Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

This review (2022) explores our current understanding of the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules. The ability of psychedelics to promote structural and functional plasticity in the prefrontal cortex (PFC) and the implications this has for many stress-related neuropsychiatric disorders like PTSD are some of the topics discussed.

Abstract

“In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioural changes relevant to the treatment of neuropsychiatric disorders that last long after the compounds have been cleared from the body. One hypothesis with the potential to explain the remarkable enduring effects of psychedelics is related to their abilities to promote structural and functional neuroplasticity in the prefrontal cortex (PFC). A hallmark of many stress-related neuropsychiatric diseases, including depression, post-traumatic stress disorder (PTSD), and addiction, is the atrophy of neurons in the PFC. Psychedelics appear to be particularly effective catalysts for the growth of these key neurons, ultimately leading to the restoration of synaptic connectivity in this critical brain region. Furthermore, evidence suggests that the hallucinogenic effects of psychedelics are not directly linked to their ability to promote structural and functional neuroplasticity. If we are to develop improved alternatives to psychedelics for treating neuropsychiatric diseases, we must fully characterize the molecular mechanisms that give rise to psychedelic-induced neuroplasticity. Here, I review our current understanding of the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules, with an emphasis on key unanswered questions.”

Authors: David E. Olson

Summary

Psychedelics, but not Ketamine, produce persistent antidepressant-like effects in a rodent experimental system for the study of depression. (6) Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Psilocybin-assisted therapy for major depressive disorder: a randomized clinical trial.

Psilocybin and MDMA are novel psychopharmacological therapies for psychiatric disorders, with psilocybin producing substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. Psychedelic drugs may have therapeutic potential for the treatment of mood disorders. A systematic review of clinical trials published in the last 25 years has shown promising results. Psychedelic drugs are being studied in more and more depth, and several papers have been written about the neurobiology of psychedelic drugs, as well as the role of psychedelics in the treatment of mood disorders.

Neuronal growth is induced by serotonin receptors in vitro. Serotonin 2A receptor regulates microtubule assembly and induces dynamics of dendritic growth cones in rat cortical neurons in vitro.

Psychedelics restore functional neural circuits disrupted by unpredictable stress in the pig brain.

Ketamine and serotonergic psychedelics share common mechanisms underlying the effects of rapid-acting anti-depressants, according to several studies.

5-HT6 and 5-HT7 receptors, novel alternative for memory formation and memory alterations: Quiedeville, A., Boulouard, M., Da Silva Costa-Aze, V., Dauphin, F., Bouet, V.; Freret, T.

LSD-induced altered states of consciousness alter global and thalamic brain connectivity, which is attributable to the 5-HT2A receptor.

The potency of hallucinogens in the mouse head-twitch response assay correlates with their behavioral and subjective effects in other species.

A single amino acid difference between mouse and human serotonin 5-HT2A receptors impacts behavioral translation of novel ligands.

Lysergic acid diethylamide promotes social behavior through mTORC1 in the excitatory neurotransmission.

Ketamine activates glutamatergic neurotransmission in human cerebral organoids, a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex.

In vivo AAV1 transduction with hRheb (S16H) protects hippocampal neurons by BDNF production.

Psychedelic drugs induce rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons, and may have implications for the treatment of mood disorders.

A convergence of distinct signaling pathways on synaptic scaling triggers rapid antidepressant action.

Scopolamine induces the immediate-early gene c-Fos in the hippocampus and the neocortex, and the hallucinogen d-lysergic acid diethylamide induces the immediate-early gene c-Fos in the rat forebrain.

Psychedelics induce complex transcriptional responses within the brain, including recruitment of multiple cellular types.

Pei, Q., Lewis, L., Sprakes, M. E., Jones, E. J., Grahame-Smith, D. G., Zetterstrom, T. S. and Sprakes, M. E. studied the role of serotonin in Arc gene expression.

A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. A single dose of psilocybin influences behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig.

LSD and lisuride are agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells.

Cussac, Boutet-Robinet, E., Ailhaud, M. C., Newman-Tancredi, A., Martel, J. C., Danty, N., Rauly-Lestienne, I. 5-HT2A receptor-mediated phosphoinositide hydrolysis in the stimulus effects of hallucinogens.

Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves, and a complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation.

Serotonin activates the serotonin 2A receptor via a beta-arrestin-2/Src/Akt signaling complex in vivo.

The serotonin/glutamate receptor complex is implicated in many psychedelic drug effects, and it is thought to be involved in the trafficking of stimulus to the receptors.

Serotonin receptor subtypes 2 heterodimers are driven by 5-HT2C protomers and interact through functional brain pathways. Genetically encoded photocrosslinkers locate the heteromeric interface of a GPCR complex in living cells.

The 5-HT2A receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists, and the group II mGlu receptor modulates DOI-induced increases in cortical BDNF expression.