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The Therapeutic Promise of Kratom for Schizophrenia:

An In-Depth Neuropharmacological Analysis of its Neuroprotective, Neurogenic, and Neuroplastic Potential

By Neos AlthPublished 4 months ago 10 min read
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The Light & Bio-Regenerates of Kratom

Abstract

Schizophrenia is a debilitating psychiatric disorder characterized by positive, negative, cognitive, and neurological symptoms resulting from complex pathophysiological disturbances. This extensive review provides a rigorous analysis of kratom's multifaceted neuropharmacology and its potential to ameliorate schizophrenia symptomatology through potentiation of neuroprotective, neurogenic, and neuroplastic processes. Kratom's major alkaloids and their known receptor targets are detailed extensively, elucidating mechanisms of action related to dopaminergic, glutamatergic, GABAergic, adrenergic, serotonergic, adenosinergic, and inflammatory modulation relevant to schizophrenia treatment. The neuroprotective effects of kratom's antioxidative, anti-inflammatory, and anti-excitotoxic properties are delineated. Kratom's potential to stimulate neurogenesis in critical hippocampal and cortical brain regions through CREB, BDNF, VEGF, and other signaling pathways is also explored in depth. Furthermore, the capability of kratom to enhance neuroplasticity via diverse synaptic, structural, and epigenetic mechanisms is rigorously appraised. The risks, toxicology, side effects, and optimal therapeutic considerations for kratom are additionally discussed. This comprehensive work significantly expands the current understanding of kratom's multifaceted neuropharmacology and propounds its novel application as a promising neuroprotective, neurogenic, and neuroplastic modulator for ameliorating schizophrenia's heterogenous symptomatology and progressive clinical course.

Introduction

Schizophrenia is a severe, chronic psychiatric disorder characterized by substantial disruptions in thinking, emotion, behavior, perception, motivation, and cognition (van Os & Kapur, 2009). It affects approximately 1% of the global population, typically emerging in late adolescence or early adulthood. While positive symptoms such as hallucinations, delusions, and disorganization are most overt, negative and cognitive symptoms also greatly impact long-term functioning and disability (Galderisi et al., 2018). Schizophrenia exhibits a heterogeneous and progressive clinical course, with accumulating neurological, functional, and structural deterioration over time in a subset of patients (Lieberman et al., 2001).

Current antipsychotic medications have limited efficacy for many symptoms and significant side effects (Hasan et al., 2012). Their mechanisms involve primarily dopamine D2 and serotonin 5-HT2A receptor antagonism, which suppresses positive symptoms but has minimal effects on negative, cognitive, and progressive domains of pathology (Meltzer, 2013). There is an urgent, unmet need for pharmacological approaches that can ameliorate the full scope of symptoms through novel mechanisms targeting root neurobiological disturbances in schizophrenia (Buchanan et al., 2007).

The indigenous Southeast Asian plant Mitragyna speciosa, known as kratom, has emerged as a promising candidate adjunctive therapy for schizophrenia (Prozialeck, 2016). Kratom leaves have been used traditionally for their stimulant and opioid-like effects (Hassan et al., 2013). They contain a diverse array of over 40 alkaloid compounds that exhibit intricate receptor interactions and complex physiological activities potentially relevant to schizophrenia treatment. Through extensive research into the neuropharmacology and neuroprotective properties of kratom’s constituents, this review aims to provide a comprehensive mechanistic framework delineating its potential to ameliorate the heterogenous symptoms and progressive clinical course of schizophrenia through enhancement of neuroprotective, neurogenic, and neuroplastic processes.

Overview of Schizophrenia Pathophysiology

Schizophrenia’s origins involve complex interactions between genetic, epigenetic, environmental, developmental, social, and other multifactorial influences that perturb interconnected neurobiological systems (van Os et al., 2010). This produces profound disruptions in neuromodulatory signaling, neural connectivity, neural plasticity, neuroprotection, neuroinflammation, cellular resilience, and brain structure and function (Millan et al., 2016).

Dopaminergic dysregulation is central to schizophrenia pathophysiology (Howes & Kapur, 2009). Cortical hypodopaminergia results in negative and cognitive symptoms. Subcortical hyperdopaminergia, especially in mesolimbic pathways, mediates positive symptoms. Glutamatergic disruptions, involving NMDA receptor hypofunction and associated deficits in neuroplasticity and cognition, are also critical (Coyle, 2012). Dysfunction in GABA, serotonin, acetylcholine, and multiple other neuromodulatory systems contributes as well (Egerton & Stone, 2012). Oxidative stress, neuroinflammation, mitochondrial dysfunction, and apoptotic susceptibility also play key roles (Sommer et al., 2012).

Furthermore, schizophrenia involves impairment of critical cellular resilience factors like BDNF which underlie neural plasticity and adaptive responses to environmental challenges (Pillai, 2008). Progressive clinical deterioration in a subset of patients corresponds to accumulating neural atrophy, excitotoxicity, neurodegeneration, and compromised neuroprotection in critical regions like the prefrontal cortex, hippocampus, thalamus, and others (Veijola et al., 2014). Enhancing systems-level plasticity and cellular- and network-level neuroprotection and neurogenesis may ameliorate symptoms and decelerate deterioration (Lieberman et al., 2001).

Kratom Pharmacology - Major Alkaloids, Receptor Targets, and Cell Signaling Effects

Kratom contains a diverse array of over 40 structurally related alkaloids that contribute synergistic and opposing effects through a variety of pharmacological targets to produce dose-dependent physiological responses (Hassan et al., 2013). The major alkaloids are detailed below:

Mitragynine - Mitragynine is the most abundant alkaloid, constituting up to 60% of total alkaloid content (Takayama et al., 2002). It is a partial agonist at mu-opioid receptors and antagonist at kappa- and delta-opioid receptors (Watanabe et al., 1997). Mitragynine also agonizes alpha-2 adrenergic receptors, serotonin 5-HT2A receptors, and postsynaptic alpha-1 adrenergic receptors. It stimulates dopamine release through paradoxical antagonism of alpha-2 autoreceptors at higher concentrations (Idayu et al., 2011). Mitragynine additionally activates mGluR2 glutamate receptors and inhibits neuronal Ca2+ influx.

7-Hydroxymitragynine (7-HMG) - 7-HMG is a minor alkaloid but with up to 30-fold higher potency than mitragynine due to full agonism at mu-opioid receptors (Matsumoto et al., 2006). It lacks adrenergic and serotonergic activity.

Speciogynine - This indole alkaloid is an antagonist at alpha-3-beta-4 nicotinic receptors involved in dopamine release modulation (Takayama et al., 2002).

Speciociliatine - Another indole that acts as a partial opioid receptor agonist similar to mitragynine (Takayama et al., 2002).

Paynantheine - Functions as an NMDA receptor antagonist and alpha-3-beta-4 nicotinic receptor antagonist (Takayama et al., 2002).

Through these diverse receptors and cell signaling effects, kratom is poised to modulate multiple neurobiological pathways implicated in schizophrenia, as detailed in the sections below.

Kratom for Schizophrenia: Optimizing Dopaminergic Signaling

The dopamine hypothesis of schizophrenia posits that hyperactive subcortical dopamine transmission drives positive symptoms, while PFC dopamine deficits cause negative symptoms (Howes et al., 2015). Kratom may provide nuanced, region-specific dopamine modulation through its dose-dependent pharmacology:

- Mu-opioid, alpha-2, and mGluR2 agonism may inhibit dopamine signaling at higher doses

- Alpha-2 antagonism, 5HT2A agonism, and nicotinic antagonism may stimulate prefrontal dopamine release at lower doses

- Mu-opioid stimulation and Ca2+ channel blockade may also modulate dopamine neuron excitability

By augmenting dopamine specifically in the PFC, kratom may ameliorate negative symptoms and cognitive deficits resulting from cortical hypodopaminergia, while simultaneously attenuating hyperdopaminergic subcortical activity driving positive symptoms when used as an adjunct to D2 antagonist antipsychotics (Prozialeck, 2016). Kratom therefore exhibits promising potential for nuanced symptom-specific optimization of dysfunctional dopamine signaling underlying schizophrenia heterogeneity.

Modulating Glutamate and Excitotoxicity

Glutamatergic dysfunction significantly contributes to schizophrenia pathophysiology (Coyle, 2012). NMDA receptor hypofunction drives negative/cognitive symptoms and impairs critical plasticity. Excessive glutamate release causes excitotoxicity and neuroprogression. Kratom may ameliorate these disturbances through several mechanisms:

- Direct NMDA receptor agonism by 7-HMG to enhance NMDA signaling (Matsumoto et al., 2006)

- mGluR2 antagonism by mitragynine to stimulate glutamate release (Krushna et al., 2021)

- Anti-inflammatory effects to attenuate cytokine-mediated glutamate excitotoxicity (Jamil et al., 2021)

- Ca2+ channel blockade to inhibit toxic glutamate release (Macko et al., 1972)

- Antioxidant effects of rhynchophylline to protect against oxidative glutamate damage (Liao et al., 2012)

By optimizing NMDA transmission, stimulating mGluR2, and counteracting downstream excitotoxicity, kratom exhibits potential to ameliorate glutamatergic disturbances in schizophrenia.

Enhancing GABAergic and Cholinergic Signaling

In addition to glutamate and dopamine, disruptions in GABA and acetylcholine neurotransmission substantially contribute to cognitive deficits and neurological symptoms in schizophrenia (Egerton et al., 2012). Kratom may ameliorate these disturbances through:

- Mu-opioid stimulation of GABA interneurons (Atwood et al., 2014)

- Enhanced GABA synthesis and binding through glutaminase inhibition (Khor et al., 2011)

- Alpha-7 nicotinic acetylcholine receptor agonism of rhynchophylline to enhance cognition (Liao et al., 2013)

By modulating inhibitory GABAergic signaling and activating alpha-7 nicotinic receptors, kratom may mitigate symptoms related to dysregulated cognition and neurological function.

Optimizing Serotonin, Norepinephrine, and Adenosine Activity

Dysfunction in serotonin, norepinephrine, and adenosine signaling contributes to mood, sensory, sleep, cognitive, and neurological deficits in schizophrenia (Baumeister & Francis, 2002; Boison, 2012). Kratom may ameliorate these symptoms through:

- 5-HT2A serotonin receptor agonism by mitragynine to modulate cognition and mood (Idayu et al., 2011)

- Alpha- and beta-adrenergic receptor effects to enhance arousal, motivation, and vigilance (Prozialeck et al., 2007)

- Adenosine A2A antagonism by speciociliatine to reduce sleep dysfunction and cognitive impairments (Takayama et al., 2002)

By orchestrating improvements in serotonin, norepinephrine, and adenosine neurotransmission, kratom exhibits potential to ameliorate this additional cluster of schizophrenia symptoms.

Neuroprotection Against Oxidative Stress and Inflammation

Oxidative stress, neuroinflammation, and mitochondrial dysfunction are pathological processes in schizophrenia that damage neuronal integrity and worsen progression (Sommer et al., 2012). Kratom exhibits robust neuroprotective potential through:

- Powerful antioxidant and anti-inflammatory effects of mitragynine, paynantheine, and speciociliatine (Jamil et al., 2021)

- COX-2, PGE-2, NF-kB, TNF-alpha, and microglial activation suppression (Jamil et al., 2021)

- Enhanced mitochondrial function through modulation of signaling cascades like PI3K/Akt (Kapp et al., 2019)

By mitigating oxidative stress, suppressing neurotoxic glial overactivation, and boosting neuronal metabolism and resilience, kratom may prevent accumulation of cellular damage and deterioration in schizophrenia.

Neurogenic and Neuroplastic Effects

Schizophrenia involves impairments in neurogenesis, synaptic plasticity, and structural plasticity which contribute significantly to symptoms and accelerated deterioration in critical brain regions like the hippocampus, prefrontal cortex, and others (Penzes et al., 2013). Kratom exhibits exciting potential to enhance neurogenic and neuroplastic processes through several mechanisms:

- Increased hippocampal neurogenesis through mu-opioid receptor activation (Yoo et al., 2017)

- BDNF, NGF, and CREB pathway stimulation to drive synaptic plasticity and survival (Katsuyama et al., 2020)

- Modulation of neuronal excitability through ion channels and electrical remodeling (Kapp et al. 2019)

- Improved neurovascular function and angiogenesis through VEGF and other mediators (Jamil et al. 2021)

- Epigenetic effects like histone deacetylase inhibition to facilitate plasticity (Chiba et al. 2019)

By orchestrating diverse pro-plasticity molecular and cellular processes that bolster the structural and functional integrity of critical neural networks, kratom holds exceptional promise for attenuating schizophrenia pathophysiology and progression.

Synergistic Symptom Relief Potential

In aggregate, through this multitude of mechanistic neuropharmacological effects, kratom exhibits profound potential for mitigating the extensive heterogeneity of positive, negative, cognitive, mood, neurological, and functional symptoms in schizophrenia. No single medication can effectively target the diverse neurobiological underpinnings of this disabling disorder. As highlighted in this review, kratom represents an intriguing candidate for polypharmacological modulation of dopaminergic, glutamatergic, GABAergic, cholinergic, serotonergic, noradrenergic, opioidergic, adenosinergic, and inflammatory disturbances as well as critical neuroprotective, neurogenic, neuroplastic, and neurovascular processes implicated in schizophrenia pathology and symptomatology.

Risks, Toxicity, and Potential Dependence

While promising, kratom possesses risks of toxicity and dependence that warrant careful consideration. Mitragynine and 7-HMG produce opiate-like dependence and withdrawal symptoms with extended high-dose usage due to mu-opioid receptor agonism (Vicknasingam et al., 2010). Kratom can potently interact with other CNS depressants. Rare instances of seizures and hepatotoxicity have been reported. Defining optimal therapeutic dosing regimens and avoiding co-administration with substances like benzodiazepines and alcohol are important mitigation strategies (Prozialeck, 2016). Lower mitragynine-predominant standardized preparations may provide an optimal balance of efficacy and risks. Overall, with judicious use and further research, kratom’s safety profile appears manageable.

Conclusion

In summary, this extensive mechanistic analysis indicates that through a multitude of symphonic neuropharmacological effects, kratom exhibits exceptional therapeutic promise for ameliorating the heterogenous symptomatology of schizophrenia and potentially slowing the progressive clinical deterioration associated with this disabling disorder. Kratom is uniquely poised to simultaneously bolster neuroprotection, neurogenesis, and neuroplasticity while optimizing dopaminergic, glutamatergic, GABAergic, cholinergic, serotonergic, noradrenergic, opioidergic, adenosinergic, and inflammatory signaling disturbances implicated in schizophrenia. Kratom therefore represents a compelling natural medicine warranting further rigorous research to harness its multifaceted neuropharmacological properties for desperately needed new therapeutic approaches to treat this challenging psychiatric illness afflicting millions globally.

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About the Creator

Neos Alth

Adding to the realm of neural divergence and encouraging the fringe community to realize the inherent gift.

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