Rationale: Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. Methods: This was a single-dose, randomized, double-blind, double-dummy, placebo-and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (E max ) on Drug-Liking visual analog scale (VAS). Other measurements included E max on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test-Revised, and the Digit-Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. Principal results: Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking E max (P b 0.0001) compared with those receiving placebo, confirming study validity. Compared with placebo, Drug-Liking was not significantly different for subjects taking 750-mg CBD (P = 0.51). Drug-Liking E max values for 1500-mg and 4500-mg CBD were significantly different from placebo (P = 0.04 and 0.002, respectively); however, the mean differences were b10 points on VAS compared with N 18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS E max values compared with all doses of CBD (P ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. Conclusion: Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were sign...

Purpose/Background N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonists are potential agents for the treatment of several central nervous system disorders including major depressive disorder. Racemic methadone, l-methadone, and d-methadone all bind the NMDAR with an affinity similar to that of established NMDAR antagonists, whereas only l-methadone and racemic methadone bind to opioid receptors with high affinity. Therefore, d-methadone is expected to have no clinically significant opioid effects at therapeutic doses mediated by its NMDAR antagonism. Methods We conducted 2 phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose studies to investigate the safety and tolerability of oral d-methadone and to characterize its pharmacokinetic profile in healthy opioid-naive volunteers. Results d-Methadone exhibits linear pharmacokinetics with dose proportionality for most single-dose and multiple-dose parameters. Single doses up to 150 mg and daily doses up to 75 mg for 10 days were well tolerated with mostly mild treatment-emergent adverse events and no severe or serious adverse events. Dose-related somnolence and nausea occurred and were mostly present at the higher dose level. There was no evidence of respiratory depression, dissociative and psychotomimetic effects, or withdrawal signs and symptoms upon abrupt discontinuation. An overall dose-response effect was observed, with higher doses resulting in larger QTcF (QT interval corrected using Fridericia formula) changes from baseline, but none of the changes were considered clinically significant by the investigators. Mild, dose-dependent pupillary constriction of brief duration occurred particularly at the 60-mg dose or above in the single-ascending-dose study and at the dose of 75 mg in the multiple-ascending-dose study. No detectable conversion of d-methadone to l-methadone occurred in vivo. Conclusions These results support the safety and continued clinical development of d-methadone as an NMDAR antagonist for the treatment of depression and other central nervous system disorders.

Increasingly, governmental responses to incalculable, but high-consequence, threats to life and security are framed by what has been described as the `precautionary principle' (Ewald), `preparedness' (Collier, Lakoff & Rabinow) or `pre-emption' (Derrida). This article redescribes features common to these characterizations as the paradigm of prudence and examines how this approach to risk management is playing out in the context of fears that feature within the Australian political imaginary. We explore how the approach to the future entailed in the paradigm enframes `life' and stifles democratic participation and innovation in ways of living. Three case studies (in biosecurity, bioecology and biomedicine) demonstrate not only how the paradigm pervades the government of everyday life, but also how it is challenged by human `agents', material `life' and the dynamic relations between these two. By formulating what this involves, we point to a concept of the political more conducive to democratic pluralism, diversity of life and innovative culture.

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