Pain lasting longer than 3 months can be classified as chronic pain, and involves neuropathic, nociceptive, musculoskeletal, inflammatory, psychogenic, and mechanical pain (Cohen et al., 2021).

Preclinical studies show great potential for CBD as an analgesic agent (Costa et al., 2007; Belardo et al., 2019; De Gregorio et al., 2019; Jesus et al., 2019; Malvestio et al., 2021). The analgesic properties of CBD are suggested to be induced by the agonistic actions of CBD at TRPV1, a mediator in pain signaling (Henson et al., 2022). Once TRPV1 channels are activated, they desensitize and enter a refractory period during which sensory neurons are not responsive to further stimulation. Via this mechanism, symptoms of nociceptive behaviour are relieved. Indeed, rodent models of neuropathic and inflammatory pain showed that the antihyperalgesic actions of CBD were reversed by TRPV1 antagonists (Costa et al., 2004; Costa et al., 2007; De Gregorio et al., 2019). Additionally, CBD’s analgesic actions may be mediated via the activation of the serotonergic system through 5-HT1A receptors. In male diabetic rats, mechanical allodynia was attenuated by treatment with CBD (0.3 or 3 mg/kg). This effect was completely prevented by the pre-treatment with the 5-HT1A antagonist WAY 100135 (Jesus et al., 2019). Furthermore, in rats subjected to a nerve injury model that induces neuropathic pain, 5-HT firing activity decreased, resulting in mechanical allodynia. Treatment with CBD (5 mg/kg/d) normalized 5-HT activity and reduced mechanical allodynia. However, after antagonism of 5-HT1A with WAY 100635 (2 mg/kg/d for 7 days) this effect was partially prevented (De Gregorio et al., 2019). These findings are in accordance with a similar study in rats subjected to a nerve injury model, which also showed that treatment with CBD (30 nmol microinjected into the prelimbic division of the medial prefrontal cortex) attenuated mechanical allodynia in a 5-HT1A-dependent manner (Malvestio et al., 2021). Interestingly, it was found that the analgesic effect of CBD was also blocked by the CB1 receptor antagonist, providing an alternative mechanism of action (Malvestio et al., 2021).

Although these preclinical studies repeatedly show the analgesic properties of CBD, evidence in human clinical trials remains scarce. A survey investigating patients’ perspectives and attitudes about CBD for the treatment of pain symptoms showed that 62% of the participants used a CBD product. Furthermore, the majority of patients (59%) who ever used CBD products perceived reductions in pain and in 67.6% of these patients, the use of CBD allowed them to reduce their pain medications (Schilling et al., 2021). Another explorative study evaluated the effect of CBD treatment on self-reported quality of life and showed that patients with (non-)cancer chronic pain symptoms reported reductions in pain scores upon CBD treatment, while patients with neurological symptoms did not perceive any improvements (Gulbransen et al., 2020). The lack of a control group in this study makes it difficult to identify any causal relationship for CBD treatment and reduced pain scores. Additionally, there was a large loss of participants (36.3%) during the study. Furthermore, the applied doses ranged from 40 to 300 mg/d and were reported inconsistently and incompletely by patients, which further added complexity to the interpretation of these results.

In a study involving seven kidney transplant patients with chronic pain, CBD treatment (100–300 mg/d for 3 weeks) resulted in total pain reduction in two patients and a partial reduction in four patients, while one patient did not perceive any change in symptoms at all (Cuñetti et al., 2018). Again, the lack of a control group and the low sample size make it impossible to draw any conclusions from this study, as acknowledged by the authors. On the other hand, a placebo-controlled randomized trial involving 29 patients with symptomatic peripheral neuropathy provided evidence that transdermal application of CBD oil (250 mg/3 fL. Oz for 4 weeks) can yield a significant reduction in intense pain, sharp pain, cold and itchy sensations compared to placebo (Xu et al., 2020).

To date, clinical studies on the effect of CBD in patients with chronic pain remain inconclusive. The majority of clinical studies for the treatment of chronic pain typically utilized a mixture of THC and CBD [reviewed in (Henson et al., 2022; Argueta et al., 2020)] and studies evaluating the isolated effect of CBD are rather scarce and unconvincing. As such, there is a high need for placebo-controlled clinical studies evaluating the effect of isolated CBD supplements to clarify the role and the underlying mechanisms of CBD in chronic pain management.

Epilepsy is a neurological disease characterized by cerebral hyperactivity or synchronous neuronal activity (Fisher et al., 2005). A large proportion of epileptic patients suffer from drug-resistant seizures that further increase the rate of cognitive impairment as well as psychiatric and physical disability.

CBD has been shown to exert anti-convulsant effects in various animal models of epileptic seizures (Jones et al., 2012; Klein et al., 2017; Costa et al., 2022). It is hypothesized that CBD may act preferentially to reduce seizure spread (Jones et al., 2012), but the exact mechanism underlying the anti-convulsant effects of CBD has not yet been elucidated. Given its low affinity for CB1 and CB2, CBD most likely modulates neuronal hyperexcitability via cannabinoid receptor-independent pathways. Proposed mechanisms include: 1) regulation of Ca²⁺ homeostasis in neurons under a normal or a highly excitable state (Ryan et al., 2009); 2) agonistic properties at 5-HT1A receptors eliciting membrane hyperpolarising responses (Theodore, 2003; Merlet et al., 2004); 3) enhancing endogenous adenosine levels in the CNS thereby increasing inhibitory adenosinergic tone which aids in seizure suppression (Boison, 2006; Carrier et al., 2006); and 4) inducing neuroprotective and anti-inflammatory actions via modulation of PPARγ (Costa et al., 2022). It is critical to understand these mechanisms of action to improve CBD’s efficacy and implementation as a therapeutic agent in epilepsy.

Also in human clinical trials, the potential of CBD as a therapeutic agent for drug-resistant seizures has recently been investigated. Its effectiveness in childhood epilepsy including, Lennox–Gastaut syndrome and Dravet syndrome has been studied extensively and summarized in recent systematic reviews (da Silva Rodrigues et al., 2023; Silvinato et al., 2022). It was concluded that treatment with CBD successfully reduced the frequency of seizures by 33%, supporting the use of CBD in these patient populations. These positive results have led to the approval of Epidiolex as a prescription medicine for seizures associated with Lennox–Gastaut syndrome and Dravet syndrome.

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by parenchymal deposition of amyloid-β in plaques and intraneuronal accumulation of hyperphosphorylated tau protein, inducing chronic inflammation and oxidative damage (DeTure and Dickson, 2019). Several studies showed a potential role for CBD in the inhibition of AD progression [reviewed in (Xiong and Lim, 2021)].

Treatment with CBD was reported to reduce amyloid-β production, tau phosphorylation, and neuroinflammation in vitro (Scuderi et al., 2014; Libro et al., 2016). These effects were also observed in in vivo studies where CBD treatment suppressed the neuroinflammatory response induced by amyloid-β deposition in mice (Esposito et al., 2007) and rats (Esposito et al., 2011), and stimulated hippocampal neurogenesis (Esposito et al., 2011) thereby delaying disease progression. CBD also improved cognitive performance, which is typically affected in AD. More specifically, long-term treatment with CBD (20 mg/kg/d for 8 months) prevented the development of social recognition deficit in a transgenic mouse model of AD (Cheng et al., 2014a). Additionally, sub-chronic treatment with CBD (20 mg/kg daily for 1 week, 3x/week for the following 2 weeks) prevented the cognitive impairment in mice injected with amyloid-β as shown by their performance in the Morris water maze test (Martín-Moreno et al., 2011). These positive effects on cognitive functioning were associated with a reduction in neuroinflammation (Martín-Moreno et al., 2011; Cheng et al., 2014a).

The mechanisms underlying the neuroprotective effect of CBD against AD progression have not yet been fully elucidated. There is emerging evidence that the effect is mediated via PPARγ activation and subsequent inhibition of Nuclear Factor-Kappa B (Esposito et al., 2011; Scuderi et al., 2014). Nevertheless, mediation via alternative receptors has also been proposed, including the activation of TRPV1 and PI3K/Akt pathway (Libro et al., 2016). Future studies that determine the underlying mechanisms are warranted.

Huntington’s disease (HD) is an inherited disorder characterized by neuronal lesions in brain areas that help to control voluntary (intentional) movement, such as the cerebral cortex and the striatum (Rikani et al., 2014). As a result, HD patients develop uncontrollable movements (chorea) and abnormal body postures.

The neuroprotective properties of CBD make it a potential candidate in the treatment of HD. Indeed, in rats where striatal lesions were induced by 3-nitropropionic acid (3NP, an inhibitor of mitochondrial complex II), CBD reversed 3NP-induced reductions in GABA contents and reduced 3NP-induced striatal atrophy. The neuroprotective effects of CBD acted preferentially on striatal neurons that project to the substantia nigra and resulted from antioxidant and cannabinoid receptor-independent mechanisms (Sagredo et al., 2007).

To the best of our knowledge, there is only one clinical trial available that investigated the effects of CBD administration in patients suffering from HD. In this study, treatment with CBD (10 mg/kg/d for 6 weeks) in neuroleptic-free patients with HD did not show any effects on chorea severity or other therapeutic outcomes (Consroe et al., 1991). Other clinical trials investigating the effects of CBD on HD symptoms included THC-containing medicines, such as nabilone or Sativex (Curtis et al., 2009; López-Sendón Moreno et al., 2016). Besides the fact that these studies showed contradicting results, they did not allow us to determine the role of isolated CBD supplements in the treatment of HD.

Overall, evidence for the potential of CBD as a therapeutic agent to treat HD is lacking and future studies should aim to elucidate the isolated effects of CBD on HD symptoms.

Parkinson’s disease (PD) is another neurodegenerative disease that is characterized by reduced dopamine levels as a result of dopaminergic neuron degeneration. Although the pathophysiology of PD is complicated, evidence suggests that α-synuclein (α-syn) aggregates play a significant role in the dopaminergic neurodegenerative process, leading to impairments of cellular function and oxidative stress (Pupyshev et al., 2018). The symptoms of PD include motor as well as non-motor signs such as depression, anxiety, apathy, sleep disorders, and psychosis (Poewe, 2008; Sveinbjornsdottir, 2016).

Currently, the dopamine replacement agent, I-DOPA, is often prescribed to treat PD. However, chronic use of I-DOPA is associated with (non-)motor complications including tardive dyskinesia (TD), a hyperkinetic movement disorder that is described by involuntary and repetitive movements (Hauser et al., 2022). Interestingly, CBD was able to reduce symptoms of orofacial dyskinesia induced by anti-dopaminergic drugs in mice (Sonego et al., 2018; Sonego et al., 2021) showing its potential as an add-on therapy in PD.

Furthermore, studies show that CBD ameliorates motor and cognitive impairments in animal models of PD and TD (da Cruz Guedes et al., 2023; Peres et al., 2016). More specifically, pretreatment with CBD (0.5 mg/kg) attenuated the increase in cataleptic behavior, oral movements and memory deficits, but not locomotor activity induced by reserpine administration in rats (Peres et al., 2016). In another study where C. Elegans were exposed to reserpine, CBD exposure recovered reserpine-induced alterations in locomotion rate/food-sensing behavior, attenuated morphologic alterations and dopaminergic neuron degeneration, and reduced human α-syn protein accumulation (da Cruz Guedes et al., 2023). These studies highlight the potential of CBD as a neuroprotector against PD.

However, clinical trials on the effects of CBD on PD symptoms show inconsistent results. Treatment with CBD for 10–15 days (titrated from 5 to 20–25 mg/kg/d) improved total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale (UPDRS) scores in 10 PD patients (Leehey et al., 2020). These results were confirmed in an open-label pilot study where six patients received a flexible dose of CBD for 4 weeks (starting at 150 mg/d with weekly increases of ∼150 mg/d, depending on the clinical response). When CBD was added to their treatments, patients showed improvements in total UPDRS score (Zuardi et al., 2009). In contrast, a placebo-controlled double-blind RCT showed no changes in UPDRS score in participants who were treated with CBD (75 or 300 mg/d), although the scores on overall wellbeing and quality of life significantly improved (Chagas et al., 2014a).

As mentioned above, symptoms of PD also include non-motor signs such as anxiety, sleep disorders, and psychosis. Acute CBD supplementation (300 mg) was shown to reduce perceived feelings of anxiety and tremor amplitude in PD patients who underwent the simulated public speaking test (de Faria et al., 2020). Furthermore, psychotic symptoms were reduced in PD patients receiving a flexible dose of CBD (starting at 150 mg/d) for 4 weeks (Zuardi et al., 2009). Since the increased psychotic symptoms in PD patients are associated with the use of dopaminergic drugs, the authors hypothesized that the reduction in psychotic symptoms upon CBD treatment resulted from attenuated dopaminergic activity in brain areas related to psychotic symptoms. Regarding the effect of CBD on sleep disorders in PD, some discrepancies are present in the existing results. A case study of 4 PD patients suffering from rapid eye movement (REM) sleep behavior disorder (RBD) showed a reduction in the frequency of RBD events, including nightmares and active behavior during dreaming in all 4 patients after treatment with CBD (75 or 300 mg/d for 6 weeks) (Chagas et al., 2014b). However, these results were not confirmed in a placebo-controlled randomized trial in PD patients with Restless Legs Syndrome and RBD. In this study, treatment with CBD (doses gradually increasing from 75 to 300 mg for 12 weeks) did not result in improvements in subjective, nor in objective sleep quality measured by polysomnography, as compared to placebo (de Almeida et al., 2023).

Because of the different nature of these study designs (i.e., case studies and randomized controlled trials), the small sample sizes, and the different dosing schedules, it is difficult to draw solid conclusions on the effect of CBD on motor and non-motor symptoms in PD. Additional placebo-controlled trials are required to properly understand the role of CBD in this neurodegenerative disease.

Conventional treatment of psychosis is through drugs that are highly selective dopamine D2 receptor antagonists, such as haloperidol and amisulpride. Although effective, these treatments are often accompanied by severe side effects including deficits in motor control (Strange, 2001). Interestingly, animal models used for screening antipsychotic drugs, show that CBD treatment inhibited catalepsy or hyperlocomotion induced by apomorphine or ketamine (Zuardi et al., 1991; Moreira and Guimarães, 2005). These preclinical data indicate that CBD acts via different mechanisms, exhibiting a profile of atypical antipsychotic drugs. Therefore, CBD may be proposed as an alternative to classical drugs. The antipsychotic potential of CBD was demonstrated in schizophrenia (Zuardi et al., 1995; Leweke et al., 2012; McGuire et al., 2018) and PD (Zuardi et al., 2009).

While still speculative, current literature suggests that CBD may reduce psychotic symptoms via the inhibition of FAAH and subsequent increases in AEA levels. Indeed, in non-medicated acute schizophrenic patients, AEA cerebrospinal fluid concentrations showed a negative correlation with psychotic symptoms (Giuffrida et al., 2004). Interestingly, CBD (800 mg/d) treatment in acute schizophrenic patients increased AEA levels which was associated with reductions in psychotic symptoms (Leweke et al., 2012). Whereas these data present a convincing mechanism, alternative mechanisms of action such as the attenuation of increased glial reactivity (Gomes et al., 2015) or via parvalbumin-positive GABA neurons (Campos et al., 2017) cannot be excluded and further research is warranted.

A first individual case report of a female schizophrenia patient in which haloperidol treatment was terminated because of severe side effects, showed that treatment with CBD (1500 mg/d for 26 days) resulted in similar improvements in psychiatric symptoms without any side effects (Zuardi et al., 1995). Additionally, a clinical trial comparing amisulpride and CBD (800 mg/d for 4 weeks) treatment in acute schizophrenic patients showed that CBD was equally effective in treating clinical effects with fewer side effects compared to amisulpride (Leweke et al., 2012). Further evidence for the antipsychotic effects of CBD were provided in a trial where schizophrenia patients added CBD (1000 mg/d for 6 weeks) to their usual medication and perceived improvements in psychotic symptoms, as was supported by the treating clinicians’ impressions of improvement and illness severity (McGuire et al., 2018).

While these results are promising, it seems that higher doses up to 800 or 1000 mg/d are required to effectively treat psychotic symptoms, since chronic (6 weeks) or acute treatment with lower CBD doses (600 mg/d) did not improve symptoms in psychotic patients (Boggs et al., 2018) or cognitive impairments in schizophrenic patients (Hallak et al., 2010), respectively. Though, even these higher doses do not always seem to be effective, as it was shown that treatment with a high CBD dose of 1280 mg/d in three treatment-resistant schizophrenic patients only mildly improved symptoms of psychosis in one of the three patients after 35 days (Zuardi et al., 2006). It should be noted that the lack of effect in this case study may be explained by the severity of the disease state and does not necessarily exclude its effectiveness in non-resistant schizophrenic patients. Nevertheless, the application of CBD in psychotic patients requires further investigation regarding the optimal dosing schedule.

CBD treatment successfully induced anxiolytic-like effects in several animal models, including the elevated plus-maze (Guimarães et al., 1990; Resstel et al., 2009; Gomes et al., 2011; Hsiao et al., 2012), Y-maze (Mori et al., 2021), Vogel conflict test (Moreira et al., 2006; Gomes et al., 2011) and social interaction test (Almeida et al., 2013). Nevertheless, the mechanisms underlying the anxiolytic effects of CBD are not fully elucidated yet.

As previously mentioned, SPECT studies in healthy individuals and social anxiety disorder patients showed that CBD reduced anxiety and fear via its action on limbic and paralimbic brain areas (Crippa et al., 2004; Crippa et al., 2011). Furthermore, several animal models showed that the anxiolytic effects of CBD were blocked when combined with a 5-HT1A antagonist (Resstel et al., 2009; Gomes et al., 2011), suggesting mediation via this receptor. Indeed, 5-HT1A receptors are widely present in brain areas related to stress and anxiety and agonism of this receptor has been associated with anxiolytic responses (Rioja et al., 2004) whereas 5-HT1A-knockout mice showed anxiogenic-like behavior (Tsetsenis et al., 2007). In rats, pretreatment with a CB1 antagonist counteracted the suppressive effect of CBD on panic-like behavior induced by GABA_A receptor blockade (da Silva et al., 2015). Since CBD administration increases AEA levels, indirect agonism of CB1 might be an alternative mediating pathway through which CBD reduces anxiety levels. In addition, the anxiolytic effects of CBD in ischemic mice were prevented by antagonism at CB1 and 5-HT1A, as well as at CB2 and PPARγ (Mori et al., 2021), showing the complex signaling role of CBD.

Also, in human clinical trials, the anxiolytic effects of CBD have been determined. For example, acute administration with 300 mg CBD reduced anxiety induced by the simulated public speaking test (SPST) in healthy individuals (Zuardi et al., 1993; Zuardi et al., 2017; Linares et al., 2019) and PD patients (de Faria et al., 2020). Furthermore, patients suffering from social anxiety disorder showed higher levels of anxiety during the SPST compared to healthy individuals, but the administration of 600 mg CBD completely abolished these differences (Bergamaschi et al., 2011). Contrarily, administration of 600 mg CBD in healthy individuals without experimentally induced anxiety did not show any anxiolytic effect, suggesting that CBD is only able to reduce anxiety levels in case of stress or fearful situations (Martin-Santos et al., 2012). Furthermore, the dose is of relevance as it was shown that CBD presents an inverted U-shape in which intermediate doses seem to be effective, whereas low and high doses are not (Zuardi et al., 2017; Linares et al., 2019). Besides reducing anxiety levels, CBD also affected fear memory expression (Lee et al., 2017) via acute reduction in fear expression (Jurkus et al., 2016), enhancement of memory extinction (Bitencourt et al., 2008; Das et al., 2013) and disruption of memory reconsolidation (Stern et al., 2012; Gazarini et al., 2014; Stern et al., 2015). These effects may be of relevance for the treatment of phobias and post-traumatic stress disorder (PTSD).

The antidepressant-like effects of CBD have been shown in several animal models including tail suspension (Schiavon et al., 2016), forced swimming (El-Alfy et al., 2010; Zanelati et al., 2010; Réus et al., 2011; Sales et al., 2019; Xu et al., 2019), the saccharine preference test (Shoval et al., 2016), and the novel object test (Shoval et al., 2016). It was repeatedly reported that CBD exerts its effect through 5-HT1A activation (Zanelati et al., 2010; Linge et al., 2016; Sartim et al., 2016) and increases in brain-derived neurotrophic factor (BDNF) levels in certain brain areas (Réus et al., 2011; Xu et al., 2019). Moreover, a recent study proposed that 5-HT1A activation by CBD, either directly or indirectly via elevated serotonin levels, may increase BDNF levels, which ultimately leads to mTOR activation and synaptogenesis (Sales et al., 2019). Nevertheless, not all animal studies replicate these findings as unaltered BDNF levels following CBD treatment have also been reported (Zanelati et al., 2010). These contradictory findings may be explained by the use of different animal species, different CBD doses, and different administration routes. In fact, the effectiveness of CBD seems highly dependent on the applied dose and studies suggest a U-shaped dose-response curve (Zanelati et al., 2010; Réus et al., 2011) as mentioned earlier. Additionally, doses that induce behavioral improvements do not always correspond to the doses that induce desired neurological adaptations (Réus et al., 2011; Schiavon et al., 2016). Future studies are warranted to properly understand the underlying mechanisms by which CBD improves symptoms of depression and to determine effective dose regimens.

Compared to the preclinical research, almost no studies investigated the effect of CBD on depression in humans. One case report showed that a patient suffering from neurofibromatosis type 1 perceived improvements in depressive symptoms when she switched from conventional antidepressants to CBD oil (Hegazy and Platnick, 2019). Given this scarcity, more clinical trials in humans are required to translate the preclinical antidepressant-like effects of CBD to therapeutic applications.

An increasing number of studies focusing on the anti-addictive properties of CBD is emerging. Animal studies show promising effects of CBD in the context of alcohol, opioids, and methamphetamine use. Accordingly, a limited number of human studies showed a positive impact of CBD on nicotine, cannabis, and opioid use (Paulus et al., 2022).

There is a wide range of possible mechanisms via which CBD may be involved in the regulation of drug use and addiction (Navarrete et al., 2021). CBD may interact with the dopaminergic system, which plays an important role in addictive disorders. The release of dopamine after drug consumption induces drug-rewarding effects via the activation of dopamine D2 receptors (Trifilieff et al., 2013). CBD potentially inhibits the increased dopaminergic signaling induced by drug intake. Indeed, animal studies report that CBD treatment inhibited the amphetamine (Renard et al., 2016) and cocaine (Galaj et al., 2020) induced increases in neuronal dopamine activity. Additionally, these effects were associated with reductions in self-administration of cocaine (Galaj et al., 2020). Furthermore, reduced intake of ethanol by CBD was associated with lower gene expression of the μ-opioid receptor and tyrosine hydroxylase (Viudez-Martínez et al., 2018a), which is the rate-limiting enzyme in the biosynthesis of dopamine. The μ-opioid receptor is known to modulate dopamine transmission via inhibition of GABAergic interneurons (Spanagel et al., 1992). As such these findings propose an interaction between CBD and the opioid system.

Furthermore, CBD might exert its actions in substance use disorders via the serotonergic system. As previously mentioned, the agonistic actions of CBD at 5-HT1A have been widely acknowledged and seem to be involved in the anxiolytic and anti-depressant effects of CBD. In addition, the activation of 5-HT1A by CBD may also play a role in its mediation of the drug-rewarding process. In fact, mice subjected to oral ethanol self-administration showed lower ethanol intake when treated with a combination of CBD (20 mg/kg/d for 2 weeks) and Naltrexone (0.7 mg/kg/d for 2 weeks) (Viudez-Martínez et al., 2018b). These effects were absent when the treatment was combined with a 5-HT1A antagonist. Accordingly, a study using a self-administering paradigm of low cocaine doses in rats reported that the reductions in cocaine intake induced by CBD (20 or 40 mg/kg) were blocked by pretreatment with the 5-HT1A antagonist (Galaj et al., 2020). Interestingly, CBD was not able to reduce cocaine intake when self-administered cocaine doses were high, suggesting a limited capacity for CBD to counteract the reward process linked to cocaine consumption.

CBD might also be involved in the process of drug memory expression (Ren et al., 2009), consolidation (de Carvalho and Takahashi, 2017), and extinction (Parker et al., 2004), which plays an important role in addiction. Indeed, even though CBD treatment (5 and 20 mg/kg) was unable to reduce self-administrated heroin intake in rats, it did inhibit cue-induced drug-seeking behavior, a measure of cue-heroin memory expression (Ren et al., 2009). Additionally, several animal studies investigated the effect of CBD on drug memory consolidation and extinction using the drug-induced conditioned place preference paradigm, where increased time spent in the drug-paired place is associated with the rewarding properties of the drug. Using this paradigm, treatment with CBD impaired the preference for the place previously associated with amphetamine, morphine, or cocaine (Parker et al., 2004; de Carvalho and Takahashi, 2017). Whether CBD enhances extinction, impairs reconsolidation or influences both processes of drug memories is currently unclear and requires further investigation.

While the mechanisms mentioned above seem promising, most research in the field of the anti-addictive properties of CBD is based on animal models. The available evidence from clinical trials is scarce and human intervention trials are required to translate the preclinical findings towards therapeutic applications of CBD in substance use disorders.

CBD has been suggested as therapeutic strategy to improve sleep. The exact mechanisms via which CBD affects sleep are not yet fully understood, but different hypotheses are based on preclinical and clinical studies. On a biological level, it can be hypothesized that FAAH inhibition via CBD increases AEA levels, which might directly affect CB1-mediated NREM stability (Pava et al., 2016). However, it remains to be confirmed whether this CBD-FAAH-CB1 axis effectively mediates sleep. Alternatively, CBD can also directly act upon GABA_A receptors (Bakas et al., 2017), which play a beneficial role in sleep regulation (Gottesmann, 2002), e.g., reduced sleep latency and improved NREM sleep (Lancel, 1999). However, depending on the context (e.g., CBD levels and exposure time) and on the receptor subtype, CBD can act as a GABA_A receptor agonist or antagonist. Therefore, the CBD-GABA_A receptor axis also requires further investigation.

Despite biological mechanisms that might explain CBD-related improvements in sleep, it appears that CBD has no effect on sleep quality and quantity in subjects with an undisturbed and healthy sleep pattern (Linares et al., 2018). However, the calming effect of CBD on the CNS might reduce anxiety and promote relaxation (Shannon et al., 2019), via which CBD can indirectly improve sleep in people suffering from anxiety. In addition, some patient populations might also benefit from CBD use, since CBD increases sleeping time in insomnia patients (Carlini and Cunha, 1981) and improves REM sleep in Parkinson’s disease patients (Chagas et al., 2014b). It should be noted that some reports showed that CBD increased the wakefulness during sleep in young adults (Nicholson et al., 2004), and even decreased the REM sleep in rats (Murillo-Rodríguez et al., 2006; Murillo-Rodríguez et al., 2008). This alerting effect of CBD requires a well-planned timing and dosing of CBD if being used as a strategy to improve sleep, but this effect also holds promise for the use of CBD as a strategy to improve excessive daytime sleepiness (Nicholson et al., 2004).

Preclinical evidence indicates that acute and prolonged CBD use does not affect motor activity or spatial learning and recognition (Schleicher et al., 2019; Viudez-Martínez et al., 2019). However, in different (preclinical models of) diseases in which motor activity is compromised, CBD might improve some features of motor learning or attention.

Locomotion remained unaffected by CBD treatment in different preclinical models of hyper- and hypolocomotion, including Parkinson’s disease (hypo) (Peres et al., 2016), fragile X syndrome (hyper) (Zieba et al., 2019), and an acute neuroinflammatory model (hypo) (Florensa-Zanuy et al., 2021). Likewise, in a genetically-induced preclinical Alzheimer’s disease model, prolonged CBD treatment did not affect features of motor performance or sensorimotor gating (pole test, accelerod) (Coles et al., 2020). However, in a preclinical model of encephalopathy, CBD improved locomotion and cognition (Magen et al., 2009). An improvement in the memory deficit and object recognition memory was also observed in a Parkinson’s (Peres et al., 2016) and Alzheimer’s (Coles et al., 2020) disease model, respectively.

In schizophrenic patients, long-term but not acute CBD treatment (Hallak et al., 2010) improved the sustained attention assessed via the Continuous Performance Test (Leweke et al., 2021). Accordingly, CBD improved the attention lapse duration during a psychomotor vigilance test in healthy adults (Rudisill et al., 2023), whereas CBD had no effect on measures of attention during a vigilance test, and even exacerbated the impairing effect of THC in healthy rats (Moore et al., 2023). Altogether, CBD seems to have no consistent effect on motor performance in preclinical disease models. Some of the motor effects ascribed to CBD can be explained by its anxiolytic effect. It remains to be determined whether findings in preclinical models, often treated with supra-physiological doses of CBD, can be translated toward clinical populations.

Several preclinical studies show the potential of CBD to restore memory impairments in a large variety of animal models that induce neurological dysfunction (Magen et al., 2009; Cassol et al., 2010; Magen et al., 2010; Avraham et al., 2011; Barichello et al., 2012; Fagherazzi et al., 2012; Pazos et al., 2012; Wright et al., 2013; Cheng et al., 2014a; Cheng et al., 2014b; Schiavon et al., 2014; Campos et al., 2015). A suggested mechanism via which CBD may improve or restore memory impairments involves its antioxidant properties. Research demonstrated that oxidative damage of nuclear as well as mitochondrial DNA in brain cells can have adverse effects on memory processing and retention during ageing (Kandlur et al., 2020). Animal models demonstrated that, by diminishing the risk of oxidative stress, CBD has the potential to safeguard brain cells (da Silva et al., 2018), thereby promoting the preservation of memory function. This notion has been supported in a study where treatment with CBD (2.5, 5, or 10 mg/kg daily for 9 days) in rats submitted to sepsis prevented memory alterations. In this study, the positive effects of CBD on memory were associated with a decrease in oxidative damage in the brain (Cassol et al., 2010).

Alternatively, the anti-inflammatory actions of CBD may play a role in restoring memory deficits. Moreover, in a murine model of cerebral malaria, treatment with CBD (30 mg/kg/d for 3 days, in addition to the traditional anti-malaria drug Artesunate) inhibited the increase in proinflammatory cytokines (TNFα and IL-6) in the hippocampus and prefrontal cortex and subsequently restored malaria-induced memory deficits (Campos et al., 2015). These results were replicated in a model of hepatic encephalopathy induced by bile-duct ligation in mice. Again, treatment with CBD (5 mg/kg/d for 4 weeks) restored impairments in cognition and locomotion and reduced the increase in hippocampal expression of the TNFα receptor 1 (Magen et al., 2009; Magen et al., 2010). These effects were mediated via 5-HT1A (Magen et al., 2010) and A2A adenosine (Magen et al., 2009) receptor activation, since treatment with their respective antagonists blocked the effects of CBD.

Interestingly, besides reducing neuroinflammation in these animal models, CBD treatment also restored hippocampal levels of BDNF (Magen et al., 2009; Magen et al., 2010; Campos et al., 2015). BDNF is a member of the neutrophin family and is highly involved in maintenance, growth, and survival of neurons. Given that previous studies show an association between increased BDNF levels and improved cognitive performance (Dincheva et al., 2012; Carlino et al., 2013), it seems plausible that CBD-induced increases in hippocampal BDNF explain, at least partly, the rescue of memory deficits in above mentioned models.

Lastly, it was hypothesized that CBD alters cerebral blood flow in brain regions that are involved in memory processing thereby influencing memory function. Moreover, in healthy human participants, acute supplementation with 600 mg CBD increased cerebral blood flow in the hippocampus (Bloomfield et al., 2020). Although higher resting hippocampal blood flow is associated with better memory performance (Heo et al., 2010), the current study was not able to show any effect of CBD supplementation on memory performance. The authors suggested that ceiling effects may have accounted for the lack of a relationship between hippocampal cerebral blood flow and memory task performance as the study population included healthy participants.

These results contrast with studies showing that CBD can restore or protect against episodic memory deficits induced by its psychotropic counterpart THC. More specifically, when healthy participants and cannabis users were administered THC (either 1.5 mg intravenously or 8 mg via inhalation) episodic memory and facial recognition performance were reduced. These effects were diminished when THC was combined with CBD (either 600 mg oral or 16 mg via inhalation) (Englund et al., 2013; Hindocha et al., 2015). However, these effects have not been confirmed in all studies and seem highly dependent on the dose, route of administration, and frequency of cannabis use of the study population (Morgan et al., 2018).