A narrative review of the therapeutic and remedial prospects of cannabidiol with emphasis on neurological and neuropsychiatric disorders

Cannabidiol

Cannabidiol (CBD), known scientifically as 2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol, has the chemical formula of C₂₁H₃₀O₂ and molecular weight of 314.5 g/mol. It is a terpenophenol and bicyclic compound consisting of a phenolic and cyclohexene ring, illustrated as A and B respectively in Fig. 1a. The pentyl chain and the location of the hydroxyl group in the phenolic ring (A), as well as the methyl group of the cyclohexene ring (B), significantly influence the chemical activity of the compound. For example, the hydroxyl groups enable it to bind to glutamine, threonine, and other amino acids through a hydrogen bond (ElSohly and Slade 2005; Jones et al. 1977; Mechoulam and Hanuš, 2002).

As an approved prescription drug for seizure disorders (Meissner and Cascella 2022), CBD is available in various forms such as oils and tinctures, capsules, and edibles (Fig. 1b). Clinically, it is often recommended for use in combination with antiepileptic therapy for the reduction of convulsive seizures in Dravet syndrome and treatment-resistant drop seizures in patients with Lennox–Gastaut syndrome (Devinsky et al. 2019; Privitera et al. 2021). While attention is commonly drawn to the natural product extracted from cannabis plants, another derivative of CBD, that is artificially/chemically synthesized – from biological processes using modified yeast or other ingredients such as limonene – is also used for various purposes ranging from cosmetic to medicinal (Abame et al. 2021; Stahl and Vasudevan 2020).

Method of literature search

This narrative review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and reporting criteria (PRISMA). Following various scoping searches, a comprehensive literature search was conducted using available online scientific databases including Scopus, Science Direct, PubMed, Web of Science and Google Scholar. No time limit was used, and the keywords were: cannabidiol, epidiolex, cannabinoids, anti-inflammatory effects, neurological infections, neurological disorders, therapeutic effects of CBD, CBD effects on cytokines, and pro-inflammatory cytokines. Scientific papers, and commentaries written in English were also included. The initial search retrieved 414 articles, but after purposive screening and selection, only 170 of these (41%) which aligned with the objectives of this study were retained for inclusion. Respectively, Table 1 and Fig. 2 shows the screening and inclusion criteria (considered keywords) for this review.

Eligibility criteria

Studies published in English language that were eligible and included in this review are those which considered the anti-inflammatory and therapeutic potentials of CBD, pharmacological/pharmacokinetic effects of CBD, effect of CBD on neurological disorders in human or animal model (s), or studies that assessed the impact of CBD on regulation of inflammation and cytokine release (Fig. 2). Articles that passed the initial screening were given full text review. Studies that were excluded were those that did not align with the aim of this study, did not deal with the effect of CBD, used standardised cannabis extracts containing both THC and CBD, or those with no appropriate controls to evaluate the influence of CBD alone. Figure 3 illustrates the article selection process.

Data extraction

After the screening procedure, research articles that met the criteria were again reviewed and vital information was extracted including author(s), publication year, journals where the articles were published, experiments/aim of the study, target population (human or animal model), information pertaining to treatment used, interventions and dosage, route of administration and outcomes of the various included studies (Tables 2 and ​and33).

This study addresses the pharmacology, modes of action, absorption, metabolism, tolerance, and therapeutic qualities of cannabidiol (CBD). In addition, this phytocannabinoid’s prospects and potentials in neurological disorders were examined, and the potential of CBD in treating neurological disorders was evaluated.

Pharmacology and mechanisms of action of CBD

Being a drug with many targets, CBD interacts with several signalling systems and modulates the γ-aminobutyric acid type A receptors, and 5-hydroxy tryptophan 1A receptors (5-HT_1a), which are involved in neurotransmission and neuromodulation, respectively (Ghit et al. 2021; Hilaire et al. 2010; Russo et al. 2005). However, it has been observed that CBD inhibits endocannabinoid signalling (Straiker et al. 2018). The endocannabinoid system regulates many physiological activities in the human body, and it involves the endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and enzymes as its main components (Lu and Mackie 2016). The endocannabinoids have been described as molecules produced by the body which are similar to cannabinoids. The two main endocannabinoids identified so far are anandamide, also known as N-arachidonoylethanolamine (AEA), and 2-arachidonoyl glycerol (2-AG), which are produced as needed and help to keep internal functions running smoothly (Rodríguez de Fonseca et al. 2005). The CB1 receptors (found mostly in the central nervous system) and the CB2 receptors (found mostly in the immune cells- peripheral nervous system) receives the endocannabinoids and signal to the endocannabinoid system to act while the fatty acid amide hydrolase (FAAH) and monoacylglycerol acid lipase (MGAL) breaks down the endocannabinoids after carrying out their function (the FAAH breaks down AEA while the MGAL breaks down 2-AG) (Basavarajappa 2007).

CBD acts as an antagonist of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are highly expressed in the hippocampus and modulate seizure activity, whereas CB2 receptors are localized in immune cells. This implies that CBD modulates neurotransmission, immune/inflammatory pathways, and other peripheral functions; thereby protecting against cellular damage that occurs during immune responses (Peyravian et al. 2020).

It has been established that CBD acts as a negative allosteric modulator of the CB1 receptor, and this is achieved by modifying the activity of a receptor on a distinct site from the antagonist binding site/agonists (Laprairie et al. 2015). It is important to note that allosteric modulators of CB1 receptors are capable of treating disorders of the peripheral and central nervous system while preventing the negative effects linked with antagonism of these receptors (Laprairie et al. 2015). At higher concentrations, CBD acts as an inverse agonist of G protein-coupled receptors (GPR, GPR6, GPR12, and 5-HT_1a), which are phylogenetically related to CB receptors, and are novel therapeutic targets for CBD (Laun et al. 2019). CBD also binds to transient receptor potential vanilloid (TRPV1), impeding synaptosomal uptake of noradrenaline, serotonin, and dopamine (Bisogno et al. 2001; De Petrocellis et al. 2011), blocks low-voltage-activated (T-type) Ca²⁺ channels, acts on mitochondria Ca²⁺ stores and constrains the activity of FAAH and it also stimulates the action of the inhibitory glycine receptor (Massi et al. 2008).

Absorption, metabolism, and tolerability of CBD

Through inhalation, CBD is rapidly absorbed with a higher bioavailability by an average of about 35% than oral bioavailability – reported to be low (~ 6% in humans) (Davidson 2022; Lucas et al. 2018). Thus, when ingested, CBD has a lower absorption rate than when inhaled, due to first-pass hepatic metabolism (Della Rocca et al. 2022). In addition to the frequently used oral and intranasal routes, CBD can also be administered through the sublingual and rectal routes. However, the potency of these routes still needs to be established as few studies and have described the pharmacokinetics of CBD administered rectally.

When administered transdermally, significant accumulation of CBD was observed in the skin as well as in the underlying muscle; steady-state levels were reached at about 24 h and lasted for 72 h (Lodzki et al. 2003). In their study, Hosseini et al. (2021) observed that administration of CBD as a sublingual wafer (50 mg CBD) to healthy human volunteers resulted in maximum concentrations of the drug after 4 h with an estimated terminal elimination half-life of 6 h. More studies are still required on the delivery of CBD through injections; however, Fu et al. (2022) found that intramuscular injection of CBD nanocrystals resulted in a 2.0- to 2.2-fold greater concentration of CBD in fasted male Sprague–Dawley rats within 24 h, compared to oral administration.

With a biological half-life of about 18–32 h, up to 1500 mg of CBD per day can be well tolerated in the body without adverse effects, especially on the brain (Machado Bergamaschi et al. 2011; Welty et al. 2014). Through the renal and biliary systems, CBD is metabolized greatly in the liver by the isoenzymes UGT1A7, UGT1A9, UGT2B7 and cytochrome P450 enzymes (CYP2B6, CYP2C19, CYP2D6, CYP2J2, and CYP3A4), thus forming several metabolites such as the 6α- and 6β-hydroxy isomers and 7-hydroxy cannabidiol (Chayasirisobhon 2020; Jiang et al. 2011; Welty et al. 2014).

Psychotic adverse effects of CBD in humans have not been reported as it is noted to be well tolerated (Machado Bergamaschi et al. 2011). In a study to evaluate the pharmacokinetics and safety of CBD oral solution in paediatric patients with treatment-resistant epilepsy – defined as recurrent seizures despite adequate trials of three or more antiepileptic drugs and one or more prior adequate treatment courses with two or more antiepileptic drugs in combination, Wheless et al. (2019) confirmed the tolerability of CBD, as they observed how CBD was well metabolized in more than sixty human patients (age 1–17) included in the study, with few adverse effects such as somnolence, diarrhoea, and anaemia.

When used as an adjunctive treatment with anti-seizure medications, as evidenced in the study of Devinsky et al. (2018), CBD reduced the frequency of seizures in four epilepsy etiologies (Doose syndrome, Aicardi, Dup 5q and CDKL 5 deficiency disorder), with moderate side effects such as diarrhoea, fatigue, and somnolence. Similarly, the study of Kochen et al. (2023) confirms the safety and effectiveness of cannabidiol as an adjuvant in adult patients with drug-resistant focal epilepsy with adverse effects including diarrhoea, somnolence, and decreased appetite (Kochen et al. 2023). It is therefore important to emphasize that despite the effectiveness and safety of CBD, minor side effects such as those stated may occur.

Therapeutic properties of CBD

The application of CBD, singularly and in combination with other medicines in the management of various health disorders, has shown beneficial effects including antibacterial, anti-inflammatory, anti-oxidative, neuroprotective, proapoptotic, anti-proliferative, anti-migratory, and anti-invasive capabilities (Aziz et al. 2022a). That is, CBD can act against specific pathogens, block pro-inflammatory cytokines, capture and convert free radicals into passive forms, safeguard against specific neurological conditions, and prevent the invasion and migration of cancer cells (Aziz et al. 2022a; Cabrera et al. 2021).

In neuroinflammation, activated microglia can migrate toward a lesion (affected neuron) and secrete inflammatory mediators, neurotrophic factors, and reactive oxygen species (ROS) which can exert beneficial or detrimental effects on the surrounding cells (Carbonell et al. 2005; Stence et al. 2001). The activation of microglia has been linked to increased inflammatory response and could result in progressive neuron damage. Hence, persistent and overactivation of microglia has been linked to multiple neurodegenerative diseases (Kim and Joh 2006).

However, CBD has been reported to be a good modulator of microglia cell migration in inflammation. According to Martín-Moreno et al. (2011) who studied and compared the effects of CBD with those of other cannabinoids on microglial cells in Alzheimer’s disease, CBD was able to regulate microglial cell function in vitro while it also caused some beneficial effects in an in vivo model of Alzheimer’s disease. Victor et al. (2022) examined the effect of CBD on microglial inflammation activation and neurogenic response in seizures and in the absence of seizures it was reported that CBD reduced microglial migration and accumulation to the hippocampus.

Table ​Table22 lists various studies performed on human cells, bacteria and animal models that have revealed some of the therapeutic characteristics of CBD. Table ​Table33 describes human clinical trials and studies that were carried out on animal models to assess the potential of CBD for managing various health issues, including brain-related disorders.

Prospects of CBD in neurological disorders

In neurological disorders, an immune response-based defense is generated, which induces systemic inflammation by the continuous production of pro-inflammatory cytokines and granulocyte–macrophage colony-stimulating factor, thereby resulting in changes in cells/tissue and the possibility of organ damage (Misri et al. 2022; Seltzer et al. 2020). Signalling on the immune system involves various pathways that achieve the release of chemokines and cytokines through mitogen-activated protein kinase (MAPK), Janus kinase-signal transducer and activator of transcription (JAK-STAT), and NF-_KB (Hu et al. 2021).

Owing to its action as an inverse agonist of the CB2 receptor (Thomas et al. 2007), CBD can help minimize inflammation caused by cytokine release through the following mechanisms:

• Reduction of oxidative stress
• Regulation of the cerebral adenosine
• Downregulation of tumour necrosis factor (TNF-α) receptor
• Restoration of brain-derived neurotrophic factor (BDNF)
• Restoration of 5-hydroxytryptamine (5-HT) levels in the brain.

These five mechanisms are discussed below; Fig. 4 summarises CBD’s remedial activity in brain-related disorders in relation to these mechanisms.

Reduction of oxidative stress and inflammation

In order to mitigate the effect of pathogens and start tissue repair, excessive production of ROS by the immune system may occur, thus leading to oxidative stress (Juan et al. 2021). In brain-related disorders, the cell and tissue damage, inflammation, and decreased performance in cognitive function which results from increased ROS production and oxidative stress, leads to brain impairment over time, by initiating cell death and disrupting the blood–brain barrier (Salimi and Klein 2019).

However, CBD can activate the adenosine A_2A receptors (A_2A), which are distributed in the brain-striatum, nucleus accumbens, and olfactory tubercule, that could lead to anti-inflammatory activity and reduce oxidative stress (Hao et al. 2015; Magen et al. 2009; Vallée et al. 2017). A_2A takes part in several pathological reactions, exhibits anti-inflammatory characteristics, and modulates inflammatory processes, thus the activation of the adenosine receptor is a major mechanism of immunosuppression in inflammation.

In the in vivo studies of Hao et al. (2015) in which the effect of CBD was examined in a mouse model of Doxorubicin-induced cardiomyopathy and that of Vallee et al. (Vallée et al. 2017) who examined the interactions of CBD and peroxisome proliferator activated receptor γ (PPARℽ) on oxidative stress and neuroinflammation, it was found that CBD is capable of reducing oxidative stress by decreasing mitochondrial dysregulation and reducing the expression of ROS-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoforms. This indicates that the reduction of mitochondrial dysfunction (which causes detrimental effects on the cells and plays a major role in the severity of several pathological conditions such as neurogenerative diseases) and the decrease in the expression of NADPH results in modulation of ROS production thereby regulating and reducing inflammation.

Vallée et al. (2017) also emphasized the suppression of pro-inflammatory cytokines by the activation of peroxisome proliferator-activated receptors which regulates inflammation. In the in vivo study of Pan et al. 2009, that was targeted at investigating the effects of CBD in a mouse model of Cisplatin-induced neuropathy (in which Cisplatin caused an increase in the generation of ROS, expression of NOX4 and NOX1, apoptosis, formation of nitrotyrosine, tumour necrosis factor α and interleukin-1 β in the kidneys of mice and impaired renal function), it was observed that CBD caused a decrease in oxidative stress and inflammation, thus resulting in the attenuation of Cisplatin-induced nephrotoxicity and improved renal function.

Regulation of the cerebral adenosine system

Adenosine is found in the extracellular fluid of most bodily tissues, including the brain, and reacts to pathogen invasion, stress, and damage. It occurs in normal cells in concentrations ranging from 1 to 10 mmol/L (Zimmerman et al. 2011); however, these concentrations rise quickly in response to cellular damage, and an excessive/chronic overproduction of adenosine disrupts the adenosine system, resulting in immune imbalances and immunosuppression. At high concentrations, adenosine becomes hazardous and toxic to the immune system, resulting in dysfunction and autoimmune disorders which adversely affect the brain (Borea et al. 2017).

Adequate concentrations of adenosine in the brain have significant effects on its health and development, and a person’s mood; hence, an adenosine imbalance may lead to detrimental effects on brain tissues (Figler et al. 2011; Zhang et al. 2011; Zhang and Xia 2012). According to Borea et al. (2017), as well as Feoktistov and Biaggioni (2011), excess production of adenosine has been associated with certain neurodegenerative disorders such as Parkinson’s disease. This is because excessive adenosine generation causes overexpression of the A2B receptors, thereby increasing inflammation because A2B most often plays an opposite role to that of A2A. In high concentrations, adenosine initiates the production of inflammatory cytokines such as transforming growth factor beta (TGFβ), tumour necrosis factor alpha (TNF-α), and interferon-gamma (IFN-γ) (Sauer et al. 2017).

CBD is able to regulate the cerebral adenosine system by impeding the uptake of adenosine through obstruction of the equilibrative nucleoside transporter ENT1 (Pandolfo et al. 2011). ENT1 is linked with the synaptic uptake of adenosine; thus, inhibition of ENT1 causes an increase in extracellular adenosine, thereby resulting in a decrease in neuronal hyperexcitability and neurotransmission (Pandolfo et al. 2011). The study by Carrier et al. (2006) on the effect of CBD on the ENT1 revealed that CBD reduced the uptake of adenosine in microglial cells and RAW 264.7 macrophages in murine models. Carrier et al. showed that CBD enhances adenosine signalling by inhibiting the uptake of adenosine and providing a non-cannabinoid receptor mechanism through which it can reduce inflammation.

However, Carrier et al. (2006) reported that while binding to the ENT transporter, CBD can also activate the A_2A receptor. Moreover, blocking the uptake of adenosine by the microglial cells may impact the neurons which are neighbouring cells with the microglial cells in the brain parenchymal, thus causing a disruption in the activities and functions (such as cerebral blood circulation, learning) of these.

Downregulation of TNF-α receptor

Tumour necrosis factor alpha (TNF-α) is a member of the 19 TNF superfamily that is secreted in the brain in response to pathogen invasions, such as bacterial and viral infections, as well as brain injuries. TNF-α is a cytokine used by the immune system for cell signalling, as it alerts other immune cells in the brain as part of an inflammatory response to infections or foreign bodies. TNF-α is also a major cytokine in neuroinflammation, which activates NF-KB, thereby causing glial activation and production of proinflammatory cytokines (Jung et al. 2019). Various studies report that CBD plays a role in downregulating TNF production.

In the study conducted by Mammana et al. (2019) on the efficacy of CBD and cannabigerol (CBG) in negating neuroinflammation using motoneuron-like cell line, it was observed that when used on its own, CBD reduced the concentration of TNF-α levels. Likewise, when used in combination with CBG, they both exerted anti-inflammatory effects on TNF-α. Aswad et al. (2022) investigated the effects of high concentrations of THC and CBD on cytokine production in immune cells both in vivo and in vitro; it was found that CBD caused significant reductions in pro-inflammatory cytokines in human T cells and neutrophils in vitro.

Also, the in vivo studies carried out by Aswad et al. (2022) using an inflamed mouse model revealed decrease in TNF-α and interleukin-1β (IL-1β) by a high concentration of CBD even though an increase in anti-inflammatory cytokine interleukin 10 (IL-10) was observed. According to Peyravian et al. (2020), CBD impedes important activators of the Janus kinase/signal transducer, transcription signalling pathway, and the nucleotide-binding oligomerization domain-like receptor signalling pathway which consequently reduces pro-inflammatory cytokine production. The downregulation of TNF-α indicates a reduction of brain damage. However, the downregulation of TNF-α by CBD does not guarantee the efficacy of CBD’s therapeutic ability as well as its safety and toxicity in chronic immune conditions. It is important to note that varying dosages of CBD influences its immunomodulatory properties, hence the need to understand the pharmacokinetics of CBD and the doses needed for modulation of the immune system.

Restoration of BDNF expression

The brain-derived neurotrophic factor (BDNF) is one of the most active proteins, called neurotrophins, which help to stimulate and control the growth of new neurons from neural stem cells (neurogenesis) (Autry and Monteggia 2012). BDNF sustains nerve cells by aiding their growth, differentiation and maintenance (Soloey-Nilsen et al. 2022). BDNF also activates the tyrosine kinase receptors which recruit substrates such as phosphoinositide 3-kinases (PI3K) and the phospholipase c gamma (PLC-γ) in promoting neuron survival and neuroplasticity (Lin and Huang 2020). Being a crucial molecule in the development of neurons, BDNF performs vital roles in memory formation (spatial, long-term and emotional, particularly fear), which are linked to learning abilities; hence, BDNF is much implicated in psychiatric disorders (Autry and Monteggia 2012).

Decreased levels of BDNF are detrimental towards normal brain functioning as it plays a part in reducing the expression of synaptic proteins (which aids early neuronal development and regulation of neurotransmitter release), thereby leading to loss of synaptic connections and consequently the loss of neuronal ability to survive and adapt to environmental changes, and hence degeneration (Mariga et al. 2017). Reduction of BDNF also alters the ability of the nervous system to reorganize its structure and functions in response to intrinsic/extrinsic stimuli (Soloey-Nilsen et al. 2022). Apart from neuronal loss, reduced levels of BDNF have been linked with certain neurodegenerative and neuropsychiatric disorders such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and mood disorders (Bathina and Das 2015). According to Lima Giacobbo et al. (2019), reduction in BDNF levels usually occurs as a result of long-term exposure to inflammation/neuroinflammation due to the negative effect of cytokines on BDNF-related signalling pathways.

CBD has been identified to be effective in the restoration of BDNF. From their studies, Mariga et al. (2017) and Sales et al. (2019) described the ability of CBD to stimulate and promote neurogenesis, cause drastic and lasting antidepressant-like effects through increased BDNF signalling, and formation of synapses in the prefrontal cortex, which is vital for the overall architecture of brain connections. These two studies also confirm that administration of CBD can increase the expression of the synaptic protein in the prefrontal cortex.

Winstone et al. (2022 doi.org/10.1089/can.2021.0025) administered 3 mg/kg of CBD to adolescent mice to evaluate the effect on BDNF, tropomyosin receptor kinase B (TrkB) and other synaptic markers. They observed that CBD significantly increased the expression of BDNF II, VI and IX, thereby causing growth stimulation as well as differentiation of synapses and neurons (neurogenesis). However, Winstone et al. 2022., reported a significant reduction in CB1 receptor protein in the ventral dentate gyrus (which regulates hormones and emotion), thus, the reduction in CB1 receptor may result in endocannabinoid dysregulation (Matias et al. 2006).

Moreover, differences were observed in the response of male and female mouse to CBD administration with the restoration BDNFII, VI and IX in females while CBD caused the restoration of only BDNF VI in males. Also, according to the report of Sales et al. (Sales et al. 2019), maintenance of a sustained elevated level of BDNF needs to be investigated.

Restoration of brain 5-hydroxytryptamine levels

5-Hydroxytryptamine (5-HT), commonly referred to as serotonin, plays a significant role in modulating the release of several neurotransmitters such as epinephrine/norepinephrine, dopamine, and glutamate (Vaseghi et al. 2022). Prolonged periods of stress, faulty metabolism, and others factors that deplete the level of serotonin, have been linked with neurological disorders such as depression and anxiety (Kanova and Kohout 2021). In addition, production of proinflammatory cytokines such as IFN-ℽ and TNF-α results into tryptophan depletion by activating the quinolinic and kynurenine acid pathways, which makes tryptophan less available for the synthesis of serotonin (Richard 2020). In response to inflammation, following platelet activation, 5-HT is released for the regulation of all immune cells, mostly in their defence against infections, thus preventing excessive cytokine (chemokine) production and consequently cell damage and necrosis (Kanova and Kohout 2021). Serotonin does not only help in the defence of the body against infection/inflammation, but also hinders oxidative damage (Muñoz-Castañeda et al. 2006).

Linge et al. (2016) confirmed the efficacy of CBD in enhancing serotonin and glutamate levels in the ventromedial prefrontal cortex of mice in vivo, depending on the treatment duration (longer – two weeks – treatment with lower dose (10 mg/kg) yielded better results vs high dose (50 mg/kg) over one week). Following administration of CBD (100 mg/kg), Abame et al. (2021) observed a significant increase in 5-HT and noradrenaline levels in the hippocampus of C57BL 6 J mice. According to Jenny et al. 2010, CBD inhibits cytokine-induced tryptophan degeneration, and because tryptophan is a major compound in the synthesis of serotonin, increase in the bioavailability of tryptophan increases the levels of serotonin. However, chronic administration of CBD has been associated with other unwanted consequences such as anxiogenic effects as shown in the study of ElBatsh et al. (2012).

The authors acknowledge the North-West University for the enabled environment provided for the research.