This review (2021) summarizes what we know thus far with regards to the ability of serotonergic psychedelics to induce neural plasticity. Proposed mechanisms of action are discussed, as are the questions that need to be addressed as we move forward.

Abstract

“Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.”

Authors: Kacper Lukasiewicz, Jacob B. Baker, Yi Zuo & Ju Lu

Summary

—Huxley and Osmond, 2018.

The term “psychedelic” was coined by the psychiatrist Humphry Osmond in 1956 to remarket a class of compounds that induce profound changes in consciousness. These compounds have been called variously entheogens, empathogens, entactogens, and hallucinogens.

Psychedelic drugs promote the structural and functional plasticity of synapses, sites where neurons connect and communicate with each other. This makes them interesting for research on learning and memory, as well as for their therapeutic potential for psychiatric disorders.

Classical psychedelics include tryptamines, ergolines, and phenethylamines, and have diverse origins. They preferentially bind to the serotonin 2A (5-HT2A) receptor, and the affinity is strongly correlated with the hallucinogenic effect.

Ketanserin, a 5-HT2A receptor antagonist, blocks the hallucinogenic effect of the classical psychedelic psilocybin, and psychedelics do not produce the head-twitch response in 5-HT2A knock-out (KO) mice. Therefore, signaling induced by 5-HT2A receptor activation is likely necessary for psychedelics to cause hallucinations.

N, N-Dimethyltryptamine (DMT) and Its Derivatives

DMT is an active ingredient in ayahuasca, a hallucinogenic drink consumed in shamanic rituals in South America. It can promote neuroplasticity both in vitro and in vivo, increasing the number, length, and complexity of neurites and dendritic spines, and increasing the frequency and amplitude of EPSCs.

DMT induces neuroplastic effects through several molecular mechanisms, including 5-HT2A signaling, TrkB and mTOR signaling, and the sigma-1 receptor, which regulates calcium signaling and voltage-gated ion channels.

5-MeO-DMT, a methoxylated derivative of DMT, disrupts oscillatory neural activity in the PFC, the visual cortex (V1), and the mediodorsal nucleus of the thalamus in mice and is also observed in 5-HT2A KO mice, but not in 5-HT2A KO mice co-treated with WAY-100635, an antagonist of 5-HT1A.

Ibogaine and Its Analog

Ibogaine is a psychoactive carboline derivative isolated from the root bark of the West African rainforest shrub Tabernanthe iboga. Ibogaine is metabolized by cytochrome P450 2D6 (CYP2D6) into noribogaine (10-hydroxyibogamine), which may be the active compound in vivo. However, a high dosage of ibogaine can be neurotoxic, raising concerns about its safety for clinical use. Researchers developed tabernanthalog (TBG), a non-hallucinogenic, non-cardiotoxic analog of ibogaine, which increases dendritic spine formation in the mouse somatosensory cortex and can rescue anxiety, cognitive inflexibility, and sensory processing deficits in mice subjected to unpredictable mild stress.

Psilocybin

Psilocybin, an active ingredient in magic mushrooms, increases synaptic growth and strength in cultured rat cortical neurons and in vivo, as evidenced by an increased AMPA/NMDA ratio at the synapses between temporoammonic inputs and the distal dendrites of hippocampal CA1 pyramidal neurons in mice.

LSD is an ergoline synthesized by Albert Hofmann in 1938 from the lysergic acid found in ergot, a fungus that grows on grains. It has been shown to increase dendritic arbor complexity and dendritic spine density in cultured rat cortical neurons.

DOI

Phenethylamines are probably the most extensively explored class of psychedelics due to their ease of synthesis. DOI, the first synthesized phenethylamine, increases dendritic spine size in cultured neurons and enhances long-term potentiation at synapses onto layer 2/3 pyramidal neurons.

DOI can perturb cellular and network activity in the cortex. It reduces low-frequency oscillations and disrupts the temporal relationship between pyramidal neuron discharges and the local field potential, implicating 5-HT2A activation.

DOI’s neuroplastic effects are blocked by ANA-12, ketanserin, or rapamycin, implicating TrkB, 5-HT2A, and mTOR signaling, and DOI also depends on kalirin-7 for its effects. However, DOI induces epigenetic changes in enhancer regions that persist for at least a week after administration.

Ketamine

Ketamine is a non-competitive NMDAR antagonist initially used as a general anesthetic, but also producing significant psychological effects. It has been shown to have an antidepressant effect.

Ketamine, like classical psychedelics, promotes neuroplasticity. In cultured rat cortical neurons, ketamine increases spinogenesis and synaptogenesis, and promotes dendritic arborization of dopaminergic neurons, and improves spine density in the mPFC and hippocampus of mice subjected to chronic social defeat stress.

CONCLUSION AND DISCUSSION

Since the early 20th century, there has been considerable interest in using psychedelics to treat mental illnesses. Numerous clinical studies have shown encouraging therapeutic potentials of psychedelics, particularly LSD and psilocybin. Psychedelics may reconfigure the neuronal networks by promoting dendritic branching and dendritic spine formation, and by modulating dendritic excitability through interactions with 5-HT receptor subtypes. This may explain the persistence of symptomatic improvements after withdrawal from psychedelics.

Psychedelics’ molecular mechanisms of action are very complex, and may involve multiple receptors, including the 5-HT2A R, the 5-HT2C R, and the 5-HT1A R. Moreover, TrkB/BDNF and mTOR signaling pathways may be involved in the neuroplastic and behavioral effects of psychedelics.

Ketamine and psychedelic treatment share cellular and behavioral phenotypes, and engage distinct signaling pathways, which may help resolve the difference in their duration of effect and other pharmacological characteristics.

Many questions remain to be addressed regarding the neuroplastic effects of psychedelics, such as the functional implications of the observed structural plasticity, and the molecular and circuit underpinnings of the differential effects generated by psychedelics and their analogs.