**2. Cannabidiol (CBD) and the brain**

CBD is a major cannabinoid of *C. sativa*, considered a metabolic by-product rather than a biosynthetic product of the plant [1]. There has been a recent burst of studies showing beneficial effects of CBD in the brain, with evidence pointing to CBD as a promising novel therapy for a range of disorders. Based on its ability to change brain function and behaviour, it is, by definition 'psychoactive', but CBD is non-intoxicating and there is currently no evidence that it causes the deleterious hallucinogenic, paranoia and anxiety-inducing effects of the delta-tetrahydrocannabinol (Δ-THC) type chemicals, particularly Δ9-THC that is primarily responsible for the 'high' induced by recreational cannabis [2]. Instead, CBD has a broad spectrum of therapeutic properties, including antipsychotic, anxiolytic, immunomodulatory, anti-inflammatory, neuroprotective and pro-cognitive benefits in humans and preclinical disease models. Although its mechanisms of action are currently unclear, studies show that CBD is a cannabinoid 1 receptor (CB1) negative allosteric modulator [3], is a partial agonist of the dopamine D2 high receptor sub-type [4] and increases anandamide (AEA) signalling [5], possibly through inhibition of the AEA catabolic enzyme, fatty acid amide hydrolase (FAAH) [6].

#### **2.1. Cannabidiol protects against cognitive harms of high-THC Cannabis**

In terms of cognition, our recent systematic review by Osborne et al. [7] revealed a body of clinical and pre-clinical evidence supporting the pro-cognitive effects of CBD. We identified reports demonstrating that CBD can protect against cognitive harms of cannabis. For example, recreational users of cannabis containing higher (>0.75%) CBD performed better in verbal memory testing during acute intoxication compared to users of cannabis with the same Δ9-THC levels but low (<0.14%) CBD [reviewed in 7]. CBD pre-treatment (600 mg oral) also protected against deficits in verbal learning and memory, and aspects of working memory during a Δ9-THC (1.5 mg/kg intravenous (i.v.)) challenge in healthy participants (n = 22) [reviewed in 7].

Imaging studies over the past decade have revealed altered brain morphology in key regions of the brain implicated in cognition in cannabis users. For example, chronic heavy cannabis users (n = 15) exhibit reduced brain volume in the hippocampus and amygdala compared to matched non-using controls (n = 16) [8], and hippocampal shape aberrations were detected in cannabis users (n = 15 male chronic heavy users) that were exacerbated in people with comorbid schizophrenia (n = 8 males) compared to healthy controls [9]. Interestingly, regular users of low CBD cannabis had reduced hippocampal volumes compared to non-users; a reduction that was not observed in the participants either using cannabis containing CBD or in former users [10]. The authors of that study concluded that CBD could reduce harm to brain health caused by cannabis use, while periods of abstinence could recover damage in the parameters examined [10]. Recently, it was reported that 10-weeks of oral CBD treatment (200 mg) increased the volume of discrete hippocampal regions in cannabis users (n = 18), with higher growth observed in heavy compared to light cannabis users [11]. Overall, these studies point to a protective effect of CBD on cognitive regions of the brain during cananbis use in humans; however, larger scale placebo-controlled trials are required. A potential mechanism for these benefits may relate to the neuroprotective characteristics of CBD, particularly its ability to stimulate neurogenesis, synaptic formation and neurite outgrowth (reveiwed in [12]).

Similar results supporting a protective role of CBD have been reported in pre-clinical studies. For example, CBD (0.5 mg/kg) increased visual learning and memory, and procedural learning in Rhesus monkeys co-administered Δ9-THC (0.2 or 0.5 mg/kg) compared to those administered Δ9-THC alone; however, spatial working memory was further impaired by combined treatment (reviewed in [7]). Chronic Δ9-THC exposure in adolescent mice (3 mg/kg daily) reduced recognition memory that persisted into adulthood, but this was not apparent in the group receiving CBD (3 mg/kg CBD) co-treatment during Δ9-THC exposure [13]. On the other hand, research shows that there are no beneficial effects of CBD on cognition, including verbal learning and memory, social recognition, executive function, spatial memory or conditioned learning, when administered to healthy subjects (humans or rodents) (reviewed in [7, 13]).

#### **2.2. Cannabidiol treatment for neurological disorders and inflammatory disease states**

#### *2.2.1. Alzheimer's disease*

decision-making, processing speed, attention span, learning and memory. Cognitive dysfunction can occur in a range of illnesses and disease states, for example Alzheimer's disease, dementia, Parkinson's disease, schizophrenia, hypoxic ischemia, stroke and meningitis. There is particularly strong evidence in the existing literature to support the pro-cognitive effects of the cannabinoid, cannabidiol (CBD) in disease states. There is also evidence that other phytochemicals in cannabis provide benefits for brain health and cognitive function. Furthermore, the suggested presence of an 'entourage effect' may mean that the therapeutic potential of CBD could be boosted through synergistic interactions with other phytochemicals. Therefore, certain cannabis strains may confer greater benefits for particular clinical indications, presenting unique opportunities for the discovery of novel personalised therapeutics. Identifying specific beneficial compounds could underpin selective breeding of plant cultivars with phytochemical profiles optimised towards restoring brain function in diseases associated with

CBD is a major cannabinoid of *C. sativa*, considered a metabolic by-product rather than a biosynthetic product of the plant [1]. There has been a recent burst of studies showing beneficial effects of CBD in the brain, with evidence pointing to CBD as a promising novel therapy for a range of disorders. Based on its ability to change brain function and behaviour, it is, by definition 'psychoactive', but CBD is non-intoxicating and there is currently no evidence that it causes the deleterious hallucinogenic, paranoia and anxiety-inducing effects of the delta-tetrahydrocannabinol (Δ-THC) type chemicals, particularly Δ9-THC that is primarily responsible for the 'high' induced by recreational cannabis [2]. Instead, CBD has a broad spectrum of therapeutic properties, including antipsychotic, anxiolytic, immunomodulatory, anti-inflammatory, neuroprotective and pro-cognitive benefits in humans and preclinical disease models. Although its mechanisms of action are currently unclear, studies show that CBD is a cannabinoid 1 receptor (CB1) negative allosteric modulator [3], is a partial agonist of the dopamine D2 high receptor sub-type [4] and increases anandamide (AEA) signalling [5], possibly through inhibition of the AEA catabolic enzyme, fatty acid amide hydrolase (FAAH) [6].

**2.1. Cannabidiol protects against cognitive harms of high-THC Cannabis**

In terms of cognition, our recent systematic review by Osborne et al. [7] revealed a body of clinical and pre-clinical evidence supporting the pro-cognitive effects of CBD. We identified reports demonstrating that CBD can protect against cognitive harms of cannabis. For example, recreational users of cannabis containing higher (>0.75%) CBD performed better in verbal memory testing during acute intoxication compared to users of cannabis with the same Δ9-THC levels but low (<0.14%) CBD [reviewed in 7]. CBD pre-treatment (600 mg oral) also protected against deficits in verbal learning and memory, and aspects of working memory during a Δ9-THC (1.5 mg/kg intravenous (i.v.)) challenge in healthy participants (n = 22)

cognitive dysfunction.

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[reviewed in 7].

**2. Cannabidiol (CBD) and the brain**

Alzheimer's disease is the most common form of dementia. It is a progressive neurological disorder characterised by the presence of plaques and neurofibrillary tangles in the brain. Amyloid β peptides form densely packed extracellular filaments (plaques) that block cell signalling and trigger neuroinflammation. Neurofibrillary tangles are caused by transportassociated proteins called tau that form twisted structures during oxidative stress and block transport of nutrients and other essentials for neuronal function [14]. The progressive disruption and destruction of synapses results in memory loss and cognitive dysfunction. A role for cannabinoids as a therapy for Alzheimer's disease has been proposed, in part due to the neuroprotective, anti-inflammatory and anti-oxidant properties of cannabinoids, as well as the role of the endocannabinoid system in memory and Alzheimer's disease pathology (reviewed in [15]). One study found that Sativex®, containing Δ9-THC and CBD, reduced tau and amyloid deposition in the hippocampus and cortex in a mouse model of tauopathy [16]. In addition, Δ9-THC and CBD administration improved memory deficits in AβPP/PS1 transgenic mice with an Alzheimer-like phenotype, but not in mice with cognitive decline associated with healthy ageing [17]. Another study attributed CBD treatment (20 mg/kg oral, daily for 8 months) of social recognition deficits in AβPP/PS1 mice with the prevention of neuroinflammation and cholesterol homeostasis rather than a reduction in amyloid load [18]. Clinical studies are required to confirm whether CBD/Δ9-THC therapies can improve brain health and function in people with Alzheimer's disease or dementia.

Rats exposed to hypoxic ischemia at birth exhibited recognition memory deficits that were attenuated by CBD (1 mg/kg) administered subcutaneously 10 min post-ischemia, while CBD treatment (3, 10 or 30 mg/kg 30 min pre- and 3, 24 and 48 h post-ischemic insult) increased spatial memory compared to placebo-treated ischemic rats (reviewed in [7]). In a subsequent study, acute CBD treatment (5 mg/kg, intraperitoneal (i.p.)) reduced apoptosis, neuronal loss and neuroinflammation in ischemic in neonatal rats [24], providing mechanistic clues about the behavioural restorative effects of CBD during hypoxic brain damage. A clinical trial investigating THC:CBD efficacy on spasticity following a stroke has been registered [25]; however,

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Sepsis is a potentially life-threatening systemic inflammatory state that occurs as the body attempts to eliminate a pathogen. It can cause rapid cognitive impairment, particularly memory decline that was initially considered a transient state restored through the destruction of the pathogen and attenuation of the inflammatory response. However, sepsis is also associated with encephalopathy, a disease state of the brain that can manifest symptoms ranging from mild personality changes to cognitive and motor impairment, lethargy and coma. Sepsisinduced encephalopathy can be caused by increased permeability of the blood brain barrier and neuroinflammation that can lead to permanent functional impairment and enhance susceptibility to subsequent neurodegenerative disorders post-recovery [26]. Sub-chronic CBD treatment improved associative learning in a rodent model of sepsis (CBD administered either 2.5, 5 or 10 mg/kg daily for 9 days) compared to vehicle-treated controls (reviewed in [7]). CBD (single acute dose 3 mg/kg, i.v.) treatment also preserved blood–brain barrier integrity, restored normal vascular endothelial function and reduced inflammation in the mouse brain during endotoxic shock induced by administration of lipopolysaccharide (LPS) [27], a cell wall component of Gram-negative bacteria that can be used to model an excessive pro-

Schizophrenia is a chronic neurodevelopmental disorder characterised by three main symptom domains: positive (e.g., hallucinations, delusions and paranoia), negative (e.g., social withdrawal, flattened emotional expression, lack of motivation) and cognitive deficits. Existing antipsychotic medications confer minimal to no cognitive benefits (in some instances can further impair cognition) [28], and can cause serious weight gain and diabetes side-effects [29, 30]. We recently discovered that chronic CBD (10 mg/kg CBD, i.p., twice daily (b.i.d.)) treated cognitive impairment (learning, working and recognition memory) and social interaction deficits in a rat prenatal infection (poly I:C) model of schizophrenia-like phenotypes [31]. No behavioural changes were observed in healthy rats administered CBD and CBD did not cause weight gain side-effects [31]. An earlier clinical study (phase II, single-centred, doubleblinded, randomised parallel-group controlled clinical trial of CBD vs. amisulpride) had reported improved positive and negative symptoms in people with schizophrenia following 4 weeks of CBD treatment, with therapeutic efficacy similar to the commercial antipsychotic, amisulpride; however, cognitive function was not examined [5]. More recently, a multi-centre

cognitive testing has not been proposed as a treatment outcome.

*2.2.5. Sepsis-induced encephalopathy*

inflammatory response in the host.

*2.2.6. Schizophrenia*

#### *2.2.2. Huntington's disease*

Huntington's disease is a progressive neurodegenerative disease of genetic origins, manifesting in motor impairment, cognitive decline and behavioural symptoms. In a double-blinded, placebo-controlled, cross-over clinical trial, Sativex® (orally administered in 12 sprays/day) was unable to improve cognitive, motor or behavioural scores in a cohort of patients with Huntington's disease (n = 24) compared to placebo-treated controls after 12-weeks of treatment [19]. In a smaller double-blinded, randomised cross-over study, CBD alone (10 mg/ kg/day, oral) also yielded no symptom efficacy, including recall memory, in 15 patients Huntington's disease after 6-weeks of treatment [20]. However, large cohort studies of CBD administration in people with Huntington's disease are required.

#### *2.2.3. Parkinson's disease*

Parkinson's disease occurs through the progressive degeneration of dopaminergic neurons in the midbrain, resulting in severe motor impairment and loss of motor control. CBD is a prime novel therapeutic candidate for the treatment of Parkinson's disease due to its neuroprotective properties. However, one clinical study reported no improvement in motor or general symptoms scores in patients treated with CBD (75 or 300 mg/day) compared to placebotreated controls (n = 7/group), although, overall quality of life was significantly improved in the 300 mg CBD treatment group compared to placebo-treated controls [21]. Another clinical study (open-label pilot study, n = 6) of Parkinson's disease patients with psychosis revealed significant improvements to psychiatric scores, but not motor function following CBD (>150 mg/day oral CBD) administration for 4-weeks in combination with existing L-dopa medication [22]. On the other hand, CBD (0.5 or 5 mg/kg CBD administered in four injections) prevented cognition and motor dysfunction when administered prior to reserpine treatment in a rodent model of Parkinson's disease [23].

#### *2.2.4. Ischemic brain injury*

Brain injury due to blood flow impediment and hypoxic damage can result in immediate and progressive cognitive decline. Ischemic brain injury can occur following events such as a stroke, cardiac arrest, near drowning or birth complications resulting in perinatal asphyxia. Rats exposed to hypoxic ischemia at birth exhibited recognition memory deficits that were attenuated by CBD (1 mg/kg) administered subcutaneously 10 min post-ischemia, while CBD treatment (3, 10 or 30 mg/kg 30 min pre- and 3, 24 and 48 h post-ischemic insult) increased spatial memory compared to placebo-treated ischemic rats (reviewed in [7]). In a subsequent study, acute CBD treatment (5 mg/kg, intraperitoneal (i.p.)) reduced apoptosis, neuronal loss and neuroinflammation in ischemic in neonatal rats [24], providing mechanistic clues about the behavioural restorative effects of CBD during hypoxic brain damage. A clinical trial investigating THC:CBD efficacy on spasticity following a stroke has been registered [25]; however, cognitive testing has not been proposed as a treatment outcome.

#### *2.2.5. Sepsis-induced encephalopathy*

the neuroprotective, anti-inflammatory and anti-oxidant properties of cannabinoids, as well as the role of the endocannabinoid system in memory and Alzheimer's disease pathology (reviewed in [15]). One study found that Sativex®, containing Δ9-THC and CBD, reduced tau and amyloid deposition in the hippocampus and cortex in a mouse model of tauopathy [16]. In addition, Δ9-THC and CBD administration improved memory deficits in AβPP/PS1 transgenic mice with an Alzheimer-like phenotype, but not in mice with cognitive decline associated with healthy ageing [17]. Another study attributed CBD treatment (20 mg/kg oral, daily for 8 months) of social recognition deficits in AβPP/PS1 mice with the prevention of neuroinflammation and cholesterol homeostasis rather than a reduction in amyloid load [18]. Clinical studies are required to confirm whether CBD/Δ9-THC therapies can improve brain

Huntington's disease is a progressive neurodegenerative disease of genetic origins, manifesting in motor impairment, cognitive decline and behavioural symptoms. In a double-blinded, placebo-controlled, cross-over clinical trial, Sativex® (orally administered in 12 sprays/day) was unable to improve cognitive, motor or behavioural scores in a cohort of patients with Huntington's disease (n = 24) compared to placebo-treated controls after 12-weeks of treatment [19]. In a smaller double-blinded, randomised cross-over study, CBD alone (10 mg/ kg/day, oral) also yielded no symptom efficacy, including recall memory, in 15 patients Huntington's disease after 6-weeks of treatment [20]. However, large cohort studies of CBD

Parkinson's disease occurs through the progressive degeneration of dopaminergic neurons in the midbrain, resulting in severe motor impairment and loss of motor control. CBD is a prime novel therapeutic candidate for the treatment of Parkinson's disease due to its neuroprotective properties. However, one clinical study reported no improvement in motor or general symptoms scores in patients treated with CBD (75 or 300 mg/day) compared to placebotreated controls (n = 7/group), although, overall quality of life was significantly improved in the 300 mg CBD treatment group compared to placebo-treated controls [21]. Another clinical study (open-label pilot study, n = 6) of Parkinson's disease patients with psychosis revealed significant improvements to psychiatric scores, but not motor function following CBD (>150 mg/day oral CBD) administration for 4-weeks in combination with existing L-dopa medication [22]. On the other hand, CBD (0.5 or 5 mg/kg CBD administered in four injections) prevented cognition and motor dysfunction when administered prior to reserpine treatment

Brain injury due to blood flow impediment and hypoxic damage can result in immediate and progressive cognitive decline. Ischemic brain injury can occur following events such as a stroke, cardiac arrest, near drowning or birth complications resulting in perinatal asphyxia.

health and function in people with Alzheimer's disease or dementia.

administration in people with Huntington's disease are required.

*2.2.2. Huntington's disease*

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*2.2.3. Parkinson's disease*

*2.2.4. Ischemic brain injury*

in a rodent model of Parkinson's disease [23].

Sepsis is a potentially life-threatening systemic inflammatory state that occurs as the body attempts to eliminate a pathogen. It can cause rapid cognitive impairment, particularly memory decline that was initially considered a transient state restored through the destruction of the pathogen and attenuation of the inflammatory response. However, sepsis is also associated with encephalopathy, a disease state of the brain that can manifest symptoms ranging from mild personality changes to cognitive and motor impairment, lethargy and coma. Sepsisinduced encephalopathy can be caused by increased permeability of the blood brain barrier and neuroinflammation that can lead to permanent functional impairment and enhance susceptibility to subsequent neurodegenerative disorders post-recovery [26]. Sub-chronic CBD treatment improved associative learning in a rodent model of sepsis (CBD administered either 2.5, 5 or 10 mg/kg daily for 9 days) compared to vehicle-treated controls (reviewed in [7]). CBD (single acute dose 3 mg/kg, i.v.) treatment also preserved blood–brain barrier integrity, restored normal vascular endothelial function and reduced inflammation in the mouse brain during endotoxic shock induced by administration of lipopolysaccharide (LPS) [27], a cell wall component of Gram-negative bacteria that can be used to model an excessive proinflammatory response in the host.

#### *2.2.6. Schizophrenia*

Schizophrenia is a chronic neurodevelopmental disorder characterised by three main symptom domains: positive (e.g., hallucinations, delusions and paranoia), negative (e.g., social withdrawal, flattened emotional expression, lack of motivation) and cognitive deficits. Existing antipsychotic medications confer minimal to no cognitive benefits (in some instances can further impair cognition) [28], and can cause serious weight gain and diabetes side-effects [29, 30]. We recently discovered that chronic CBD (10 mg/kg CBD, i.p., twice daily (b.i.d.)) treated cognitive impairment (learning, working and recognition memory) and social interaction deficits in a rat prenatal infection (poly I:C) model of schizophrenia-like phenotypes [31]. No behavioural changes were observed in healthy rats administered CBD and CBD did not cause weight gain side-effects [31]. An earlier clinical study (phase II, single-centred, doubleblinded, randomised parallel-group controlled clinical trial of CBD vs. amisulpride) had reported improved positive and negative symptoms in people with schizophrenia following 4 weeks of CBD treatment, with therapeutic efficacy similar to the commercial antipsychotic, amisulpride; however, cognitive function was not examined [5]. More recently, a multi-centre double-blinded parallel-group clinical trial examined the efficacy of CBD co-treatment with the patient's existing antipsychotic medication on a range of endpoints, including positive, negative and cognitive scores and Clinical Global Impression scales (CGI, measuring illness severity, improvement and response to treatment) [32]. Results showed significant improvements in positive (not negative) symptoms and CGI scores, as well as some improvement in cognitive performance (did not reach statistical significance, *p* = 0.068 CBD vs. placebo) when CBD was combined with the patient's existing antipsychotic medications [32].

endogenous molecules (2-linoleoyl-glycerol (2-LG) and 2-palmitoyl-glycerol (2-PG)) potentiated the effects of the endocannabinoid, 2-AG [33]. Interestingly, cultured hippocampal neurons exposed to CBD-rich plant extracts exhibit a significantly greater intracellular signalling response compared to CBD alone [37]. This provides preliminary (*in-vitro*) evidence that CBD-rich plant extracts exert greater effects on cells of the hippocampus (a region of the brain highly implicated in learning and memory) than isolated CBD. Overall, it may be possible to boost the pro-cognitive therapeutic efficacy of CBD through a synergistic approach. Studies show that cannabinoids other than CBD could confer beneficial effects on the brain through synergistic mechanisms, for example, the parent phytocannabinoid cannabigerol (CBG) exerted greater analgesic effects on mice than Δ9-THC alone, while CBG and cannabichromene (CBC) both have anti-depressant effects in rodents (reviewed in [38]) and CBG is neuroprotective in a mouse model of Huntington's Disease [39]. However, section 4 will focus on several key non-cannabinoid cannabis phytochemicals with promising evidence of

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**4. Non-cannabinoid phytochemicals of Cannabis: terpenes,** 

The cannabis plant contains hundreds of phytochemicals, with new compounds and metabolites frequently identified. The concentration of chemicals in a cannabis plant can be influenced by multiple factors including nutrition, humidity, temperature, age of plant, strain, harvest time, plant stress, organ and storage conditions [1, 40]. Therefore, plant phytochemical composition is highly variable. Variability identified even within the same strain has led some authors to conclude that the name of a plant strain does not necessarily indicate potency or chemical composition [41]. However, others found that when grown under standardised conditions, certain cannabis strains can provide reproducible terpene and phytocannabinoid profiles that have been considered chemotaxonomic markers [42]. Furthermore, cannabinoid content can be used to classify plants into chemovars (plants with distinct photochemical profiles): Type I Δ9-THC-dominant, Type II Δ9-THC and CBD, Type III CBD-dominant and distinctions can be made outside these classes based on specific terpene profiles [43]. Therefore, it is possible to optimise plants to reproduce a distinct chemical composition and, potentially,

Terpenes have been described as the most abundant class of small natural molecules by mass on Earth, undertaking innumerable structural and functional roles in most life forms on the planet (e.g., cholesterols for structural and signalling components of cell membranes, retinal in the eye for vision, carotenoids in photosynthesis) [44]. In cannabis, they create fragrances and flavours, but are also found in other plants and commonly used as safe food additives [38]. Terpenes can cross the blood brain barrier due to their lipophilic nature and studies have

demonstrated a range of health benefits for some terpenes found in cannabis.

positive effects on brain function.

**flavonoids and anthocyanins**

specific medicinal characteristics.

**4.1. Terpenes: linalool, alpha-pinene and beta-caryophyllene**

#### **2.3. Conclusions on the use of CBD in neurological disease**

There is substantial scientific evidence to show the beneficial effects of CBD in the brain, with protection and treatment efficacy for various cognitive behaviours conferred in multiple disease states. Overall, there seems to be a general requirement for further placebocontrolled clinical trials, as well as investigation of long-term efficacy and safety in different populations of people. Evidence for illness-specific optimal dosing regimens (dose, route of administration, timing and number of daily doses, effect of concurrent medications, etc.) is also required. In addition, similar to our rodent study of CBD effects on cognition in schizophrenia [31], most studies use either isolated CBD or combined THC and CBD. While this methodology enables investigators to attribute results to a specific compound, it may not be the optimal therapeutic approach as cannabis-derived plant molecules are thought to interact and produce a synergy that enhances therapeutic effects—termed the 'entourage effect'.
