Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish

Gaoni, Yehiel; Mechoulam, Raphael

doi:10.1021/ja01062a046

Cited by 2,143 publications

(1,333 citation statements)

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“…In the United States alone, over 94 million individuals have used cannabis at least once in their lifetime (approximately 40% of the population; Substance Abuse Mental Health Services Administration, 2004). The principal psychoactive constituent in cannabis, D-9-tetrahydrocannabinol (THC; Gaoni and Mechoulam, 1964), affects the brain via the action of central cannabinoid receptors (CB1; Devane et al, 1988). The subsequent discovery of several endogenous cannabinoid neuromodulators, namely anandamide and 2-arachidonylglycerol (2-AG) has led to an exponential growth in cannabinoid research (Devane et al, 1992;Stella et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Skosnik

Edwards

O’Donnell

et al. 2007

Neuropsychopharmacol

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While the cerebellum contains the highest density of cannabinoid receptor (CB1) in the brain, no studies have assessed the effect of exogenous cannabinoids on cerebellar-dependent learning in humans. The current study, therefore, examined the effect of chronic cannabis use on classical eyeblink conditioning (EBC), a cerebellar-mediated task which has been shown to be disrupted in CB1 knockout mice. Chronic cannabis users (24 h abstinence before study; positive THC urine drug test) free of DSM-IV Axis-I or -II disorders, were evaluated. A delay EBC task was utilized, in which a conditioned stimulus (CS; 400 ms tone) co-terminated with a corneal air puff unconditioned stimulus (US; 50 ms), thus eliciting a conditioned blink response (CR). The cannabis group exhibited markedly fewer, and more poorly timed CRs as compared to drug-naive controls. There were no differences between the groups in either the unconditioned response (UR) or an EEG measure of selective attention to the CS (N100 auditory ERP), indicating that the disruption observed in the cannabis group was specific to CR acquisition. These results suggest that cannabis use is associated with functional deficits in the cerebellar circuitry underlying EBC, a finding which corroborates the recent work in CB1 knockout mice.

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Section: Introductionmentioning

confidence: 99%

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Skosnik

Edwards

O’Donnell

et al. 2007

Neuropsychopharmacol

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“…71 The dye was reconstituted with assay buffer of composition (mM): NaCl 145, HEPES 22, Na 2 HPO 4 0.338, NaHCO 3 4, osmolarity 315 ± 5). Prior to the assay, cells were loaded with 90 μL/well of the dye solution without removal of the L-15, giving an initial assay volume of 180 μL/well.…”

Section: ■ Methodsmentioning

confidence: 99%

The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse

Banister

Wilkinson

Longworth

et al. 2013

ACS Chem. Neurosci.

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Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure−activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB 1 (EC 50 = 16−43 nM) and CB 2 (EC 50 = 29−216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB 2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ 9 -tetrahydrocannabinol (Δ 9 -THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ 9 -THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ 9 -THC, JWH-018, and SDB-001.

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“…This was of considerable importance, since the elucidation of the structure of cannabidiol (Mechoulam and Shvo, 1963) was a basis for the later elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC), which is now recognized as the principal psychoactive component of marijuana. THC was first isolated in the laboratory of Raphael Mechoulam (Gaoni and Mechoulam, 1964) and this discovery reactivated cannabinoid research worldwide.…”

Section: Introductionmentioning

confidence: 99%

Self-administration of cannabinoids by experimental animals and human marijuana smokers

Justinová

Goldberg

Heishman

2005

Pharmacology Biochemistry and Behavior

115

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Drug self-administration behavior has been one of the most direct and productive approaches for studying the reinforcing effects of psychoactive drugs, which are critical in determining their abuse potential. Cannabinoids, which are usually abused by humans in the form of marijuana, have become the most frequently abused illicit class of drugs in the United States. The early elucidation of the structure and stereochemistry of delta-9-tetrahydrocannabinol (THC) in 1964, which is now recognized as the principal psychoactive ingredient in marijuana, activated cannabinoid research worldwide. This review examines advances in research on cannabinoid self-administration behavior by humans and laboratory animals. There have been numerous laboratory demonstrations of the reinforcing effects of cannabinoids in human subjects, but reliable self-administration of cannabinoids by laboratory animals has only recently been demonstrated. It has now been shown that strong and persistent self-administration behavior can be maintained in experimentally and drugnaïve squirrel monkeys by doses of THC comparable to those in marijuana smoke inhaled by humans. Furthermore, reinforcing effects of some synthetic CB 1 cannabinoid agonists have been recently reported using intravenous and intracerebroventricular self-administration procedures in rats and mice. These findings support previous conclusions that THC has a pronounced abuse liability comparable to other drugs of abuse under certain experimental conditions. Self-administration of THC by squirrel monkeys provides the most reliable animal model for human marijuana abuse available to date. This animal model now makes it possible to study the relative abuse liability of other natural and synthetic cannabinoids and to preclinically assess new therapeutic strategies for the treatment or prevention of marijuana abuse in humans.

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Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish

Cited by 2,143 publications

References 0 publications

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse

Self-administration of cannabinoids by experimental animals and human marijuana smokers

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