The Role of Cannabis within an Emerging Perspective on Schizophrenia
Jegason P. Diviant, Jacob M. Vigil, and Sarah S. Stith
Medicines, 2018, 5, 86, 1-11.
doi : 10.3390/medicines5030086
Abstract
Background : Approximately 0.5% of the population is diagnosed with some form of schizophrenia, under the prevailing view that the pathology is best treated using pharmaceutical medications that act on monoamine receptors.
Methods : We briefly review evidence on the impact of environmental forces, particularly the effect of autoimmune activity, in the expression of schizophrenic profiles and the role of Cannabis therapy for regulating immunological functioning.
Results : A review of the literature shows that phytocannabinoid consumption may be a safe and effective treatment option for schizophrenia as a primary or adjunctive therapy.
Conclusions : Emerging research suggests that Cannabis can be used as a treatment for schizophrenia within a broader etiological perspective that focuses on environmental, autoimmune, and neuro-inflammatory causes of the disorder, offering a fresh start and newfound hope for those suffering from this debilitating and poorly understood disease.
Keywords : schizophrenia; cannabis; marijuana; autoimmunity; monoamine therapy; mental illness;
cannabidiol; tetrahydrocannabinol; endocannabinoid system
Schizophrenia is arguably among the most severe, costly, and mechanistically complex mental illnesses, and yet is relatively common, affecting roughly 0.5% of the US population. [1–4]. Historical theories of the etiology of schizophrenia have changed over time, and with them the types of interventions conventionally used for treating people with schizophrenic-like, i.e., positive and negative, symptoms. Currently, genetic and epigenetic vulnerability models remain the prevailing dogma, whereby schizophrenic symptoms are believed to manifest from an aberrant or sensitive underlying genotype, independent of or in coincidence with exposure to an environmental (biological or social) risk factor at some point in early development [5–7].
The genotypic-centered perspective has mostly been coupled with the assumption that the primary locations of health disturbances are pathophysiological perturbations in neurotransmission or the regulation of brain chemicals [8,9]. Antipsychotic medications frequently prescribed to treat schizophrenia are often designed around a monoamine neurotransmitter hypothesis, typically the dopamine hypothesis, which associates the disorder with a dysfunction in the dopaminergic pathways,
contributing to positive, negative, and cognitive symptoms of the disease [10–12]. First-generation (typical) antipsychotics share the primary pharmacological property of D2 antagonism. The postulate is that a hyperactive mesolimbic pathway may cause positive psychotic symptoms. The desired efficacy of typical antipsychotics is achieved by blocking 60–65% of D2 receptors in the mesolimbic pathway. Unfortunately, the D2 receptors are simultaneously blocked throughout the brain in other pathways, such as the mesocortical, nigrostriatal, and tuberoinfundibular pathways. The mesocortical pathway is thought to be associated with negative symptoms. Therefore, blocking this pathway may induce secondary negative symptoms and cognitive effects. Occupying approximately 77% or more of the D2 receptors in the nigrostriatal pathway may increase the risk of extrapyramidal symptoms, such as dystonia (involuntary muscle contractions), akathisia (restlessness), bradykinesia (slow movements), and tardive dyskinesia. Chronic treatment with typical antipsychotics may result in 70–90% of D2 receptors being occupied [13]. It is estimated that about 5% of patients that maintain treatment with
typical antipsychotics will develop tardive dyskinesia each year, making long-term therapy undesirable. A D2 blockade in the tuberoinfundibular pathway increases the risk for hyperprolactinemia, which may lead to more rapid demineralization of the bones, weight gain, and sexual dysfunction in both men and women. Several typical antipsychotics also block muscarinic M1 receptors, which may worsen cognitive blunting. Blocking the M1 receptor may also cause dry mouth, constipation, blurred vision, and urinary retention [14,15].
Second-generation (atypical) antipsychotics have a lower affinity for dopamine D2 receptors and greater affinities for other neuroreceptors, such as norepinephrine and serotonin receptors, especially at 5-HT2A. The risk for neurologic symptoms may be reduced with atypical antipsychotics, but the risk for metabolic problems, including weight gain, dyslipidemia, hypertension, and diabetes, has been observed to be higher, especially in patients treated with Clozapine or Olanzapine [13,16,17]. Antipsychotic medications, whether typical or atypical, can be toxic, potentially inducing any number of a lengthy list of neurologic, metabolic, and cardiovascular side effects that can ultimately contribute to a significantly decreased quality of life and reduced life expectancies [12,18–22]. Overall, typical antipsychotics often reduce the severity of positive symptoms, but are generally less effective at addressing negative symptoms [23–25]. Atypical antipsychotics are often assumed to be more efficacious for treating negative symptoms. However, intolerable side effects still lead to discontinuation of treatment [26–28]. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) failed to demonstrate that atypical antipsychotics were any more efficacious at treating negative psychotic symptoms than typical antipsychotics [16]. The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) failed to show a significant difference in the rates of treatment discontinuation, quality of life, or improvement in psychotic symptoms in comparing typical and atypical antipsychotics [29]. Common side effects of antipsychotics (e.g., constipation, weight gain, tardive dyskinesia, cardiovascular disturbances, and glucose metabolic dysregulation) can also contribute to the need for additional prescription medications for treating those side effects, resulting in added polypharmaceutical risks to patients [30–32].
Perhaps more fundamental to the drawbacks of the antipsychotic medication model for treating schizophrenia is the misapplication of the concept of “reductionism,” or the belief that complex mental illnesses, often characterized by unique mental symptoms, including mental intentions (e.g., obsessive beliefs, hypersensitivity to threatening stimuli, and low self-worth) can be reduced to biophysiological mechanisms, i.e., monoamine receptor sites, that function in basic or fundamental ways [33]. In fact, there is still little evidence and certainly no consensus on the innate biological (physiological or mental) functions of serotonergic, glutamatergic, or dopaminergic activity (up- or down-regulation) in their absolute and isolated forms, irrespective of the seemingly infinite factors, including past experiences and environmental conditions, associated with normative and anomalous mental states. Reductionist proposals of schizophrenia involve hyperactive dopaminergic signal transduction and the use of antidopaminergics as treatment, hyperactive glutamatergic signaling via NMDA receptors and the use of glutamatergics as treatment, and the role of muscarinic acetylcholine receptors and the use of positive allosteric modulators (PAMs) to indirectly regulate dopamine levels in areas of the brain involved in psychosis [34–37].
Another problem with antipsychotic pharmaceutical treatments is they are designed to act on particulate sites for treating the breadth of mental, behavioral, morphological and somatic symptoms associated with the diagnosis of schizophrenia [12,38]. The American Psychiatric Association’s criteria for a schizophrenic diagnosis includes only mental and behavioral symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and the presence of negative symptoms, which may include anhedonia, asociality, apathy, and alogia [39]. Two or more of the presentations must have existed for at least one month along with a few other criteria typically considered in a diagnosis, such as a major impairment in functioning for a significant period of time, signs of the disorder lasting for a continuous period of at least six months, and ruling out schizoaffective, bipolar, or depressive disorder with psychotic features.
However, schizophrenic symptomology also can occur in association with microglia activation and neuroinflammation [40–43], which increase permeability of the blood-brain barrier (BBB) [44]. This allows a wide range of both inorganic and organic toxins to disrupt neurological functioning, creating neuronal antibodies associated with schizophrenic symptomology [45–47]. Similar neuronal auto-antibodies have been shown to arise as an immunological response to various cancers as well [48,49]. Non-paraneoplastic neural autoantibodies include those associated with hundreds of potential pathogens (e.g., rubella, influenza, Varicella zoster, Candida albicans, herpes, Lyme disease, Toxoplasma gondii, and several types of enteroviruses) that can lead to mental symptoms often described as “schizophrenic” (e.g., hallucinations, unusual involuntary movements) [50–52]. Additional sources of pathology leading to microglia activation and neuroinflammation may include food sensitivities, gastrointestinal inflammation, intestinal epithelial permeability, intestinal dysbiosis, nutrient deficiencies, environmental toxin exposure, and sleep deprivation, in addition to potential genetic sensitivities to express schizophrenic profiles [53–57].
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medicines-05-00086