The effects of cannabinoid 1 receptor compounds on memory : a meta-analysis and systematic review across species
Faith Borgan, Katherine Beck, Emma Butler, Robert McCutcheon, Mattia Veronese, Anthony Vernon, Oliver D. Howes
Doi : 10.1007/s00213-019-05283-3
Rationale : While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse cognitive effects is poorly understood. The cannabinoid 1 receptor modulates memory performance via intracellular and extracellular mechanisms that alter synaptic transmission and plasticity. While previous literature has consistently shown that chronic cannabis users exhibitmarked cognitive impairments,mixed findings have been reported in the context of placebo-controlled experimental trials. It is therefore unclear whether these compounds inherently alter cognitive processes or whether individuals who are genetically predisposed to use cannabis may have underlying cognitive deficits.
Objective : We conducted a meta-analysis to investigate the effects of full and partial cannabinoid 1 receptor (CB1R) agonists, antagonists, and negative allosteric modulators on non-spatial and spatial memory.
Methods : In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining the effects of CB1R agonists, antagonists, and negative allosteric modulators on memory performance.
Results : We systematically reviewed 195 studies investigating the effects of cannabinoid compounds on memory. In humans (N = 35 studies, comprising N = 782 subjects), delta-9-tetrahydrocannabinol (THC) (1.5–5 mg/kg) relative to placebo impaired performance on non-spatial memory tests, whereas only high THC doses (67 mg/kg) impaired spatial memory. Similarly, THC (0.2–4 mg/kg) significantly impaired visuospatial memory in monkeys and non-human primates (N = 8 studies, comprising N = 71 subjects). However, acute THC (0.002–10 mg/kg) had no effect on non-spatial (N = 6 studies, comprising 117 subjects; g = 1.72, 95% confidence interval (CI) − 0.18 to 3.63, p = 0.08) or spatial memory (9 studies, comprising 206 subjects; g = 0.75, 95% confidence interval (CI) − 1.09 to 2.58, p = 0.43). However, acute, full CB1R agonists significantly impaired non-spatial memory (N = 23 studies, 519 subjects; g = − 1.39, 95% CI − 2.72 to − 0.06, p = 0.03). By contrast, the chronic administration of CB1R agonists had no effect on non-spatial memory (N = 5 studies, comprising 146 subjects; g = − 0.05, 95%confidence interval (CI) − 1.32 to 1.22, p = 0.94). Moreover, the acute administration of CB1R antagonists had no effect on non-spatial memory in rodents (N = 9 studies, N = 149 subjects; g = 0.40, 95% CI − 0.11 to 0.92, p = 0.12).
Conclusions : The acute administration of THC, partial CB1R agonist, significantly impaired non spatial memory in humans, monkeys, and non-human primates but not rodents. However, full CB1R agonists significantly impaired non-spatial memory in a dose-dependent manner but CB1R antagonists had no effect on non-spatial memory in rodents. Moreover, chronic THC administration did not significantly impair spatial or non-spatial memory in rodents, and there is inconclusive evidence on this in humans. Our findings highlight species differences in the effects of cannabinoid compounds on memory.
Keywords : Cannabinoid 1 receptor . CB1R agonists . CB1R antagonists . Cognition . Memory
Recent changes in legislation in many countries around the world, including the UK, Canada, and 30 states across the USA, have led to the widespread availability of cannabisbased medicinal products. Emerging evidence indicates that cannabis-based medicinal products may have analgesic (De Vita et al. 2018; Fitzcharles et al. 2016), antiemetic (Chang et al. 1979; Orr and McKernan 1981), antidyskinetic (Fox et al. 2002), antispasmodic (Zajicek et al. 2003), antiepileptic (Devinsky et al. 2014), and antipsychotic effects (McGuire et al. 2017; Boggs et al. 2018). However, the evidence base regarding the adverse cognitive effects of these cannabinoid compounds is unclear.
While the marijuana plant contains over 546 chemicals including over 104 cannabinoid compounds (ElSohly et al. 2016), the two most widely studied cannabinoids include delta-9-tetrahydrocannabinol (THC), a partial cannabinoid 1 receptor agonist (Huestis et al. 2001), and cannabidiol (CBD), a cannabinoid 1 receptor (CB1R) negative allosteric modulator (Morales et al. 2016). The concentration of THC is higher relative to CBD in street cannabis (THC:CBD ratio, 1:13) (ElSohly et al. 2016) and medical cannabis (THC:CBD ratio, 1:3) (Belendiuk et al. 2015). Since these two compounds have opposite pharmacological effects, the effects of THC are likely to outweigh the effects of CBD in the context of recreational or medicinal cannabis use.
Chronic cannabis users show impairments in memory encoding, storage, and retrieval (Solowij et al. 2011), and these deficits are greater if cannabis use commences prior to the age of 16 (Schuster et al. 2016). While some studies have reported that cannabis-induced memory impairments are no longer shown following abstinence (28 days) (Pope et al. 2001), other studies have shown that prior cannabis users continue to show marked memory impairments despite abstinence (28–60 days) (Thames et al. 2014; Schwartz et al. 1989; Schweinsburg et al. 2008). In line with these findings, cannabis use has also been found to impairmemory in first episode psychosis (Núñez et al. 2016) and multiple sclerosis (Patel and Feinstein 2017), whereas cannabidiol has been shown to prevent the adverse effects of THC on memory (Englund et al. 2013a).
However, placebo-controlled experimental trials comparing the effects of THC relative to placebo on memory have reported discrepant findings, reporting no effects on memory (Ganon-Elazar and Akirav 2009; Geresu et al. 2016), memory enhancing (Amal et al. 2010; Bilkei-Gorzo et al. 2017), and memory-impairing effects (Yousefi et al. 2013; Santana et al. 2016; Goodman and Packard 2014). Similarly, while cannabidiol has been postulated to have cognitive enhancing effects (Englund et al. 2013b), the evidence regarding the therapeutic potential of these compounds is largely mixed (McGuire et al. 2017; Boggs et al. 2018; Rosenberg et al. 2017). Moreover, it is unclear if CB1R affinity, dose, treatment duration or treatment paradigms used may influence the effects of these compounds on memory.
Since THC is a partial CB1R agonist (Huestis et al. 2001) that has dose-dependent effects on memory (D’Souza et al. 2005), we aimed to investigate the effects of THC as well as compounds acting as agonists, antagonists, and negative allosteric modulators. We conducted a systematic review and meta-analysis of the acute and chronic effects of all full and partial CB1R agonists, CB1R antagonists, and CB1R negative allosteric modulators on spatial and non-spatial memory in humans, monkeys, non-human primates, rats, and mice. We predicted that the acute and chronic administration of full and partial CB1R agonists would induce spatial and non-spatial memory impairments, whereas CB1R antagonists and negative allosteric modulators would improve spatial and nonspatial memory performance.