Beyond the Trip: Psychedelic Therapy

Nov 23, 2023 | Written by Priyanka Puranik, MSc | Reviewed by Scott Sherr, MD and Marion Hall

Beyond the Trip: Psychedelic Therapy

Once emblematic of countercultural exploration, psychedelics have re-entered the scientific spotlight as potential therapeutics for a range of psychiatric disorders.

The use of psychedelics for their potential cognitive and mental health benefits is a topic that has gained attention in recent years. Psychedelics like LSD, psilocybin, DMT, ketamine, and MDMA have been explored for their nootropic and psychoplastogenic properties, making them intriguing subjects for research and clinical trials.

Unlike conventional pharmacotherapies, the unique mechanisms of action of these substances offer a glimpse of hope in alleviating distress in disorders such as depression, bipolar disorder, and schizophrenia.

This article unravels the molecular and cellular mechanisms unearthed in recent research concerning psychedelic substances and explores their potential implications in treating bipolar disorder, depression, and other neuropsychiatric conditions. Through a careful analysis of cutting-edge research, we aim to uncover the therapeutic potential encapsulated within the enigmatic nature of psychedelics.

Serotonin Soiree: Unlocking Psychedelic Potentials

Psychedelics, often termed as serotonergic psychedelics, primarily exert their effects by interacting with the serotonin (5-HT) receptor systems in the brain. Among the various serotonin receptors, the 5-HT2A receptor is instrumental in mediating the effects of psychedelics. This section sheds light on the key findings from the body of literature underscoring the serotonergic mechanisms of psychedelics.

  • 5-HT2A Receptor Agonism: The serotonergic action of psychedelics is chiefly mediated through their agonistic activity on the 5-HT2A receptors. Psychedelics, owing to their 5-HT2A agonism, may disrupt the activity of the default mode network (DMN), which is often hyperactive in individuals with depression. This modulation of DMN is thought to underlie the antidepressant effects observed post psychedelic administration [1,2].
  • Dendritic Growth and Spine Density: Hess [3] sheds light on another aspect of serotonergic action; namely, that the activation of 5-HT2A receptors promotes dendritic growth and enhances spine density in rat cortical neurons. This mechanism is believed to underpin the neuroplastic changes observed post psychedelic exposure, facilitating the rewiring of neural circuits that may be maladaptive in nature.
  • Receptor Downregulation and Modulation of Brain-derived Neurotrophic Factor (BDNF): Serotonergic psychedelics are also recognized for modulating the expression of BDNF, a crucial molecule involved in neuronal survival, differentiation, and synaptic plasticity. The modulation of BDNF and receptor downregulation are suggested to play key roles in mediating the antidepressant effects of psychedelics [4,5].

Neurochemical Tango: When Serotonin Meets Glutamate

The intricacies of how psychedelics affect our brain extend beyond the serotonergic system and into an interactive play with the glutamatergic system. This section delves into how the interplay between serotonin and glutamate receptors contributes to the myriad effects of some psychedelics, and how this interaction can potentially be harnessed for therapeutic purposes in neuropsychiatric conditions.

  • mGluR2/3 Receptor Modulation: Recent studies indicate that metabotropic glutamate receptor 2/3 (mGluR2/3) modulation presents a potential pathway for neuroprotection, possibly explored through psychedelics. Glutamate, a primary excitatory neurotransmitter in the brain, is pivotal in many neurological conditions, with disruptions in its transmission implicated in various neurodegenerative and neuropsychiatric disorders [6].

    mGluR2 and mGluR3, part of the Group II mGluR family, are viewed as potential drug targets due to their role in inhibiting glutamate release and modulating numerous signaling pathways in both pre and postsynaptic nerve terminals, and neuroglia. They are being explored for treating conditions like amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, schizophrenia, and depression [6].

  • AMPA Receptor Potentiation: Some psychedelics have also shown the ability to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a subtype of glutamate receptor. This potentiation is thought to promote synaptic plasticity, which could be instrumental in ameliorating symptoms of depression and other mood disorders.

  • NMDA Receptor Modulation: Additionally, the interaction of psychedelics with N-methyl-D-aspartate (NMDA) receptors has sparked interest within the scientific community. Particularly, the potential of psychedelics to act as NMDA receptor antagonists may hold promise in the treatment of disorders such as depression and schizophrenia.

  • Indirect Glutamate Release: Furthermore, some psychedelics may indirectly augment glutamate release in certain brain regions, which in turn could mediate neuroplastic changes conducive to the amelioration of neuropsychiatric symptoms.

Neurotransmitter Nexus: Psychedelics, Serotonin, and NMDA

The delicate interplay between psychedelics and the serotonin and NMDA receptors in the brain is a nexus potentially crucial for understanding and addressing various neuropsychiatric conditions. Through substances like LSD, psilocybin, DMT, ketamine, and MDMA, let’s discover how these compounds might navigate neural pathways, opening doors to new therapeutic possibilities. Unravelling the mechanisms of these substances lays the groundwork for a deeper comprehension of their effects on the brain and mental health.

  • LSD (Lysergic acid diethylamide): LSD has nootropic effects, enhancing neural plasticity, visuo-spatial memory, and cognitive function. It is known for its interaction with the 5-HT2A receptors. The improved neural plasticity induced by LSD is attributed to the upregulation of dendritic spines, increased dendritic complexity, and increased synaptic responses [7]. While it predominantly interacts with the serotonergic system, it may indirectly impact NMDA receptor modulation by affecting glutamate release.
  • Psilocybin: Psilocybin, found in "magic mushrooms," interacts with the serotonin system and specifically with 5-HT2A receptors. It promotes increased neurogenesis and can mitigate fear responses, suggesting its potential for conditions like post-traumatic stress disorder (PTSD). Psilocybin therapy also enhances cognitive flexibility and mood changes in patients with major depressive disorder [7].
  • DMT (Dimethyltryptamine): According to Barker, DMT, famously found in some traditional Amazonian plant brews like ayahuasca, has been studied for its potential to increase neurogenesis and dendritic spine density, which might help mitigate symptoms of depression and anxiety while enhancing cognitive performance [8]. It also has a serotonergic component, interacting primarily with serotonin receptors. Barker further suggests that DMT affects both the serotonergic and glutamatergic systems, aligning with the broader discussion of psychedelic interactions with neurotransmitter systems.
  • Ketamine: Ketamine, at low concentrations, offers promise for addressing treatment-resistant depression by acting on the glutamatergic system, particularly through NMDA receptor antagonism [9]. It influences the protein BDNF in the hippocampus, which is crucial for its antidepressant effects [9]. While it primarily interacts with the glutamatergic system, ketamine's mechanisms may indirectly affect serotonin receptors.
  • MDMA (Ecstasy): MDMA is known for its serotonergic effects, primarily as a central nervous system stimulant, impacting serotonin receptors [9]. It is being explored in the context of PTSD and has shown promise in reducing PTSD symptoms and improving depressive symptoms when used with psychotherapy [9].

The mechanism of action of these psychedelics involves complex interactions between both the serotonergic (5-HT2) and glutamatergic (NMDA) systems, highlighting the intricate neurochemical dance they perform in the brain to produce their effects. These interactions contribute to their potential therapeutic applications in various neuropsychiatric conditions.

Psychedelic Horizons: Illuminating Mental Health

The exploration of serotonin-glutamate receptor interactions by psychedelics unveils promising therapeutic prospects for a variety of neuropsychiatric disorders. This section aims to elucidate the potential impact of psychedelics on bipolar disorder, depression, and schizophrenia, building upon the mechanisms discussed earlier.

  • Bipolar Disorder: The neuroplastic changes potentially induced by psychedelics could usher in a new era of treatment for bipolar disorder. By targeting the structural and functional brain abnormalities often seen in this disorder, psychedelics could foster a more balanced neural activity, possibly mitigating the severe mood swings associated with bipolar disorder.

  • Depression: The modulatory actions of psychedelics on serotonergic and glutamatergic systems could lay a solid foundation for novel antidepressant therapies. By aiding in the reset of maladaptive neural circuits and promoting neurogenesis, psychedelics might offer rapid and lasting relief from depressive symptoms.

    Specifically, the agonistic action of psychedelics on 5-HT2A receptors could lead to mood elevation, potentially providing immediate relief from depressive symptoms [1]. Moreover, the promotion of synaptic plasticity and neurogenesis might address the underlying neural deficits often seen in depression [10,11].

  • Schizophrenia: Although the use of psychedelics in schizophrenia is approached with extreme caution due to the risk of exacerbating psychosis, the insights gained from studying the modulation of glutamatergic neurotransmission by psychedelics could illuminate novel antipsychotic strategies. For instance, the potential of psychedelics to act as NMDA receptor antagonists may hold promise in the treatment of schizophrenia.

Brain Bloom: Psychedelics and the Plasticity Phenomenon

Psychedelics' ability to promote neuroplasticity, the brain's inherent ability to reorganize and form new neural connections, stands as a cornerstone of their therapeutic potential in neuropsychiatric conditions.

  • Synaptic Plasticity: By enhancing synaptic plasticity, a fundamental mechanism underlying learning and memory, psychedelics potentiate AMPA receptors and modulate other glutamate receptors, supporting synaptic strengthening and the formation of new neural pathways [10].
  • Neurogenesis: Additionally, psychedelics may boost neurogenesis, especially in the hippocampus, a region crucial for memory and emotional regulation, which could significantly impact disorders like depression and anxiety [11].

Mind Metamorphosis: Psychedelics and Neurotransmitters

The principal mechanism of psychedelics is their modulation of neurotransmitter systems, especially the serotonergic system, pivotal in mood regulation.

  • Serotonin 2A Receptor Agonism: The agonistic action on serotonin 2A (5-HT2A) receptors by psychedelics can lead to altered states of consciousness and mood elevation, possibly providing a therapeutic pathway for conditions like depression and anxiety [1].
  • Glutamatergic Modulation: Beyond serotonergic modulation, psychedelics interact with the glutamatergic system, influencing excitatory neurotransmission and synaptic plasticity. This modulation of glutamate receptors like mGluR2/3, AMPA, and NMDA is essential for cognitive functions and mood regulation [12].

Beyond Brainwaves: Psychedelics in Soothing Storms

Psychedelics could extend their therapeutic potential beyond neural modulation. Emerging research hints at their capability to mitigate inflammatory processes, crucial for alleviating symptoms of certain neuropsychiatric disorders.

  • Anti-inflammatory Effects: Psychedelics have shown promise in modulating inflammatory responses, which could be beneficial for various inflammatory and neuropsychiatric disorders. The anti-inflammatory effects of psychedelics such as LSD and psilocybin have been observed in some preclinical studies, where they have demonstrated the ability to suppress the release of pro-inflammatory cytokines and modulate immune cell activity [13,14]. Particularly, psychedelics are found to influence the serotonergic system, which plays a vital role in modulating immune system responses [14].
  • Microglial Modulation: Microglia, the resident immune cells of the central nervous system, play a crucial role in neuroinflammation and neuroplasticity. Recent research has begun to unveil the interactions between psychedelics and microglia. Psychedelics like psilocybin and LSD are hypothesized to modulate microglial activity, which might contribute to their therapeutic effects in treating neuropsychiatric disorders. Specifically, psychedelics may influence microglial phagocytic activity and inflammatory mediator release through various pathways, including sigma-1 receptors, serotonergic and γ-aminobutyric acid signaling, and tryptophan metabolism [15].
  • Entropic Brain Hypothesis: The entropic brain hypothesis is a fascinating concept that suggests psychedelics increase brain entropy. This change potentially allows for enhanced neural flexibility and adaptability, instrumental in breaking free from rigid and maladaptive thought patterns characteristic of many neuropsychiatric disorders [2]. By fostering more flexible and adaptive neural processing, psychedelics could potentially aid in the management of disorders like depression and anxiety.

A New Dawn in Mental Health: Psychedelics and the Future of Wellness

Psychedelics have surfaced as a promising frontier in neuropsychiatric treatment, addressing the gaps inherent in traditional approaches. The mechanistic underpinnings of psychedelics, grounded in their ability to modulate brain network connectivity and promote neural plasticity, offer a novel pathway for alleviating the symptoms of various neuropsychiatric disorders, including depression, anxiety, PTSD, and addiction.

The recent resurgence of research into psychedelics has unveiled their potential to create a paradigm shift in psychiatric care by promoting long-term symptom alleviation and facilitating a deeper understanding of the mind. Their ability to foster a state of heightened neurogenesis and synaptic plasticity is particularly noteworthy, enabling a reconfiguration of the maladaptive brain circuits that underlie many psychiatric conditions.

Moreover, the holistic experience induced by psychedelics, often referred to as a "psychedelic experience,” embodies a therapeutic process that transcends mere symptom alleviation, encircling broader aspects of psychological well-being, self-awareness, and personal growth. This holistic aspect aligns well with the current trend towards integrative and personalized medicine, which seeks to understand and treat individuals in a more comprehensive and individualized manner.

As legal barriers are gradually diminishing and societal acceptance grows, psychedelics are poised to play a critical role in advancing psychiatric care. Their integration into mainstream medical practice could significantly enhance the efficacy and holistic nature of neuropsychiatric treatment, thereby bridging the existing therapeutic gaps and contributing to a more profound understanding and treatment of mental health disorders.

In light of these findings, it's evident that psychedelics hold substantial promise for evolving the landscape of neuropsychiatric care, making them a worthy subject of continued research and clinical exploration. The journey from countercultural taboo to potential therapeutic marvel reflects the evolving understanding and acceptance of psychedelics, not just as substances of recreation, but as serious contenders in the quest for comprehensive mental health treatment solutions.



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