A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids.

Various countries and US States have legalized cannabis, and the use of the psychoactive1 and non-psychoactive cannabinoids is steadily increasing. In this review, we have collated evidence from published non-clinical and clinical sources to evaluate the abuse, dependence and associated safety risks of the individual cannabinoids present in cannabis. As context, we also evaluated various synthetic cannabinoids. The evidence shows that delta-9 tetrahydrocannabinol (Δ9-THC) and other psychoactive cannabinoids in cannabis have moderate reinforcing effects. Although they rapidly induce pharmacological tolerance, the withdrawal syndrome produced by the psychoactive cannabinoids in cannabis is of moderate severity and lasts from 2 to 6 days. The evidence overwhelmingly shows that non-psychoactive cannabinoids do not produce intoxicating, cognitive or rewarding properties in humans. There has been much speculation whether cannabidiol (CBD) influences the psychoactive and potentially harmful effects of Δ9-THC. Although most non-clinical and clinical investigations have shown that CBD does not attenuate the CNS effects of Δ9-THC or synthetic psychoactive cannabinoids, there is sufficient uncertainty to warrant further research. Based on the analysis, our assessment is cannabis has moderate levels of abuse and dependence risk. While the risks and harms are substantially lower than those posed by many illegal and legal substances of abuse, including tobacco and alcohol, they are far from negligible. In contrast, potent synthetic cannabinoid (CB1/CB2) receptor agonists are more reinforcing and highly intoxicating and pose a substantial risk for abuse and harm. 1 "Psychoactive" is defined as a substance that when taken or administered affects mental processes, e.g., perception, consciousness, cognition or mood and emotions.

Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.

Psychedelic drug abuse potential assessment for new drug applications and controlled substance scheduling: A United States perspective.

BACKGROUND: Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. FINDINGS: Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokinetic/pharmacodynamic safety studies and Phases 2/3 efficacy/safety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. RECOMMENDATIONS: Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.

Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans.

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e., no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e., schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e., drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates (CDER/FDA, 2017). We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

The National Trauma Institute: Lessons learned in the funding and conduct of 16 trauma research studies.

BACKGROUND: To increase trauma-related research and elevate trauma on the national research agenda, the National Trauma Institute (NTI) issued calls for proposals, selected funding recipients, and coordinated 16 federally funded (Department of Defense) trauma research awards over a 4-year period. We sought to collect and describe the lessons learned from this activity to inform future researchers of barriers and facilitators. METHODS: Fifteen principal investigators participated in semistructured interviews focused on study management issues such as securing institutional approvals, screening and enrollment, multisite trials management, project funding, staffing, and institutional support. NTI Science Committee meeting minutes and study management data were included in the analysis. Simple descriptive statistics were generated and textual data were analyzed for common themes. RESULTS: Principal investigators reported challenges in obtaining institutional approvals, delays in study initiation, screening and enrollment, multisite management, and study funding. Most were able to successfully resolve challenges and have been productive in terms of scholarly publications, securing additional research funding, and training future trauma investigators. CONCLUSION: Lessons learned in the conduct of the first two funding rounds managed by NTI are instructive in four key areas: regulatory processes, multisite coordination, adequate funding, and the importance of an established research infrastructure to ensure study success. Recommendations for addressing institution-related and investigator-related challenges are discussed along with ongoing advocacy efforts to secure sustained federal funding of a national trauma research program commensurate with the burden of injury.

Implications of climate change for economic development in northern Canada: energy, resource, and transportation sectors.

Northern Canada is projected to experience major changes to its climate, which will have major implications for northern economic development. Some of these, such as mining and oil and gas development, have experienced rapid expansion in recent years and are likely to expand further, partly as the result of indirect effects of changing climate. This article reviews how a changing climate will affect several economic sectors including the hydroelectric, oil and gas, and mining industries as well as infrastructure and transportation, both marine and freshwater. Of particular importance to all sectors are projected changes in the cryosphere, which will create both problems and opportunities. Potential adaptation strategies that could be used to minimize the negative impacts created by a climate change are also reviewed.