Synthetic Pot: Not Your Grandfather’s Marijuana

Ford, Benjamin M.; Tai, Sherrica; Fantegrossi, William E.; Prather, Paul L.

doi:10.1016/j.tips.2016.12.003

Cited by 81 publications

(73 citation statements)

References 174 publications

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“…As such, because non-biased, full agonists ( e.g. , JWH-018) at hCB 1 Rs produce tolerance and dependence following chronic administration (70), this study tested if PNR-4-20 would exhibit diminished levels of these adverse effects. In vivo studies revealed that chronic PNR-4-20 treatments result in less persistent tolerance to cannabinoid-induced hypothermia while producing no significant withdrawal behaviors when challenged with a CB 1 R antagonist.…”

Section: 0 Discussionmentioning

confidence: 99%

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Ford

Franks

Tai

et al. 2017

Pharmacological Research

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The human cannabinoid subtype 1 receptor (hCB1R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB1R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB1Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB1Rs might be improved by development of G-protein biased hCB1R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB1 receptors. Our studies found that a novel IQD-derived hCB1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB1R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB1Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ9-THC. Finally, studies of a structurally similar analog PNR-4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.

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Section: 0 Discussionmentioning

confidence: 99%

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Ford

Franks

Tai

et al. 2017

Pharmacological Research

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“…As well as this change in cannabis itself, the preferred routes of administration and development of associated cannabis concentrates have increased the levels of potency that users are exposed to. [10] To further complicate matters, the role that synthetic cannabinoids play is not clear, with a growing body of evidence to suggest that not only is their use becoming more popular but also that there are significant toxic effects on brain and behavior. [11] It also seems that exogenous factors play a role in how effective cannabis might be as an antidepressant with its effects being greatest under aversive conditions.…”

Section: Introductionmentioning

confidence: 99%

Effects of cannabis use and subclinical depression on the P3 event-related potential in an emotion processing task

et al. 2017

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The effects of residual cannabis use on emotional expression recognition and the P3 event-related potential in participants who scored highly for subclinical depression were investigated. Comparisons were made between participants who were classified as depressed or nondepressed cannabis users, depressed non-cannabis users and controls who neither used cannabis nor were characterized as being depressed. In an emotional expression recognition task, participants were asked to respond to faces depicting happy, angry, fearful, and neutral faces either implicitly, explicitly, or empathically. Residual cannabis use and mood was shown to modulate the P3 event related potential during the task. There was a significant reduction in the P3 amplitude between depressed and nondepressed participants. Residual cannabis use further reduced the P3 amplitude with the greatest deficits being associated with cannabis users who scored highly for subclinical depression. These effects were greatest for explicit and empathic processing of faces depicting negative emotions. We conclude from our study that cannabis and mood state interact to reduce the amplitude of the P3 which has been associated with attention to emotion.

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“…However, highly variable and serious adverse clinical effects including altered mental status, cardiotoxicity, seizures, acute kidney injury, hyperthermia, and death have been reported [2]. While these effects have been well documented, the degree to which users are impaired in the context of motor vehicle operation has not been thoroughly addressed in literature.…”

Section: Discussionmentioning

confidence: 99%

“…Synthetic cannabinoids are the most common NPS and are a structurally diverse class with over 250 specific cannabinoids reported to be available [1]. Illegal laboratories make simple modifications to one or more structural components to mimic the effects of Δ9-tetrahydrocannabinol (Δ-THC), evade laboratory detection, and challenge law enforcement, regulatory frameworks, and medical care providers [2]. These new designer drugs are commonly referred to as either “K2” or “Spice”.…”

Section: Introductionmentioning

confidence: 99%

Impaired Driving Associated with the Synthetic Cannabinoid 5F-ADB

McCain

Jones²,

Chilbert

et al. 2018

Journal of Forensic Science & Criminology

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Synthetic marijuana compounds are more potent than Δ9-tetrahydrocannabinol (Δ9-THC) and are known to produce a wide variety of clinical symptoms including cardiac toxicity, seizures, and death. Erratic driving by a 45 y/o male was witnessed in the fall of 2017 and roadside evaluation of the driver by the responding law enforcement officer concluded that the driver was intoxicated. Comprehensive analysis of the cigarettes by gas chromatography-mass spectrometry detected the synthetic cannabinoid 5-fluoro-ADB (5F-ADB or 5F-MDMB-PINACA). Validated forensic liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to detect the 5-fluoro ADB metabolite 7 (26.37 ng/mL) in the driver’s blood sample. No other drugs were detected. This case report is one of the first to conclusively show that designer synthetic cannabinoids, commonly referred to as “K2” and “Spice”, can significantly impair driving at relatively low concentrations.

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Synthetic Pot: Not Your Grandfather’s Marijuana

Cited by 81 publications

References 174 publications

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Effects of cannabis use and subclinical depression on the P3 event-related potential in an emotion processing task

Impaired Driving Associated with the Synthetic Cannabinoid 5F-ADB

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