rodent models was done with isolated DMT (and other tryptamines), whereas ayahuasca is a two-plant preparation that contains DMT plus β-carboline harmala alkaloids acting as monoamine oxidase A inhibitors. The MAOI component is what allows DMT to be orally active — without it, DMT is broken down in the gut before it reaches circulation — and it also independently modulates serotonin, dopamine, and norepinephrine turnover. Effects that hold for isolated DMT in a dish may or may not hold for the full brew in a human. This is not an argument against the psychoplastogen hypothesis; it is an argument for keeping the preclinical and clinical evidence explicitly separate rather than folding them together in shorthand.

Ayahuasca in Neuroimaging

Palhano-Fontes and colleagues also reported (PLoS One, 2015) that a single ayahuasca session acutely modulated default mode network connectivity in healthy volunteers — reductions in DMN internal integrity, similar in direction to the reported effects of psilocybin and LSD. Whether these acute network changes translate to durable structural remodeling is not established in humans, but they are consistent with the broader story that classic serotonergic psychedelics acutely reduce constrained self-referential processing. Related discussion of the DMN mechanism is in our DMN and psychedelics piece.

What the Next Round of Studies Needs to Answer

Three specific questions would move the ayahuasca neuroplasticity story from suggestive to confirmed. First: does the acute serum BDNF signal correspond to actual synaptic remodeling as measured by more direct techniques (e.g., PET imaging of synaptic density markers such as SV2A)? Second: does the acute plasticity signal translate to durable clinical improvement in adequately-powered controlled trials, and at what effect size versus active comparator? Third: does the botanical ayahuasca preparation behave differently from isolated DMT plus a separate MAOI, and if so, in what direction? Answers to any of those would change how confidently the current framework can be stated. Answers to all three would move the story into settled clinical science.

A Note on Sanctuary Tulum

Sanctuary Tulum has offered medically supervised ayahuasca ceremonies in Tulum, Mexico since 2011, under a federal health license. We do not make clinical claims beyond the published evidence. See our safety credentials for medical protocols.

References

US-based readers evaluating travel logistics can also review our detailed guide on ayahuasca ceremonies near me for a NYC-focused breakdown of the legal landscape and licensed Mexico alternative.