Milos Vojvodic1, Prof. Nitin Mantri 2
1BHSc, Neuroscience, Swinburne University of Technology, Melbourne, Australia.
2 The Pangenomics Laboratory, School of Science, RMIT University, Melbourne, Australia.
Schizophrenia is a severe mental illness affecting nearly twenty-one million people worldwide; it encompasses symptoms of delusions, hallucinations, and a general disconnect from reality. The neural mechanisms underlying schizophrenia are not yet completely understood; this has led an investigation into neural processes with the hope of identifying effective treatment targets. Current literature establishes that the endocannabinoid system (ECS) plays a role in schizophrenia and that phytocannabinoids can mediate the ECS, therefore, this article combines literature focused on the neurobiology of schizophrenia in conjunction with the ECS. The article explores Cannabidiol’s (CBD) ability to increase concentrations of Anandamide (AEA) and its potential impact on alleviating schizophrenia symptoms. Studies have shown that AEA can bind to TRPV1 sites to initiate a significant neurological process that may be associated with alleviating schizophrenia symptoms. For example, TRPV1 initiates a neuroprotective mechanism that could facilitate the regulation of glutamate and dopamine neurotransmission while also preventing the degeneration of dopaminergic neurons. The article concludes by proposing a novel target mechanism of action and suggests a research-design-parameter intended to increase accuracy throughout the medical-cannabis research-community in hope of improving quality of life for those who are living with schizophrenia.
There are approximately 3.1 cases of schizophrenia per 1,000 people between 18 and 64 years of age.1-3 A continuing investigation into the causes of schizophrenia has, unfortunately, yielded no direct source attributable to the disorder. However, many contributing factors have been linked to its onset, such as genetic, neurobiological, and neurodevelopmental factors.4-5 There is no absolute cure for schizophrenia; this has led to a continuing investigation into neural mechanisms in the hope of identifying a viable target mechanism for the treatment of schizophrenia-related symptoms.
Research has shown that cannabis is one biological factor that can interact with neural mechanisms associated with the disorder. 4-5 A compound of cannabis known as cannabidiol (CBD) has shown promising signs in reducing psychotic symptoms and may even serve as a possible treatment.5-11 This review links existing findings to propose a potential mechanism of action that enables cannabidiol to safely treat schizophrenia symptoms.
2. Overview of Schizophrenia
Schizophrenia is a mental disorder exhibited by disruptions in thought, perception, mood, and movement.4,12 The disorder is typically defined by positive and negative symptoms. 4,12 Positive symptoms are often severe and persistent; they include bizarre experiences such as delusions, hallucinations, catatonia, and a general disconnection from reality.13Negative symptoms are defined by an absence of specific cognitive abilities such as planning, motivation, judgment, abstract reasoning, and problem-solving. People who have schizophrenia may also demonstrate emotional flattening and social withdrawal.13
Currently, no known treatment completely cures schizophrenia or returns a sufferer to a pre-schizophrenic state of functioning; there is continuing investigation into identifying the mechanism responsible for the disorder.13,14 Studies suggest those with schizophrenia tend to exhibit larger lateral ventricles than healthy controls, which reflects the deterioration of brain tissue around the ventricles. Another anatomical abnormality observed in schizophrenia is a reduction in cortical thickness and abnormal neuronal lamination.4 At first diagnosis of schizophrenia, cortical abnormalities, and enlargement of the ventricles are generally apparent.15 Abnormalities thought to be present in schizophrenia are also related to the neurophysiology of the brain, in particular, the neurotransmitter systems involving dopamine, glutamate, and vital elements of neurotransmitter release such as calcium (Ca2+).14,15
3. Neurobiology of Schizophrenia
3.1. Dopamine Dysregulation
Dopamine is a neurotransmitter responsible for many neural functions, including reward-motivated behavior and motor control.12,13 Three different dopaminergic systems are disturbed in people with schizophrenia.16 The first dopaminergic system is the nigrostriatal system, located in the basal ganglia.4,12 Low levels of dopamine in the striatum and nigrostriatal are believed to contribute to motor symptoms present in schizophrenia.16 Postmortem studies have shown that those with schizophrenia have an increase in dopamine receptors in the striatum, located in the basal ganglia.13
The second dopaminergic system is the mesolimbic system, which is generally associated with the reward circuit and found in the ventral medial portion of the striatum. Research suggests that abnormal dopamine activity within this pathway underlies psychotic symptoms related to schizophrenia. 5,13,14 Studies indicate that dopamine dysfunction underlies the pathophysiology of schizophrenia, specifically dopamine hyperactivity in the mesolimbic system.17
Finally, low levels of dopamine in the mesocortical pathway are thought to contribute to cognitive impairment and negative symptoms of schizophrenia.13,14,16 The fact that positive symptoms of schizophrenia, such as hallucinations, can be alleviated with dopamine antagonists reiterates the dopamine hypothesis.5,13,18
Studies have demonstrated that drugs like amphetamines and cocaine can produce positive symptoms reflective of schizophrenia due to an increase of dopamine in synapses, implicating dysregulation in the dopamine system.12 Furthermore, the activation of dopamine receptors has been shown to trigger psychotic episodes; knock-out of the dopamine transporter or the overexpression of D2 receptors in the forebrain contributes to behavioral abnormalities reflective of the cognitive symptoms present in schizophrenia. 4,18
3.2. Calcium Dysfunction (Ca2+)
Ca2+ is a vital element in the process of neurotransmitter release; when Ca2+ channels are blocked, neurotransmitter release is inhibited. Elevated Ca²⁺ concentrations have been observed in the sensory neurons of most people with schizophrenia.19 People with schizophrenia often report distorted sensory experiences, suggesting that poor regulation of Ca²⁺ channels in sensory neurons may contribute to hallucinations associated with the disorder.19,20
Additionally, a study on cognitive effects of risk variants at loci implicated in synaptic transmission found an association between the rs2007044 (risk allele G) within calcium channel subunit α1c (CACNA1C) and poorer working memory performance.21 Recently, a first episode schizophrenia cohort was assessed for variants within the calcium channel subunit genes with antipsychotic treatment response. The treatment outcome was significantly associated with 12 regulatory variants within seven genes. Importantly, the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect.22
3.3. Glutamate Dysregulation
The N-Methyl-D-aspartic receptor (NMDAr) is a primary excitatory glutamate receptor in the central nervous system (CNS). NMDA receptor antagonists such as ketamine and phencyclidine have been observed to produce cognitive abnormalities and psychotic symptoms reflective of schizophrenia.4,12,18,23 Dysregulation of glutamate interneurons located in the hippocampus, striatum, and cerebral cortex has also been shown to impair cognitive abilities.16 These neurons regulate the firing of pyramidal neurons, which are vital to healthy cognitive functioning, suggesting a relationship between hyperactivity of the glutamate system and symptoms of schizophrenia.16 Consequently, drugs that modulate NMDA receptors and reduce hyperactivity of glutamate have therapeutic benefits associated with negative symptoms such as emotional inexpressiveness and apparent unresponsiveness.13,18,23
3.4. Transient receptor potential cation channel subfamily V member 1 (TRPV1) Dysfunction
TRPV1 activation down-regulates voltage-gated Ca²⁺ channels (Figure 1).24 Voltage-gated Ca²⁺ channels are known to influence dopamine and glutamate release in sensory neurons, suggesting that TRPV1 activation may be a viable target for facilitating Ca²⁺ homeostasis in sensory neurons and thus helping to suppress hallucinations associated with schizophrenia.25,26 Importantly, alterations in TRPV1-containing sensitive primary afferent neurons have been suggested to be associated with a lack of pain perception seen in schizophrenia patients.27 Further, neonatal administration of capsaicin – a TRPV1 agonist – in rats induces schizophrenia-like behavioral abnormalities later in life.28
4. Endocannabinoid System History
Cannabis has been mentioned as a sacred plant in the Atharva Veda (a collection of sacred texts thought to be compiled in about 1200 BC - 1000 BC.) and believed to provide mankind a source of happiness and freedom. Therefore, cannabis use became part of numerous social and religious rituals in India.29 Although descriptions of the therapeutic properties of cannabis date back to 200 C.E Chinese-pharmacopeia, its medicinal properties were not methodically assessed until the 1840s.30 Scientific cannabinoid research only began to spread its roots in 1899 after a method to isolate Cannabidiol (CBD) from cannabis resin was developed.31 By 1932, Neurobiologists were then able to shed light on the chemical structure of CBD.32 Further research was undertaken in 1964 to explain the synthesis of CBD and to annotate the structure of THC.33,34
During the early 1980s, the National Institute on Drug Abuse (NIDA) set out to prove the deleterious effects of cannabis and unintentionally facilitated several landmark neurophysiological studies leading to the discovery of a previously unknown human biological system; the Endocannabinoid System.35,36 In 1982, the National Institute of Medicine (NIM) released an extensive report on cannabis that sparked considerable interest and debate within scientific communities around the world.37 NIM's report provided conclusive evidence that the effects of cannabis were due to its actions on the brain and nervous system, mediated through the ECS.38
By 1986, pharmacologists had begun to synthesize potent cannabinoid agonists; these agonists turned out to be a key component for discovering the first cannabinoid receptor (CB1).39 THC binding sites were identified within the brain just two years later.40 In 1992, researchers had discovered the first naturally occurring cannabinoid within the human body; this endocannabinoid was named Anandamide (AEA).41 The second cannabinoid receptor (CB2) was discovered and successfully cloned the following year.42,43 The first cannabinoid receptor antagonist was developed in 1994 and marketed as Rimonabant Cl (SR141716A).44 The second endogenous cannabinoid was discovered in 1995 and was named 2-Arachidonoylglycerol (2-AG).45 In 1996, scientists had successfully cloned an endocannabinoid degrading enzyme known as fatty acid amide hydrolase (FAAH).46 By 1998, biomolecular chemists had discovered a cannabinoid antagonist (SR144528), which could distinguish between CB1 and CB2 receptors.47
Subsequently, in 2003, an enzyme with the ability to biosynthesize the endocannabinoid 2-AG was successfully cloned and named Diacylglycerol lipase (DAG lipase).48 More recent research has shown that Anandamide can also activate vanilloid receptors such as TRPV1.49-51 TRPV1 responds to neurotoxicity, modulates CB1 receptors, and facilitates neuroprotection mechanisms such as preventing the degeneration of dopamine neurons.49,52-55
5. Endocannabinoid System Function
The ECS can be viewed as a comprehensive neuromodulatory system that plays essential roles in CNS development, function, synaptic plasticity, and recovery.56 The ECS spans the entire body in varying concentrations of critical components such as cannabinoid receptors, neurotransmitters, and their respective enzymes.57 The ECS also plays a role in the regulation of many vital biological processes such as fertility, pregnancy, pre and postnatal development.58-60 Medicinal Cannabinoid research is already applicable to treating a wide range of ailments such as chronic acne, spasticity, anxiety, epilepsy, inflammation, auto-immune disorders, and has even been shown to reduce bone fracture healing time in early animal studies.56,61-66
The two known endocannabinoids (AEA and 2-AG) have a similar chemical structure, yet they are synthesized and degraded by distinct enzymatic mechanisms, both of which conduct fundamentally different physiological roles within the body. AEA is synthesized from N-arachidonoyl phosphatidylethanolamine (NAPE) and degraded by the fatty acid amide hydrolase (FAAH).46,67 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG) and degraded by Monoacylglycerol lipase (MAGL).48,68
Endocannabinoids are synthesized in the postsynaptic neuron, released into the synaptic cleft, and then travel retrogradely to bind to CB1 receptors on the presynaptic neuron; once attached to the receptor, they inhibit neurotransmitter release in the presynaptic neuron eliciting a calming effect to overactive neurotransmission.4 The endocannabinoid system mediates and regulates neurotransmitter systems, such as GABAergic, glutamatergic, and dopaminergic synaptic functions.6,14,15,69-71 Scientists have been able to modulate the activity of the D1 and D2 receptor agonists by applying an antagonist to the CB1 receptors in rodents, suggesting that endocannabinoids may play a role in regulating a hyperactive dopaminergic system via retrograde transmission.14
6. The Endocannabinoid System and Schizophrenia
Paranoid schizophrenia is characterised by increased CB1 density and binding in the dorsolateral prefrontal cortex.72 Postmortem studies demonstrated that those who have been diagnosed with schizophrenia and not exposed to cannabis also have increased CB1 density in the brain, suggesting that cannabis does not cause schizophrenia, but rather that it has an influence on the biological system underlying the pathology.73 People with schizophrenia also exhibit disrupted CB1 receptors in cognitive brain areas associated with learning and memory .6,14,15,72-75
Furthermore, disruption of AEA concentration was also associated with schizophrenia symptoms; this concept was established based on observations of increased levels of AEA present in the cerebrospinal fluid (CSF) of people who experienced both, chronic and acute psychotic symptoms.14,76 In addition, unusual patterns of AEA regulation were observed in schizophrenia pathology, which suggests that AEA plays a neuroprotective role in the brain; for example, AEA levels in the CSF are elevated during the time between the first onset of symptoms and the acute manifestation of the disorder, while lower levels are associated with an earlier transition into acute psychosis.6,14 Studies have reiterated this by demonstrating a correlation between AEA levels and schizophrenia symptoms, suggesting that the lower the AEA levels, the stronger the psychotic symptoms. 6,14,76
7. Treating Schizophrenia with Cannabidiol
Positive symptoms of schizophrenia have traditionally been alleviated by blocking receptors associated with the transmission of dopamine.5,12,18,77 The first wave of antipsychotics, also known as ‘typical’ antipsychotics, were developed to specifically target dopamine receptors and included drugs such as chlorpromazine and haloperidol.12 These antipsychotics were effective but also accompanied by side effects reflective of Parkinson’s disease, such as tremors, rigidity, and involuntary muscle spasms.12,18 Parkinson’s disease results in a loss of dopaminergic neurons within the midbrain, suggesting that these antipsychotic drugs were directly occupying dopamine receptors and thus decreasing endogenous dopaminergic communication as a side-effect.12
Other antipsychotics attributed to alleviating schizophrenia symptoms are known to modulate receptors associated with the transmission of glutamate.5,77 These more recent pharmaceuticals have also been unsatisfactory, as none have the same efficacy as clozapine, and they are unable to wholly and consistently suppress schizophrenia symptoms.12-14
The ECS system provides a promising target for new schizophrenia treatments. While cannabis ligands such as THC contribute negatively to symptoms associated with schizophrenia, other cannabis ligands such as CBD contribute to a reduction in these symptoms.5,6 CBD normalizes behaviours related to schizophrenia, such as performance on novel object recognition tests and social interactions.7
A 1995 study examined a patient with treatment-resistant-schizophrenia and found that administering 1500mg of CBD/day for 26 days improved symptoms with no aversive side effects.9 Another study conducted in 2011 acknowledged that certain cannabinoids such as THC produce a negative effect on schizophrenia symptoms while cannabinoids, such as CBD, appear to have at least in part, a “restorative” effect on neurotransmitter dysfunctions in schizophrenia.5 Subsequently, a 2015 study corroborated THC to have a negative effect on schizophrenia symptoms and added that synthetic cannabinoids produce severe acute psychosis, and agitation among a host of other physical and psychological problems; whereas CBD was very well tolerated and had few psychoactive effects on its own. It counteracted several effects of THC and other CB1R agonists in healthy subjects, including anxiety, euphoria, and psychosis.6
Recently, a 2016 study administered and compared amisulpride, an antipsychotic drug used to treat schizophrenia, with CBD; amisulpride was effective but unfortunately produced significant side effects.10 Both compounds demonstrated similar improvement in positive and negative symptoms; however, CBD caused little to no side effects.10 The group that was administered CBD also showed an increase in AEA levels, which was associated with improved schizophrenia symptoms.10 More recently, a 2018 human trial showed conclusive evidence that six weeks of 1000mg/d CBD has beneficial effects in patients with schizophrenia; the CBD group had significantly lower levels of positive psychotic symptoms and showed more significant improvements in cognitive performance.11
7.1. Proposed Mechanism to Alleviate Schizophrenia Symptoms
The neural mechanism that enables CBD to alleviate schizophrenia symptoms is not yet completely understood. However, dysregulation of calcium (Ca²⁺), dopamine, and glutamate play a significant role in schizophrenia pathology.13,17,19,23,78 Therefore, the following model pieces together scientifically verified findings into a potential neurobiological mechanism by which CBD may play a significant role in facilitating the healthy regulation of these contributing factors and thus helping to alleviate schizophrenia symptoms (Figure 1).
7.2. CBD competes with AEA for FABP Transport to FAAH
FABPs are Fatty-acid binding-proteins that transport Anandamide (AEA) to its catabolic enzyme, FAAH.79 The FAAH then breaks AEA down into Oleic Acid and Arachidonic Acid.79 CBD competes with AEA for a spot on these AEA-degrading transporter-proteins;79 while CBD occupies these transporter proteins, it acts as a false substrate, allowing AEA concentrations to rise within the nervous system.79-81 The inhibition of FAAH’s ability to break down AEA safely and indirectly increases concentrations of this endogenous cannabinoid, as opposed to flooding the CNS with synthetic exogenous-ligands, which often cause unwanted side-effects.79-81
7.3. AEA’s Concentration-Specific TRPV1 Activation.
AEA generally binds to CB1 receptors. However, AEA also binds to TRPV1 sites 41,49,52-54,80,81; this is a remarkable phenomenon to take into account as TRPV1 activation has been shown to prevent the degeneration of dopamine neurons and impart different subsequent biological processes compared to CB1 activation.54,55 For example, TRPV1 activation mediates intracellular Ca²⁺ concentration directly, whereas CB1 activation does not.82
Ca²⁺-signaling-dysfunction has been demonstrated in most people who have schizophrenia.19 Furthermore, Ca²⁺ signaling has been shown to regulate cognitive processes which are generally dysfunctional in those with schizophrenia, such as associative learning and memory.83,84 Administering Ca²⁺ can induce the same structural and cognitive deficits seen in patients who have schizophrenia; further supporting the idea that inadequate regulation of Ca²⁺ may be a contributing factor for schizophrenia related cognitive deficits.19 The significance of Ca²⁺ dysfunction in schizophrenia is substantiated further since Clozapine, the most successful antipsychotic drug for treating the disorder, works by influencing Ca²⁺ homeostasis. 12-14,19
7.4 Glutamate Regulation and Dopamine Regulation
TRPV1 channels facilitate healthy glutamate transmission in the striatum; this is significant because postmortem biopsies have shown abnormally high levels of glutamate within the striatum of people who were living with schizophrenia. 85,86 CBD may also play a significant role in alleviating schizophrenia symptoms by indirectly facilitating the healthy transmission of glutamate via TRPV1 binding. Glutamate is involved in the striatal dopamine regulation, as well as in many other brain regions87-89; this is a significant association because striatal dopamine imbalances have been linked to schizophrenia. 5,13-18,77,78
The accuracy and effectiveness of endocannabinoid research-study-design could be improved with the addition of a new design parameter based on the following logic:
Levels of CBD administered vary between research groups.90,39 Variations in CBD dosages change the concentration of AEA within the nervous system. 46,79,81,94 When AEA reaches a patient-specific concentration threshold, it binds to TRPV1 sites. 53,54,79,94-97 TRPV1 binding leads to different subsequent biological processes compared to CB1 activation. 24,82 Therefore, endocannabinoid researchers should aim to identify the threshold-concentration required to trigger AEA’s ability to activate TRPV1 sites on a per-patient-basis. Therefore, personalised metabolic-rate and genetic-testing kits could be beneficial tools for tailoring CBD dosages. AEA’s TRPV1 binding threshold may very likely be a necessary component for developing a successful phytocannabinoid-based treatment for schizophrenia; therefore, future medical cannabis researchers should consider incorporating this phenomenon into their research-design-parameters.
This paper has summarized the historical discoveries encompassing the endocannabinoid system and the neurological mechanisms thought to underlie schizophrenia. The dopamine and glutamate dysfunction hypotheses remain the most dominant theories within the literature; these theories are the basis for current treatment options.
Unfortunately, significant side-effects have been associated with the drugs used to treat such dysfunctions; These drugs are predominantly synthetic, ligand-based formulations that target dopamine receptors directly.
Introducing synthetic ligands into any biological system can cause unwanted side effects as they can bind to unintended receptor sites before reaching the intended receptor. Fortunately, extensive investigation into the endocannabinoid system yields new hope for people living with schizophrenia. Phytochemicals such as CBD could achieve similar outcomes by empowering the body to regulate it’s endogenous dopaminergic and glutamatergic neurotransmitter systems, thereby reducing the risk of adverse side effects associated with current treatment options.
AEA’s TRPV1 binding threshold may very likely be a necessary component for developing a successful phytocannabinoid-based treatment for schizophrenia; therefore, future medical cannabis researchers should consider incorporating this phenomenon into their research-design-parameters and Medical Cannabis prescribers should consider utilizing metabolic-rate and genetic-testing kits as tools for tailoring CBD dosages on a per-patient basis.
9.1. Future Research Questions
1) What concentration of CBD is required for anandamide to bind to TRPV1 sites in relation to the patient’s basal metabolic rate and body mass index?
2) How does CBD affect other factors such as GPR18, GPR119, GPR55, TRPA1, and 5HT1A in relation to schizophrenia?
3) Is plant derived CBG more suitable for schizophrenia?
4) Are any terpenes beneficial for alleviating schizophrenia symptoms?
ECS - Endocannabinoid System
THC - Tetrahydrocannabinol
CBD – Cannabidiol
CBG - Cannabigerol
AEA - Anandamide
CB1 - Cannabinoid receptor 1
CB2 - Cannabinoid receptor 2
2-AG - 2-Arachidonoylglycerol
FAAH - Fatty acid amide hydrolase
TRPV1 - Transient receptor potential cation channel subfamily V member 1
Ca2+ - Calcium ion
CACNA1C - Calcium channel subunit α1c
NMDAr - N-Methyl-D-aspartic receptor
CNS – Central nervous system
NIDA - National Institute on Drug Abuse
NIM – National Institute of Medicine
DAG - Diacylglycerol lipase
MAG - Monoacylglycerol lipase
CSF - Cerebrospinal fluid
GPR18 - G Protein-Coupled Receptor 18
GPR119 - G protein-coupled receptor 119
GPR55 - G protein-coupled receptor 55
TRPA1 - Transient receptor potential cation channel, subfamily A, member 1
5HT1A - Serotonin 1A receptor
11 Author’s contributions
Milos Vojvodic – Write-up and references 1-19, 23-26, 28, 30-97.
Prof Nitin Mantri – Final review and references 20,21,22,27, 29.
12 Honourable mentions
Sharon Bentley (Medical Cannabis Australia), William Hamilton and Guillaume Auvinet (Conscious Energy Initiative), Roby Zomer (MGC Pharmaceuticals), The Knox Docs (American Cannabinoid Clinics), Russell Harding (MedReleaf Australia), Adam Miller (MediPharm Labs), Haleh Mahmoudi (RMIT), Professor David Liley (Cortical Dynamics), Stephanie Robinson Ph.D (Green Cross Cannabis), Tobias Schappeler (Scitek), and Ing. Krisztina Lozsi (ANTG).
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