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.
Abstract
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.
1. Background
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
8. Discussion
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.
9 Conclusions
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?
10 Abbreviations
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).
References
1. AIHW. Mental health services in Australia, Prevalence and policies - Australian Institute of Health and Welfare. 2018; https://www.aihw.gov.au/reports/mental-health-services/mental-health-services-in-australia/report-contents/summary/prevalence-and-policies Accessed 17 Mar,, 2018.
2. health DoHM. Mental health. 2019; http://www.health.gov.au/mentalhealth Accessed 2 Apr. , 2018.
3. Organization WH. Schizophrenia. 2019; http://www.who.int/mediacentre/factsheets/fs397/en/ Accessed 4 October,, 2019.
4. Bear MF, Connors BW, Traduction MAP. Neurosciences (4e édition): A la découverte du cerveau. 2016.
5. Coulston CM, Perdices M, Henderson AF, Malhi GS. Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use %J Schizophrenia Research and Treatment. 2011;2011:9.
6. Manseau MW, Goff DCJN. Cannabinoids and schizophrenia: risks and therapeutic potential. 2015;12(4):816-824.
7. Levin R, Almeida V, Fiel Peres F, et al. Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia. 2012;18(32):4960-4965.
8. Iseger TA, Bossong MGJSr. A systematic review of the antipsychotic properties of cannabidiol in humans. 2015;162(1-3):153-161.
9. Zuardi AW, Morais S, Guimarães FS, Mechoulam RJTJocp. Antipsychotic effect of cannabidiol. 1995.
10. Rohleder C, Müller JK, Lange B, Leweke FJFip. Cannabidiol as a potential new type of an antipsychotic. A critical review of the evidence. 2016;7:422.
11. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. 2017;175(3):225-231.
12. Kandel ER, Schwartz JH, Jessell TM, et al. Principles of neural science. Vol 4: McGraw-hill New York; 2000.
13. Pearlson GDJAoNOJotANA, Society tCN. Neurobiology of schizophrenia. 2000;48(4):556-566.
14. Desfossés J, Stip E, Bentaleb LA, Potvin SJP. Endocannabinoids and schizophrenia. 2010;3(10):3101-3126.
15. Saito A, Ballinger MD, Pletnikov MV, Wong DF, Kamiya AJNod. Endocannabinoid system: potential novel targets for treatment of schizophrenia. 2013;53:10-17.
16. Fatani BZ, Aldawod R, Alhawaj A, et al. Schizophrenia: Etiology, Pathophysiology and Management - A Review %J The Egyptian Journal of Hospital Medicine. 2017;69(6):2640-2646.
17. Perez SM CF, Frazer A, Lodge D. Vagal nerve stimulation as anovel therapy for the treatment of schizophrenia. Paper presented at: The 4th Biennial Schizophrenia International Research Conference.2014; Florence,Italy.
18. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JTJN. Neurobiology of schizophrenia. 2006;52(1):139-153.
19. Lidow MSJBrr. Calcium signaling dysfunction in schizophrenia: a unifying approach. 2003;43(1):70-84.
20. Wojda U, Salinska E, Kuznicki JJIl. Calcium ions in neuronal degeneration. 2008;60(9):575-590.
21. Cosgrove D, Mothersill O, Kendall K, et al. Cognitive characterization of schizophrenia risk variants involved in synaptic transmission: evidence of CACNA1C's role in working memory. 2017;42(13):2612.
22. O’Connell KS, McGregor NW, Malhotra A, Lencz T, Emsley R, Warnich LJTpj. Variation within voltage-gated calcium channel genes and antipsychotic treatment response in a South African first episode schizophrenia cohort. 2019;19(1):109-114.
23. Coyle JTJC, neurobiology m. Glutamate and schizophrenia: beyond the dopamine hypothesis. 2006;26(4-6):363-382.
24. Wu Z-Z, Chen S-R, Pan H-LJJoBC. Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons. 2005;280(18):18142-18151.
25. Belardetti F, Ahn S, So K, Snutch TP, Phillips AGJN. Block of voltage-gated calcium channels stimulates dopamine efflux in rat mesocorticolimbic system. 2009;56(6-7):984-993.
26. Linnertz R, Wurm A, Pannicke T, et al. Activation of voltage-gated Na+ and Ca2+ channels is required for glutamate release from retinal glial cells implicated in cell volume regulation. 2011;188:23-34.
27. Madasu MK, Roche M, Finn DP. Supraspinal transient receptor potential subfamily V member 1 (TRPV1) in pain and psychiatric disorders. In: Pain in Psychiatric Disorders. Vol 30. Karger Publishers; 2015:80-93.
28. Newson PN, van den Buuse M, Martin S, Lynch-Frame A, Chahl LAJBbr. Effects of neonatal treatment with the TRPV1 agonist, capsaicin, on adult rat brain and behaviour. 2014;272:55-65.
29. Touw MJJopd. The religious and medicinal uses of Cannabis in China, India and Tibet. 1981;13(1):23-34.
30. O'Shaughnessy WBJPMJ, Sciences RotM. On the preparations of the Indian hemp, or Gunjah: Cannabis indica their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. 1843;5(123):363.
31. Wood TB, Spivey WN, Easterfield THJJotCS, Transactions. III.—Cannabinol. Part I. 1899;75:20-36.
32. Cahn RSJJotCS. 174. Cannabis indica resin. Part III. The constitution of cannabinol. 1932:1342-1353.
33. Jacob A, Todd AJN. Cannabidiol and Cannabol, Constituents of Cannabis indica resin. 1940;145(3670):350.
34. Gaoni Y, Mechoulam RJJotAcs. Isolation, structure, and partial synthesis of an active constituent of hashish. 1964;86(8):1646-1647.
35. Newton DE. Marijuana: a reference handbook. Abc-Clio; 2017.
36. Anonymous. Conversation with Raphael Mechoulam. 2007;102(6):887-893.
37. Relman ASea. Chemistry and Pharmacology of Marijuana. In "Marijuana and Health", the national academic press, Washington DC 1982.
38. Joy JE, Watson S, Benson JJAtSBWDNA. Marijuana and medicine. 1999.
39. Mechoulam RJBR, FL. Cannabinoids as Therapeutic Agents CRC Press. 1986.
40. Howlett A, Johnson MR, Melvin L, Milne GJMp. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. 1988;33(3):297-302.
41. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. 1992;258(5090):1946-1949.
42. Munro S, Thomas KL, Abu-Shaar MJN. Molecular characterization of a peripheral receptor for cannabinoids. 1993;365(6441):61.
43. Pertwee RGJBjop. Cannabinoid pharmacology: the first 66 years. 2006;147(S1):S163-S171.
44. Rinaldi-Carmona M, Barth F, Héaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. 1994;350(2-3):240-244.
45. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. 1995;50(1):83-90.
46. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NBJN. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. 1996;384(6604):83.
47. Rinaldi-Carmona M, Barth F, Millan J, et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. 1998;284(2):644-650.
48. Bisogno T, Howell F, Williams G, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. 2003;163(3):463-468.
49. Bisogno T, Hanuš L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. 2001;134(4):845-852.
50. Di Marzo V, Bisogno T, Melck D, et al. Interactions between synthetic vanilloids and the endogenous cannabinoid system. 1998;436(3):449-454.
51. Ralevic V, Kendall D, Randall M, Zygmunt P, Movahed P, Högestätt EJBjop. Vanilloid receptors on capsaicin‐sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arteries. 2000;130(7):1483-1488.
52. Price MR, Baillie GL, Thomas A, et al. Allosteric modulation of the cannabinoid CB1 receptor. 2005;68(5):1484-1495.
53. Ross RAJBjop. Anandamide and vanilloid TRPV1 receptors. 2003;140(5):790-801.
54. Tognetto M, Amadesi S, Harrison S, et al. Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. 2001;21(4):1104-1109.
55. Chung YC, Baek JY, Kim SR, et al. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson’s disease. 2017;49(3):e298.
56. Lu H-C, Mackie KJBp. An introduction to the endogenous cannabinoid system. 2016;79(7):516-525.
57. Mechoulam R, Parker LAJArop. The endocannabinoid system and the brain. 2013;64:21-47.
58. Klein C, Hill MN, Chang SC, Hillard CJ, Gorzalka BBJTjosm. Circulating endocannabinoid concentrations and sexual arousal in women. 2012;9(6):1588-1601.
59. Wang H, Xie H, Dey SKJTAj. Endocannabinoid signaling directs periimplantation events. 2006;8(2):E425-E432.
60. Fride EJEjop. The endocannabinoid-CB1 receptor system in pre-and postnatal life. 2004;500(1-3):289-297.
61. De Petrocellis L, Orlando P, Moriello AS, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. 2012;204(2):255-266.
62. Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. 2014;124(9):3713-3724.
63. Kogan NM, Melamed E, Wasserman E, et al. Cannabidiol, a Major Non‐Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts. 2015;30(10):1905-1913.
64. Bluett R, Gamble-George J, Hermanson D, Hartley N, Marnett L, Patel SJTp. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. 2014;4(7):e408.
65. Abidi AH, Presley CS, Dabbous M, Tipton DA, Mustafa SM, Moore II BMJAoob. Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts. 2018;87:79-85.
66. Acharya N, Penukonda S, Shcheglova T, Hagymasi AT, Basu S, Srivastava PKJPotNAoS. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. 2017;114(19):5005-5010.
67. Liu J, Wang L, Harvey-White J, et al. A biosynthetic pathway for anandamide. 2006;103(36):13345-13350.
68. Griebel G, Pichat P, Beeské S, et al. Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents. 2015;5:7642.
69. Heifets BD, Castillo PEJArop. Endocannabinoid signaling and long-term synaptic plasticity. 2009;71:283-306.
70. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe MJPr. Endocannabinoid-mediated control of synaptic transmission. 2009;89(1):309-380.
71. Katona I, Freund TFJAron. Multiple functions of endocannabinoid signaling in the brain. 2012;35:529-558.
72. Dalton V, Long L, Weickert C, Zavitsanou K. Paranoid schizophrenia is characterized by increased cannabinoid CB1 receptor binding in the dorsolateral prefrontal cortex. 2011.
73. Ferretjans R, Moreira FA, Teixeira AL, Salgado JVJRBdP. The endocannabinoid system and its role in schizophrenia: a systematic review of the literature. 2012;34:163-193.
74. Zavitsanou K, Garrick T, Huang XFJPiN-P, Psychiatry B. Selective antagonist [3H] SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. 2004;28(2):355-360.
75. Newell KA, Deng C, Huang X-FJEBR. Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. 2006;172(4):556-560.
76. Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. 2004;29(11):2108.
77. Zhang W, Bymaster FPJP. The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors. 1999;141(3):267-278.
78. Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. 2014;5:47.
79. Elmes MW, Kaczocha M, Berger WT, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). 2015;290(14):8711-8721.
80. Leweke F, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. 2012;2(3):e94.
81. Deutsch DG, Glaser ST, Howell JM, et al. The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. 2001;276(10):6967-6973.
82. Ahmed M, King K, Pearce S, Ramsey M, Miranpuri G, Resnick DJMrimc. Novel target for Spinal Cord Injury Neuropathic Pain. 2012.
83. Gomez M, De Castro E, Guarin E, et al. Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans. 2001;30(1):241-248.
84. Rannikko I, Haapea M, Miettunen J, et al. Changes in verbal learning and memory in schizophrenia and non-psychotic controls in midlife: A nine-year follow-up in the Northern Finland Birth Cohort study 1966. 2015;228(3):671-679.
85. Musella A, De Chiara V, Rossi S, et al. TRPV1 channels facilitate glutamate transmission in the striatum. 2009;40(1):89-97.
86. De La Fuente-sandoval C, León-Ortiz P, Favila R, et al. Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. 2011;36(9):1781.
87. Barbeito L, Cheramy A, Godeheu G, Desce J, Glowinski JJEJoN. Glutamate receptors of a quisqualate‐kainate subtype are involved in the presynaptic regulation of dopamine release in the cat caudate nucleus in vivo. 1990;2(4):304-311.
88. Desce J, Godeheu G, Galli T, Artaud F, Cheramy A, Glowinski JJN. L-glutamate-evoked release of dopamine from synaptosomes of the rat striatum: involvement of AMPA and N-methyl-D-aspartate receptors. 1992;47(2):333-339.
89. Sakae DY, Marti F, Lecca S, et al. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. 2015;20(11):1448.
90. Maureen A Leehey et al. A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson's Disease. 2017; https://clinicaltrials.gov/ct2/show/NCT02818777.
91. Iffland K, Grotenhermen FJC, research c. An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. 2017;2(1):139-154.
92. Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. 2006;20(5):683-686.
93. Zuardi AW, Crippa J, Hallak JEC, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. 2009;23(8):979-983.
94. Ross RA, Gibson TM, Brockie HC, et al. Structure‐activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. 2001;132(3):631-640.
95. Ruggiero RN, Rossignoli MT, De Ross JB, Hallak JE, Leite JP, Bueno-Junior LSJFip. Cannabinoids and vanilloids in schizophrenia: Neurophysiological evidence and directions for basic research. 2017;8:399.
96. Huang SM, Bisogno T, Trevisani M, et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. 2002;99(12):8400-8405.
97. Marinelli S, Di Marzo V, Berretta N, et al. Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. 2003;23(8):3136-3144.