Unraveling the Biological Underpinnings of Psychedelics
An attempt to summarize the evidence that psychedelics induce neuroplasticity by focusing on molecular and cellular effects.
Psychedelics are powerful psychoactive substances that produce profound changes in perception, processing, and responding to stimuli in the environment which results in altered states of consciousness.
Clinical studies suggest therapeutic potentials of the so-called classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), N, N-dimethyltryptamine (DMT), and the DMT-containing brew ayahuasca in various stress-related disorders.
These psychoactive molecules induce antidepressant, anxiolytic, anti-addictive, and cognitive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine.
The proposed route is by inducing brain neuroplasticity, potentially the key factor underlying the beneficial effects.
In the first article I published on Medium I discussed why psychedelics are so effective for treating mental illnesses. The role of psychedelic-induced neuroplasticity on the deep-rooted patterns of behavior and thinking, often seen in mental health disorders, is discussed.
Moreover, I hypothesize why psychedelics can eradicate these ruminating patterns of behavior in just one or a few treatments. If you’re interested, you can read the article here.
In this article, we dive deeper into the biological underpinnings of psychedelic-induced neuroplasticity, based on a recently published review in Frontiers in Psychiatry from researchers of the Department of Neuropsychology and Psychopharmacology, Maastricht University.
Introduction
Classic serotonergic psychedelics are so-called because they exert their powerful effects by primarily binding to serotonin (5-hydroxytryptamine or 5-HT) receptors in the brain.
A brief look at the molecular structures below explains this interaction — the structure of serotonin is seen in the structures of the psychedelic compounds, therefore, psychedelics have a high affinity for 5-HT receptors.
Besides the fact that psychedelic compounds can bind to a range of serotonin receptors in the brain, psychedelics also exhibit affinity for dopamine and adrenergic receptors, as listed below.
Keep in mind, molecules can exert an antagonist or agonist action at the receptor site. An antagonist action means that a molecule blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist, such as psychedelic molecules acting primarily as an agonist or partial agonist.
Both psilocybin and its active metabolite psilocin exhibit affinity for:
- A range of serotonin receptors (5-HT1A/B/D/E, 2B, 5, 6, 7) with a high affinity for the 5-HT2A receptor.
- The dopamine D3 receptor
LSD exhibits affinity for:
- 5-HT1A/D, 2A/B/C, and 5-HT6
- The dopamine D1 and D2. It displays a shared agonism for 5-HT2A and dopamine D2 receptors.
- The α-adrenergic receptors
DMT exhibits affinity for:
- 5-HT1A/D, and 5-HT6 receptors, with a high affinity for the 5-HT2A receptors.
- The sigma-1 receptor
Neuroplasticity
Besides their acute effects, research has demonstrated that psychedelics induce changes in behavioral and cognitive processes. Given the persisting nature of the psychological effects beyond the presence of the psychoactive substance in the blood, a biological adaptation is suggested.
Changes in neuroplasticity are the key component of biological adaptations that can underlie psychedelics’ persisting behavioral and cognitive changes.
Neuroplasticity is the brain’s ability to change throughout life and consists of changes in cell structure, structural plasticity, and changes in the efficacy of communication between neurons across a synapse, also called functional plasticity.
The nervous system’s ability to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, function, or connections is very interesting. This means that the brain can grow neurons and reorganize neuronal pathways between parts of the brain.
So in short, it is plasticity that enables the process of developing and pruning connections, allowing the brain to adapt itself to its environment. Although plasticity occurs over an individual’s lifetime, it dominates mostly the time from birth to the age of 25.
Molecular level
Structural and functional plasticity are interconnected processes at a molecular and (sub)cellular level. To fully understand the extent of psychedelics’ effects on these levels, the levels at which neuroplasticity can occur will be discussed below.
We start at the molecular level where neuroplastic changes occur via signaling pathways. These are cascades of intracellular proteins transmitting signals from receptors on the cell membrane to eventually DNA expression in the nucleus of the cell.
Activation of signaling pathways at the molecular levels can occur in two ways:
- By Ca2+ influx (movement of substance into the cell) through depolarization
- Or via N-methyl-D-aspartate (NMDA) receptor activation
Through depolarization of the cell membrane or via activation of the NMDA receptor on the cell membrane, multiple signaling pathways within the cell are activated. These pathways include the:
- Ca2+/calmodulin-dependent protein kinase (CaMK2)
- Extracellular regulated kinase 1/2 (ERK1/2)
- Mitogen-activated protein kinase (MAPK)
- Brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB)
Subsequently, within the nucleus of the cell, two proteins are activated allowing modulation of gene transcription and protein synthesis related to neuronal plasticity. These two proteins are:
- The cyclic AMP-responsive element-binding protein (CREB)
- The nuclear factor kappa B protein complex (NF-kB)
For example, upon the neuronal activity, immediate early genes (IEGs) are rapidly expressed and are essential for synaptic plasticity.
The names of IEGs are not that important but the crucial thing to remember is that changes in the expression of plasticity-related genes can influence neuroplasticity at the cellular level.
Cellular level
Changes at the cellular level can be structural or functional, and both types have different levels that will be listed here.
Structural plasticity consists of:
- Neuronal plasticity
- Dendritic plasticity
- Synaptic plasticity
Neuronal plasticity is the process of neuronal networks in the brain to change to growth and reorganization induced by the generation of neurons — this is called neurogenesis.
This occurs in 5 distinctive phases.
- Proliferation
- Differentiation
- Survival
- Migration
- Maturation
In the proliferation phase, proliferating progenitor cells — descendants of stem cells — are generated in the hippocampal subgranular zone and differentiate into dentate granule neurons.
Then, the proliferating cells that survive the elimination via apoptotic cell death migrate and mature into newborn granule cells — one of the small neurons that form the layers of the cerebral cortex — and eventually fully integrate into the hippocampal network.
Dendritic plasticity includes changes in the number of the complexity of dendritic spines, where a high number of spines and complex dendritic branches reflect more synaptic strength. Dendritic spine formation is caused by an extensive release of γ-aminobutyric acid (GABA) or glutamate.
The strength of synapses is related to learning and memory formation and can change in two directions, either increasing, known as long-term potentiation (LTP), and decreasing, called long-term depression (LTD).
Synaptic plasticity alters the neuron’s structure and its functional properties. This type of plasticity is regulated by various factors, with the protein BDNF as the primary regulator. BDNF is expressed highly throughout the central nervous system, particularly in the hippocampus.
The protein BDNF is involved in multiple levels of neuroplasticity including
- Synaptic modulation
- Adult neurogenesis
- Dendritic growth
Interestingly, in a pathological population suffering from depression, anxiety, and addiction, BDNF levels are diminished. Preclinical and clinical research has shown that BDNF levels can be increased by selective serotonin reuptake inhibitors (SSRIs) or ketamine to manage the symptoms of these disorders.
“To summarize, it is hypothesized that neurobiological changes, specifically enhanced neuroplasticity, underlie psychedelics’ therapeutic effects.”
The authors wrote.
“Understanding the biological pathways of psychedelics’ acute and persisting effects is essential to grasp these compounds’ full therapeutic potential. Although psychedelics do not have an established therapeutic use in psychiatry yet, promising preliminary findings of their therapeutic potential support further investigation and give insight into psychiatric disorders’ biological underpinnings.”
Findings
The authors of this review evaluated preclinical and clinical studies to understand the acute, subacute (24 h−1 week post-treatment), and longer-term effects of (serotonergic) psychedelics on molecular and cellular neuroplasticity.
Four main findings are reported that stand out from the review.
- The first finding concerns dose differences between preclinical and clinical studies and their translation from animal to human.
“… findings suggest that the highest doses given in clinical studies resemble the lowest doses of LSD in preclinical studies, highlighting an important factor that should be considered in the translation of preclinical findings to humans.”
- The second significant finding concerns sex differences in response to psychedelics which could be related to sex-specific changes in neuroplasticity.
“The female sex hormone estrogen exhibits antidepressant effects through stimulation of BDNF and synaptic plasticity, in a manner that is distinct for males and females.”
The researchers explained in the study.
“The antidepressive effects of ketamine and psychedelics are both suggested to result from changes in neuroplasticity, and these findings indicate a potential role for gonadal hormones in the sex-specific response to these substances. Neurobiological research in animal models is biased toward males.”
- The third finding concerns the measurement of BDNF in clinical studies.
“All clinical studies reported peripheral BDNF levels, an indirect measure of BDNF levels in the brain. It would be more precise to examine cerebrospinal fluid (CSF) BDNF levels as this directly reflects brain activity.
The researchers commented.
“Furthermore, while previously it was not clear whether clinical response was related with plasma BDNF levels, evidence suggests that there is a positive relation with clinical improvement being linked with improved neuroplasticity.”
- The fourth finding concerns the sample size of some in vivo studies, which was low.
“This is a well-known problem in (neuro)biological research. Researchers are to justify the number of animals used in their experiments, which should be designed to minimalize the number of animals used. This could explain the low sample size in in vivo studies reviewed here, and is essential to consider because it reduces the statistical power and limiting the reliability of conclusions.”
Neuroplasticity upon 5-HT2A receptor activation
Evidence suggests that the psychedelic-induced changes in neuroplasticity result from the neurobiological pathways activated by 5-HT2A receptors upon activation, see illustration below.
5-HT2A receptors activation affects the serotonergic and glutamatergic system. Psychedelics primarily act on 5-HT2A receptors expressed on glutamatergic pyramidal cells in the cortex leading to the activation of intracellular signaling pathways such as phospholipase C (PLC), phospholipase A (PLA), and Src. Activation of the latter pathway is suggested to be essential for psychedelics’ hallucinogenic effects.
Activation of intracellular signaling pathways stimulate synaptic plasticity via the release of molecules in two ways:
- CA2+ influx
- Glutamate influx
“Increased glutamate in the cortex release can further stimulate synaptic plasticity via AMPAR [receptor] on pyramidal neurons in cortical layer V and subsequent transportation (trafficking) of AMPAR to the postsynaptic cell membrane. This increases AMPAR density, resulting in more extracellular glutamate and BDNF release in the cortex.”
Indirectly, via the expression of BDNF and other plasticity-related genes (including IEGs) and proteins psychedelics can influence plasticity.
- Cortical BDNF mRNA was upregulated by LSD and ayahuasca
- IEGs are implicated in synaptogenesis and synaptic plasticity
- Many IEGs encode for proteins involved in specific signaling cascades
Some examples of IEGs:
- Arc is localized at dendrites and involved in cytoskeletal rearrangements
- Egr2 has coupled activity with the NMDA receptors
- Sgk promotes cell survival
- Neuron-derived orphan receptor 1 (Nor1; NR4A3) is important for long-term potentiation (LTP)
Sigma-1 receptor
Different effects on neuroplasticity between psychedelics can be attributed to differences in receptor affinity, given that psychedelics are not pure 5-HT2A receptor agonists. Besides a high affinity for the 5-HT2A receptor, DMT exhibits also a high affinity for the sigma-1 (S1) receptor.
The S1 receptor is highly expressed in the hippocampus and is a stimulator of synaptic plasticity.
- Activation of the S1 receptor by DMT stimulates synaptic plasticity in addition to 5-HT2A receptor-induced modulation. Presumably responsible for ayahuasca’s antidepressant effects.
- LSD indirectly stimulates the S1 receptor via activation of dehydroepiandrosterone (DHEA), which stimulates synaptic plasticity and neurogenesis.
- Activation of S1 receptors by SSRIs enhances BDNF expression.
“These findings support the hypothesis that the psychedelics’-induced stimulation of neuroplasticity underlies a mechanism similar to SSRIs.”
Ketamine
Ketamine is an NMDA receptor antagonist and its antidepressant effects are also suggested to result from enhanced synaptic plasticity and BDNF.
- Ketamine blocks postsynaptic NMDA receptors located on glutamatergic neurons in the cortex.
- Therefore, ketamine deactivates the eukaryotic Elongation Factor-2 (eEF2) kinase, which subsequently alleviates its block on BDNF translation, resulting in heightened BDNF levels.
In addition,
- ketamine is hypothesized to block NMDA receptors on GABA interneurons, releasing the inhibition of glutamate release.
- This activates AMPA receptors on glutamatergic cells and subsequently increases BDNF and glutamate in the cortex.
- Psychedelics and ketamine activate cortical AMPA receptors and subsequently stimulate BDNF and synaptic efficacy.
Conclusion
This review is the first to explain psychedelics’ rapid antidepressant and cognitive effects, by investigating molecular and cellular changes related to neuroplasticity.
A clearer understanding of the underlying biological mechanisms of serotonergic psychedelics emphasizes the need for scientific research in this field.
Not only because psychedelics are beneficial in populations suffering from psychopathologies, but also for healthy individuals, enhancing social and cognitive skills such as empathy and creativity, but also general well-being.
“Further research is essential to establish the specific (intra)cellular mechanism activated by different psychedelics, their long-term effects, and their relation with altered behavior. The current findings support research exploring psychedelics’ potential in the treatment of psychopathologies.”
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