Human Abuse Potential and Cognitive Effects of Taranabant, a Cannabinoid 1 Receptor Inverse Agonist

Schoedel, Kerri A.; Addy, Carol; Chakraborty, Bijan; Rosko, Kim; Dunbar, Stephanie; Maes, Andrea; Chen, Nancy; Stoch, S. Aubrey; Wagner, John A.; Chodakewitz, Jeff; Sellers, Edward M.

doi:10.1097/jcp.0b013e31825d380d

Cited by 13 publications

(5 citation statements)

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“…The Strength of Drug Effect of solriamfetol appeared to last longer than one would predict from the half-life ( t 1/2 , 5–6 h) (Zomorodi et al, 2017), and the phentermine time course of Strength of Drug Effect was shorter relative to its half-life ( t 1/2 , 20 h) (VIVUS, 2014). However, the 2–3 h time to E max for solriamfetol effects on Drug Liking at the Moment and Strength of Drug Effect correspond with the median time to maximum plasma concentration ( T max , 2-3 h) (Zomorodi et al, 2017), and the magnitude and time course of the effects of phentermine were consistent with what has previously been reported at these doses (Schoedel et al, 2012).…”

Section: Discussionsupporting

confidence: 87%

“…Comparisons of solriamfetol with both placebo and a positive control were performed, consistent with FDA guidance (US Food and Drug Administration and Center for Drug Evaluation and Research, 2017), to enable evaluation of acute effects of single-dose administrations of drugs over a period of time commensurate with the time course of the relevant drug effects. Phentermine was used as the positive control at the studied doses because it is a Schedule IV stimulant drug with previously established measurable abuse potential at these doses (Jasinski et al, 2008; Schoedel et al., 2012). Phentermine is a well-characterized amphetamine-type central nervous system stimulant that releases norepinephrine, and does so at a similar potency as amphetamine and methamphetamine (Rothman et al, 2001).…”

Section: Methodsmentioning

confidence: 99%

“…The study sample size was determined by a power analysis based on the differences observed between placebo and 45 or 90 mg of phentermine on the primary endpoint of Liking at the Moment from a previous study (Schoedel et al, 2012); these findings indicated that a sample size of 30 participants would have >95% power to detect significant differences at the (two-tailed) 5% level. Analyses of primary and secondary endpoints were performed on the per protocol population defined as participants who completed all six Test Phase treatments.…”

Section: Methodsmentioning

confidence: 99%

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A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor

Henningfield²,

et al. 2018

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Background:This study evaluated the human abuse potential of solriamfetol (formerly JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects.Methods:Adults with a recent history of recreational polydrug use, including stimulants, and who met criteria in a Qualification Phase were randomized to one of six sequences in a Test Phase. Each Test Phase sequence included a single administration of placebo, solriamfetol (300, 600, and 1200 mg), and phentermine (45 and 90 mg), with a two-day washout between periods. The primary endpoint was peak rating (Emax) of Liking at the Moment across the first 12 h on a liking/disliking visual analog scale; key secondary endpoints were Next Day Overall Drug Liking, how much the participant would like to Take the Drug Again, and positive and negative subjective effects. Safety was also assessed throughout the study.Results:Of 43 participants (74.4% male; mean age 29.3 years), 37 completed the study. Peak Emax Liking at the Moment for all solriamfetol doses was significantly greater than placebo and significantly less than phentermine 90 mg (p < 0.05). Overall Next Day Drug Liking was greater than placebo for solriamfetol 300 mg and phentermine 45 and 90 mg (p < 0.05). Willingness to Take the Drug Again was significantly greater than placebo and significantly less than both doses of phentermine for all doses of solriamfetol (p < 0.05). Ratings of negative subjective effects (bad effects, disliking, anxiety, agitation) were higher with solriamfetol 600 and 1200 mg relative to phentermine. The most common treatment-emergent adverse events with solriamfetol were hypervigilance, elevated mood, dry mouth, hyperhidrosis, and insomnia.Conclusion:Solriamfetol appears to have abuse potential similar to or lower than phentermine.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor

Henningfield²,

et al. 2018

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“…Here, individuals with depression show impairment relative to matched healthy controls across multiple cognitive domains, including memory, processing speed, and cognitive flexibility [11–16]. Additional studies point towards alterations in performance on executive functioning tasks involving the selection, timing, monitoring and interpretation of behavior, and on measures of working memory and selective attention [11, 17, 18]. …”

Section: Introductionmentioning

confidence: 99%

The impact of obesity on neuropsychological functioning in adults with and without major depressive disorder

et al. 2017

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BackgroundEvidence suggests obesity exerts a negative impact on cognition. Major Depressive Disorder (MDD) is also linked to problems in cognitive functioning. Obesity is highly prevalent in individuals with MDD and is linked to a failure to return to a full level of functioning. The study’s objective was to investigate the effect of obesity on cognitive impairment in participants with MDD.MethodsThis study compared cognitive performance in obese individuals with MDD and two control populations (obese individuals without a psychiatric illness and non-obese controls). A standardized battery of neuropsychological tests specifically designed to assess performance in declarative memory, executive functioning, processing speed and attention was administered. Mood ratings, physical measurements, nutritional and health questionnaires were also completed.ResultsWe observed a consistent pattern across measures of memory, executive functioning, attention and processing speed. Whereas healthy controls performed better than both bariatric groups across the majority of measures administered, bariatric controls tended to outperform bariatric MDD patients.LimitationsThe overall sample size of our study was small and thus largely explorative in nature. However, it provides compelling results (while controlling for extraneous variables such as medication load, nutritional status and common metabolic comordidities) that strongly urges for further investigation and study replication with larger sample sizes.ConclusionsWe found obesity has a subtle impact on cognition in obese individuals, and when obesity is present in individuals with MDD, this impact may be significant. It is important to minimize all modifiable variables that can add to cognitive burden in this population.

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“…Phentermine has been used in studies as an example of a liked drug 36. However, patients taking phentermine often “like” the drug for a variety of valid reasons but do not have other signs or symptoms of addiction or physical dependence.…”

Section: Introduction To Epidemiology Of Obesity and Developments In mentioning

confidence: 99%

Off-label drugs for weight management

Hendricks

2017

DMSO

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The global pandemic of obesity and overweight now affects between 2.8 and 3.5 billion of the world population and shows no signs of abatement. Treatment for what is now recognized as a chronic disease includes pharmacotherapy, considered an essential component of comprehensive therapy. New drug discovery is robust, but the pace of the US Food and Drug Administration approval for obesity drugs has been glacial, and only a handful of approved drugs are available for treating obesity. In the last 20 years, the US Food and Drug Administration has approved 208 drugs for cancer, 118 for cardiovascular diseases, 168 for neurological diseases, and 223 endocrinologic drugs, but only 6 for obesity, 2 of which have been taken off market. Currently, there are only 9 drugs approved by the FDA for obesity treatment. US physicians have turned to off-label drug use in their effort to care for increasing numbers of patients with excess adiposity. Phentermine is the most commonly used drug for treating obesity. Although approved only for short-term use, US physicians have used it successfully for long-term since its initial approval in 1959. This drug, used off-label for long-term, has proven to be safe and effective, far safer than the disease it is used to treat. Phentermine and diethylpropion, an equally safe but somewhat less effective drug, are both generic and therefore inexpensive. These drugs have been maligned inappropriately because their two-dimensional structure diagrams resemble amphetamine and also because of unproven presumptions about their potential adverse effects. In the face of an increasing epidemic, worldwide obese and overweight patients deserve effective treatment that prescribing these drugs could provide, if rehabilitated and used more frequently. US physicians will likely continue to use any drug proven useful off-label for this illness until such time as more effective drugs are approved.

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Human Abuse Potential and Cognitive Effects of Taranabant, a Cannabinoid 1 Receptor Inverse Agonist

Cited by 13 publications

References 43 publications

A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor

A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor

The impact of obesity on neuropsychological functioning in adults with and without major depressive disorder

Off-label drugs for weight management

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