Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ9-THC in humans discriminating Δ9-THC

Lile, Joshua A.; Kelly, Thomas C.; Hays, Lon R.

doi:10.1016/j.drugalcdep.2014.07.016

Cited by 18 publications

(20 citation statements)

References 33 publications

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“…These results are concordant with the ability of CB agonists to impact VDCC function via CB 1 receptor mediated G-protein activation as well as CB-receptor-independent mechanisms (Howlett et al, 2010; Lozovaya et al, 2009). In previous studies, drug discrimination procedures like those used here revealed that the cannabinoid agonist nabilone substituted for Δ 9 -THC, but the dopamine/norepinephrine reuptake inhibitor methylphenidate, the opioid agonist hydromorphone and the GABA A positive allosteric modulators triazolam and diazepam did not, demonstrating the pharmacological selectivity of the Δ 9 -THC discrimination (Lile et al, 2009, 2010, 2014). The present results support this selectivity by demonstrating Δ 9 -THC stimulus generalization to a compound having a common neurobiological target.…”

Section: Discussionsupporting

confidence: 51%

“…To further investigate potential similarities, particularly as they relate to the abuse-related interoceptive effects of cannabis, the present study determined the separate and combined effects of gabapentin and Δ 9 -tetrahydrocananbinol (i.e., Δ 9 -THC, the primary active constituent of cannabis) using pharmacologically selective drug-discrimination procedures (Lile et al, 2009, 2010, 2012, 2014). Gabapentin was hypothesized to occasion Δ 9 -THC-like discriminative-stimulus alone and shift the discriminative-stimulus effects of Δ 9 -THC leftward/upward when administered concurrently.…”

Section: Introductionmentioning

confidence: 99%

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Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol

Lile

Wesley

Kelly

et al. 2016

Behavioural Pharmacology

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The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating Δ9-THC using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received gabapentin (600 and 1200 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ9-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate and impaired psychomotor performance. Both doses of gabapentin substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of Δ9-THC leftward/upward, and combinations of Δ9-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to Δ9-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol

Lile

Wesley

Kelly

et al. 2016

Behavioural Pharmacology

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“…In heavy users, high-dose smoked cannabis resulted in more collisions in a virtual maze task (106) but did not affect critical tracking (89,90). Oral administration of THC [or IV (37)], nabilone, or dronabinol impaired psychomotor function in seven of eight studies (37,43,68,74,76,77,107), with only one study finding no significant impairment (73). Findings regarding the chronic effects of cannabis on psychomotor function are mixed, being reported as impaired (51,54,80,108), improved (48), and unaffected (46,78).…”

Section: Psychomotor Functionmentioning

confidence: 99%

“…Whether working memory is impaired by cannabis is less clear, possibly because of the wide range of different working memory tasks employed. Acute administration of THC, dronabinol, or nabilone affected working memory inconsistently across Sternberg, delayed matching to sample, spatial or numeric working memory, n-back, digit recall, and digit span tasks (36)(37)(38)(39)(40)42,43,(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Similarly, chronic cannabis use was shown to impair working memory in young adults on immediate recall (79), verbal reasoning (80), and verbal n-back (81) working memory tasks, but not on spatial working memory (48,82) or digit span (52,53), whereas spatial working memory was impaired in adolescent users (46), suggestive of differential effects in the developing brain.…”

Section: Acute and Chronic Effects Of Cannabinoids On Cognitionmentioning

confidence: 99%

Acute and Chronic Effects of Cannabinoids on Human Cognition—A Systematic Review

Broyd

Hell

Beale

et al. 2016

Biological Psychiatry

539

395

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Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains underresearched. Associations between poorer performance and a range of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm. Review Acute and Chronic Effects of Cannabinoids on Human Cognition-A Systematic ReviewSamantha J. Broyd, Hendrika H. van Hell, Camilla Beale, Murat Yücel, and Nadia Solowij ABSTRACT Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistenc...

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“…Similarly, diazepam partially substitutes for THC in rats (Wiley, 1999) and for SA-57 in mice (Owens et al, 2016). Likewise, diazepam showed some evidence of partial substitution in a human THC discrimination study, though the magnitude of this effect was only 25% (Lile et al, 2014). Diaz-epam may partially substitute for cannabimimetic discriminative stimuli through a common mechanism, such as a GABA component, which is under CB 1 receptor modulation (Selley et al, 2004).…”

Section: 1 Discussionismentioning

confidence: 99%

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

et al. 2017

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Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arach-idonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1–2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.

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Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ9-THC in humans discriminating Δ9-THC

Cited by 18 publications

References 33 publications

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol

Acute and Chronic Effects of Cannabinoids on Human Cognition—A Systematic Review

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

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