Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem.

STUDY OBJECTIVES: Abuse potential properties have been reported for the dual orexin receptor antagonists (DORAs) suvorexant and lemborexant. Daridorexant is a new DORA currently in late-stage clinical development. This randomized, double-blind, double-dummy, placebo- and active-controlled six-period crossover study assessed its abuse potential in healthy recreational sedative drug users (n = 63). METHODS: In each study period, a single, oral, morning dose of either daridorexant (50, 100, and 150 mg), placebo, or active control, i.e. suvorexant (150 mg) or zolpidem (30 mg), was administered. Primary pharmacodynamic (PD) endpoint was the Emax of the drug-liking visual analog scale (VAS) assessed over 24 h. Several secondary subjective and objective PD endpoints were also assessed. RESULTS: Study validity was confirmed based on drug-liking of suvorexant and zolpidem greater than placebo applying a predefined 15-point validity margin (p < 0.0001). Drug-liking VAS Emax (mean; 95% confidence interval) of daridorexant at 50 mg (73.2; 69.0-77.5) was significantly lower compared to suvorexant (80.7; 77.0-84.5) and zolpidem (79.9; 76.2-83.5) (p < 0.001), but similar at 100 mg (79.1; 75.0-83.3) and 150 mg (81.3; 77.7, 84.8). Such dose-related patterns were also observed for most secondary endpoints. At each daridorexant dose, Drug-liking VAS scores were greater than placebo. Both control drugs and daridorexant were safe and the pharmacokinetics of daridorexant was consistent with earlier trials indicating quick absorption and elimination. CONCLUSIONS: In this large, valid human abuse potential study, daridorexant showed dose-related drug-liking among recreational sedative drug users with lower effects at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of suvorexant and zolpidem. CLINICAL TRIAL REGISTRATION: Study to Evaluate the Abuse Potential of ACT-541468 in Healthy Recreational Drug Users, https://www.clinicaltrials.gov/ct2/show/NCT03657355?term=ACT-541468&draw=3&rank=18, NCT03657355.

Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data.

Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

Identification of Optimal Measures of Human Abuse Potential: A Post Hoc Assessment of 19 Studies.

BACKGROUND: Human abuse potential studies include multiple measures to assess the subjective effects of central nervous system-active drugs. In this retrospective analysis, measurement properties of commonly used measures were assessed, and factor analysis was conducted to identify a core battery of measures. METHODS: Measures of positive, negative and other effects, for example, bipolar "at-the-moment" Drug Liking visual analog scale (VAS), were derived for active controls and placebo from 19 studies in recreational drug users (N = 570). Distribution, placebo response, variability, convergent/discriminant validity, parameter effect sizes (eg, maximum effect [Emax], time-averaged area under the effect curve), and predictive validity were evaluated. A factor analysis was conducted with 9 studies. RESULTS: Most parameters were not normally distributed. Bipolar VAS exhibited the lowest variability. Drug Liking VAS Emax was very sensitive, showed large effect sizes (>1.0), and was moderately to strongly correlated with Emax of other positive effects measures (r > 0.5), but weaker with less specific scales (eg, high, Any Effects VAS); time-averaged area under the effect curve showed higher variability and lower effect sizes. Maximum effect at any dose (EmaxD) was significantly correlated with Emax across all selected measures and showed higher effect sizes. In the overall factor analysis, factors could be categorized into positive effects/euphoria (77% of variance), negative effects (17.9%), and pharmacologic effects (5%). For predictive validity, effect sizes for Drug Liking VAS Emax/EmaxD were moderately correlated with postmarket adverse events related to abuse (R = 0.52). CONCLUSIONS: A core battery of 7 subjective measures was proposed, with additional measures added based on pharmacologic effects.

Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2  = 0.4446], PK AQ [ρ2  = 0.5179], Tmax [ρ2  = 0.5093], and early systemic exposure [ρ2  = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study.

BACKGROUND: Cebranopadol is a nociceptin/orphanin FQ peptide/opioid receptor agonist with central antinociceptive activity. We hypothesize that this novel mechanism of action may lead to a lower risk of abuse compared with pure µ-opioid peptide receptor agonists. METHODS: We conducted a single-dose, nested-randomized, double-blind crossover study in nondependent recreational opioid users to evaluate the abuse potential of single doses of cebranopadol relative to hydromorphone immediate release and placebo. The study consisted of a qualification phase and a 7-period treatment phase (cebranopadol 200, 400, and 800 µg; hydromorphone 8 and 16 mg; and 2 placebos). The primary end point was the peak effect of drug liking at this moment, measured by visual analog scale (VAS). Various secondary end points (eg, VAS rating for good drug effects, high, bad drug effects, take drug again, drug similarity, and pupillometry) were also investigated. RESULTS: Forty-two subjects completed the study. Cebranopadol 200 and 400 µg did not differentiate from placebo on the abuse potential assessments and generated smaller responses than hydromorphone. Responses observed with cebranopadol 800 µg were similar to hydromorphone 8 mg and smaller than hydromorphone 16 mg. The maximum effect for VAS drug liking at this moment was delayed compared with hydromorphone (3 and 1.5 hours, respectively). Cebranopadol administration was safe; no serious adverse events or study discontinuation due to treatment-emergent adverse events occurred. CONCLUSIONS: These results confirm our hypothesis that cebranopadol, a nociceptin/orphanin FQ peptide/opioid receptor agonist, has lower abuse potential than hydromorphone immediate release, a pure µ-opioid peptide agonist.

Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial.

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 (Emax) on Drug-Liking visual analog scale (VAS). Other measurements included Emax 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 Emax (P < 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 Emax 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 <10 points on VAS compared with >18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS Emax 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 significantly lower than those observed with alprazolam and dronabinol.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design: Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting: One US site. Subjects: Healthy, adult, nondependent, recreational opioid users. Methods: Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on "at the moment" Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results: Mean maximum effect for "at the moment" Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled "at the moment" Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions: The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Human abuse potential of brivaracetam in healthy recreational central nervous system depressant users.

BACKGROUND: Brivaracetam is a new antiepileptic drug indicated for adjunctive treatment of focal seizures in adults at a dose of 50-200mg/day taken in two equal doses. The objective of this study was to evaluate the abuse potential of brivaracetam compared with alprazolam (positive control), placebo, and levetiracetam. METHODS: This was a randomized, double-blind, triple-dummy, crossover study in healthy male and female recreational central nervous system (CNS) depressant users aged 18-55years, who could distinguish between the subjective effects of alprazolam 2mg and placebo. All participants received single doses of brivaracetam (50 [therapeutic dose], 200, 1000mg [supratherapeutic doses]), alprazolam (1.5, 3mg), placebo, and levetiracetam (4000mg) in random order each separated by 7-10days. Subjective Visual Analogue Scales (VAS) and Addiction Research Center Inventory (ARCI) scales were completed at intervals up to 24h postdose. Primary endpoints were Drug Liking (at this moment) VAS, Overall Drug Liking VAS, Feeling High VAS, and ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG, sedation) maximum effect (Emax). Maximum effect values on each scale were analyzed using a mixed-effect model (per protocol population, N=44). RESULTS: The maximum effect for both alprazolam doses was significantly greater versus placebo for six designated endpoints, confirming study validity. Drug Liking (at this moment) VAS Emax was significantly lower for brivaracetam 50mg than alprazolam (both doses); there were no significant differences between brivaracetam 200mg and alprazolam (both doses), and brivaracetam 1000mg and alprazolam 1.5mg. Brivaracetam 1000mg (supratherapeutic single dose) had significantly higher Drug Liking (at this moment) VAS Emax than alprazolam 3mg. Overall, Drug Liking VAS Emax for brivaracetam 50 and 200mg was not significantly different from alprazolam (both doses). Brivaracetam 1000mg had significantly higher Overall Drug Liking VAS Emax than alprazolam 1.5mg, but was not significantly different from alprazolam 3mg. Feeling High VAS Emax was lower versus alprazolam with brivaracetam 50 and 200mg, while brivaracetam 1000mg was comparable with alprazolam (both doses). Addiction Research Center Inventory PCAG Emax for brivaracetam (all doses) was significantly lower than alprazolam (both doses). On the secondary/supportive endpoints, compared with alprazolam, brivaracetam had fewer positive effects (ARCI Morphine Benzedrine Group [euphoria]; Good Drug Effects VAS [50mg]) and fewer negative effects (Bad Drug Effects VAS; ARCI Lysergic Acid Diethylamide [dysphoria]). Brivaracetam was not significantly different from alprazolam for Take Drug Again VAS (50, 200mg). For most endpoints, brivaracetam (50-200mg) was not significantly different from levetiracetam (4000mg). CONCLUSION: This study in healthy recreational CNS depressant users showed that single doses of brivaracetam 50mg (therapeutic single dose) had lower sedative, positive, and negative drug effects than alprazolam, while brivaracetam 200 and 1000mg (supratherapeutic single doses) were more similar to alprazolam. The subjective profile of brivaracetam appeared to be similar to that of levetiracetam, but further evaluation using a range of levetiracetam doses would be needed to confirm similar abuse potential.

Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Crossover Study Evaluating the Abuse Potential of the Antiepileptic Drug Lacosamide in Healthy Recreational Drug Users.

PURPOSE: This phase 1, randomized, double-blind, placebo- and active comparator-controlled crossover study assessed the abuse potential of the antiepileptic drug, lacosamide. METHODS: After a qualification phase, 38 healthy, recreational central nervous system-depressant users were randomized to treatment sequences comprising single oral therapeutic (200 mg) and supratherapeutic (800 mg) doses of lacosamide, alprazolam (1.5 and 3 mg), and placebo. Subjective effects were assessed for 24 hours following each dose using a range of scales, with a 5- to 9-day washout between treatments. FINDINGS: Mean subjective effects for 200 mg lacosamide were statistically similar to placebo and significantly lower than with alprazolam for most end points. Lacosamide 800 mg elicited transient, statistically significant positive effects compared with placebo, but also persistent Bad Drug Effects including statistically greater maximum effect (Emax) scores for Nausea and Dysphoria compared with other treatments (P < 0.0002). Consistent with this, the 800 mg lacosamide dose showed a significantly lower "at this moment" Drug Liking visual analog scale (VAS) Emax compared with 3 mg alprazolam, but was not different from 1.5 mg alprazolam (73.1/100, 85.4/100, and 78.9/100, respectively, where 50 is neutral). Overall Drug Liking VAS and Take Drug Again VAS Emax for 800 mg lacosamide were not significantly different from placebo and were lower than those for both alprazolam doses (P < 0.0001). IMPLICATIONS: These results suggest that in recreational central nervous system-depressant users, lacosamide has detectable abuse-related subjective effects, but a relatively low potential for abuse compared with alprazolam. These findings contributed toward placement of lacosamide into Schedule V of the US Controlled Substances Act.

Evaluating the abuse potential of opioids and abuse-deterrent -opioid formulations: A review of clinical study methodology.

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current "best practices" and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of "opioid," "opiate," "abuse potential," "abuse liability," "liking," AND "pharmacodynamic," and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a "nondependent recreational user"), as applicable, and offer key principles and "best practices" when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.

Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.

OBJECTIVE: To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users. DESIGN: Randomized, blinded, dose ratio escalation study. SETTING: Single center. PARTICIPANTS: Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3). INTERVENTIONS: Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios. MAIN OUTCOME MEASURES: Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS). RESULTS: Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios. CONCLUSIONS: This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

Abuse liability assessment of eslicarbazepine acetate in healthy male and female recreational sedative users: A Phase I randomized controlled trial.

RATIONALE: Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug for the treatment of partial-onset seizures. Adverse events such as dizziness and somnolence reported in clinical studies suggest that ESL has detectable central nervous system (CNS) effects in addition to its antiepileptic effects. This Phase I study evaluated the abuse liability of ESL compared with that of alprazolam (ALP) and placebo (PBO) in recreational CNS depressant users. METHODS: In this single-dose, randomized, double-blind, PBO- and active-controlled crossover study, healthy recreational CNS depressant users who could discern between ALP 2mg and PBO received single oral doses of each of the following treatments with a washout interval of ≥7days between each treatment: ESL (800mg, 1600mg, 2000mg, and 2400mg); ALP (1.5mg and 3.0mg); and PBO. Subjective measures, including visual analog scales (VASs) e.g., Drug-Liking (primary endpoint), and Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Group (MBG), Pentobarbital Chlorpromazine Alcohol Group (PCAG), and Lysergic Acid Diethylamide Group scales were evaluated at multiple time points up to 24h postdose. Cognitive effects were evaluated using the Choice Reaction Time (CRT), Divided Attention (DAT) and Hopkins Verbal Learning Task-Revised tests. PRINCIPAL RESULTS: Peak scores for Drug-Liking VAS (maximum effect [Emax]) were significantly higher for both ALP doses than for PBO (p<0.0001), thereby confirming study validity. Drug-Liking VAS Emax was significantly lower for all ESL doses than both ALP doses (p<0.0001). Drug-Liking VAS Emax for ESL 800mg was similar to that for PBO (least squares [LS] mean difference: 3.6; p=0.19). At the three higher ESL doses (1600mg and the supratherapeutic doses of 2000mg and 2400mg), Drug-Liking VAS Emax was significantly higher than for PBO, although the differences were minimal (LS mean difference: 9.3-13.3 out of 100). For most secondary subjective endpoints (i.e., Good Effects VAS and High VAS, ARCI-MBG, Take Drug Again VAS, Overall Drug-Liking VAS, and ARCI-PCAG; p<0.05), the effect of ESL (all doses) was significantly less than that of ALP (both doses). On most secondary measures, the dose-response relationship was relatively flat or showed saturation at higher ESL doses. Although significant differences were observed for ESL compared with those for PBO for some specific CRT and DAT endpoints (i.e., reaction time, manual tracking, hit latency), ALP demonstrated significant and dose-dependent impairment on the majority of cognitive endpoints when compared with PBO and ESL. Mean plasma concentrations of the active metabolite of ESL, eslicarbazepine, increased with increasing ESL dose. Pharmacokinetic parameters estimated for eslicarbazepine were generally comparable with results from previous studies in healthy volunteers. CONCLUSION: This study demonstrated that single doses of ESL may have less abuse liability than ALP in recreational sedative users. Although ESL had detectable subjective effects and showed some drug-'liking' at higher doses, the magnitude of these effects was small.

Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.

Assessment of Pharmacokinetic and Pharmacodynamic Interactions Between Albumin-Fused Mutated Butyrylcholinesterase and Intravenously Administered Cocaine in Recreational Cocaine Users.

UNLABELLED: Cocaine dependence presents a major public health issue, and to date, no pharmacotherapies are approved for its treatment. TV-1380 is a novel recombinant albumin-fused mutated butyrylcholinesterase (Albu-BChE) that has increased catalytic efficiency for cocaine compared with wild-type BChE and therefore has the potential to facilitate abstinence in cocaine-dependent subjects by decreasing exposure to cocaine and its reinforcing effects. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study in nondependent cocaine users was conducted to evaluate the effect of a single intramuscular dose of Albu-BChE (50, 100, and 300 mg) on the pharmacokinetic and metabolic profile of intravenous cocaine infusions (40 mg) administered at baseline and at 24, 96, and 168 hours after Albu-BChE dosing, to assess safety of coadministering Albu-BChE and cocaine, and to explore the subjective responses to cocaine infusions after Albu-BChE dosing. RESULTS: Administration of Albu-BChE resulted in significant dose-dependent reductions in cocaine exposure (maximum concentration, area under the curve) and half-life. Effects were greatest at 24 hours after Albu-BChE dose, but were sustained up to 168 hours. Spearman correlations indicated a significant negative relationship between Albu-BChE concentration and cocaine clearance and exposure. Consistent with its mechanism of action, Albu-BChE also shifted cocaine metabolism toward preferential formation of ecgonine methyl ester. Administration of Albu-BChE was associated with modest decreases in subjective reports of feeling high and willingness to take cocaine again after cocaine infusion. Coadministration of Albu-BChE and cocaine was safe and well tolerated. CONCLUSIONS: Administration of Albu-BChE at single doses of 50, 100, and 300 mg safely resulted in long-lasting decreases in cocaine exposure in recreational cocaine users.

Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect.

Pseudobulbar affect (PBA) is a common manifestation of brain pathology associated with many neurological diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease, and traumatic brain injury. PBA is defined by involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Dextromethorphan/quinidine (DM/Q) is a combination product indicated for the treatment of PBA. The quinidine component of DM/Q inhibits the cytochrome P450 2D6-mediated metabolic conversion of dextromethorphan to its active metabolite dextrorphan, thereby increasing dextromethorphan systemic bioavailability and driving the pharmacology toward that of the parent drug and away from adverse effects of the dextrorphan metabolite. Three published efficacy and safety studies support the use of DM/Q in the treatment of PBA; significant effects were seen on the primary end point, the Center for Neurologic Study-Lability Scale, as well as secondary efficacy end points and quality of life. While concentration-effect relationships appear relatively weak for efficacy parameters, concentrations of DM/Q may have an impact on safety. Some special safety concerns exist with DM/Q, primarily because of the drug interaction and QT prolongation potential of the quinidine component. However, because concentrations of dextrorphan (which is responsible for many of the parent drug's side effects) and quinidine are lower than those observed in clinical practice with these drugs administered alone, some of the perceived safety issues may not be as relevant with this low dose combination product. However, since patients with PBA have a variety of other medical problems and are on numerous other medications, they may not tolerate DM/Q adverse effects, or may be at risk for drug interactions. Some caution is warranted when initiating DM/Q treatment, particularly in patients with underlying risk factors for torsade de pointes and in those receiving medications that may interact with DM/Q.

Human abuse liability evaluation of CNS stimulant drugs.

Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'.

Assessing subjective and physiologic effects following intranasal administration of a new formulation of immediate release oxycodone HCl (Oxecta™) tablets in nondependent recreational opioid users.

OBJECTIVE: To evaluate the pharmacodynamic effects (subjective and physiologic) of a new formulation of immediate release oxycodone HCl (IRO-A; Oxecta™) tablets compared with immediate release oxycodone HCl (IRO; Roxicodone®) tablets when crushed and administered intranasally to nondependent recreational opioid users. DESIGN: Single-center, single-dose, randomized, double-blind, active-controlled two-way crossover study. SETTING: Inpatient Clinical Pharmacology Unit, Toronto, Canada. PARTICIPANTS: Nondependent, recreational opioid users aged 18-55 years. INTERVENTIONS: Subjects able to discriminate intranasally administered crushed IRO from placebo were randomized to receive 15 mg crushed IRO-A and crushed IRO in crossover fashion in treatment phase. MAIN OUTCOME MEASURES: Primary subjective endpoints were maximum effect (E(max)) for Drug Liking and effect at 8 hours (E(8h)) postdose for Take Drug Again and Overall Drug Liking. All were assessed using bipolar 0-100 visual analog scale (VAS; 50 points = neutral). Secondary pharmacodynamic endpoints included other VAS endpoints, pupillometry, and subject-rated scales for nasal effects. RESULTS: Forty subjects were randomized to treatment; 39 were evaluable, one subject was excluded for postdose vomiting. Subjects were mostly male (80 percent) and White (75 percent). Least squares mean Drug Liking VAS E(max) (70.8 vs 93.5), Overall Drug Liking E(8h) (47.8 vs 87.4), and Take Drug Again E(8h) (45.9 vs 91.3) were significantly lower for crushed IRO-A vs IRO (all p < 0.0001). A significant sequence effect was found, but lower liking of IRO-A was observed for both treatment sequence groups. Pupillary responses between treatments were similar overall, but differences were noted for some endpoints/time points. Adverse events common to opioids were observed with both treatments. Subjects experienced more nasal-related symptoms with IRO-A. CONCLUSIONS: Crushed IRO-A tablets demonstrated lower scores on "drug liking," "overall drug liking," and "take drug again" than crushed IRO when administered intranasally to nondependent recreational opioid users.

A study of potential pharmacokinetic and pharmacodynamic interactions between dextromethorphan/quinidine and memantine in healthy volunteers.

BACKGROUND AND OBJECTIVE: Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist. METHODS: This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30 mg (dextromethorphan 30 mg/quinidine 30 mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan - the dextromethorphan metabolite - and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed. RESULTS: A total of 52 subjects were randomized. In both group 1 (n = 23) and group 2 (n = 29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8-1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic variables were either similar or slightly improved with DMQ added to memantine and memantine added to DMQ, compared to monotherapy with either agent. CONCLUSION: Minimal pharmacokinetic and pharmacodynamic interactions were observed between memantine and DMQ, suggesting they can be coadministered without dose adjustment.

Subjective and physiological effects of oromucosal sprays containing cannabinoids (nabiximols): potentials and limitations for psychosis research.

Cannabis use is associated with a spectrum of effects including euphoria, relaxation, anxiety, perceptual alterations, paranoia, and impairments in attention and memory. Cannabis is made up of approximately 80 different cannabinoid compounds, which have synergistic or antagonistic effects on the principle active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC). The net overall effect of cannabis is thought to be related to the ratio of its composite constituents; in particular, the ratio of THC to cannabidiol (CBD). Since cannabinoids induce subjective and cognitive changes that share qualitative similarities with schizophrenia, cannabinoids have been used to model psychosis. Some limitations of cannabinoid models of psychosis include the relatively high variability in experiences between different individuals, the potential for inducing unwanted effects, such as toxic psychosis in study subjects, and the lack of data showing that effective anti-psychotic treatments can reverse the behavioural and cognitive/motor effects of cannabinoids. Nabiximols (Sativex®) is an oromucosal spray containing THC and CBD in an approximate 1:1 ratio. While not extensively studied, most studies confirm that nabiximols, despite the different route of administration and presence of CBD, have similar or slightly reduced subjective/cognitive effects compared to similar doses of oral THC. While the presence of CBD may have utility in some models, it is likely that the concentrations are not high enough to meaningfully affect those aspects important for psychosis research. This review suggests that while it may present an alternative to the use of oral THC, oromucosal nabiximols may not present substantial advantages for use in psychosis research.

Human abuse potential and cognitive effects of taranabant, a cannabinoid 1 receptor inverse agonist: a randomized, double-blind, placebo- and active-controlled, crossover study in recreational polydrug users.

INTRODUCTION: Taranabant is a cannabinoid 1 receptor inverse agonist that was in development for treatment of obesity. Because of central nervous system effects, the study was performed to assess the abuse potential and cognitive effects of taranabant in recreational polydrug users compared with phentermine, dronabinol, and placebo. METHODS: Stimulant- and cannabis-experienced polydrug users (N = 30) were randomized in a double-blind crossover study to receive taranabant 2, 4, 10, and 20 mg; phentermine 45 and 90 mg; dronabinol 20 mg; and placebo. Subjective and neurocognitive measures were administered for 24 hours, and peak/peak change from baseline effects were analyzed using a linear mixed-effects model. RESULTS: Phentermine 45 and 90 mg showed abuse-related subjective effects versus placebo, including drug liking, overall drug liking, and other positive/stimulant effects, whereas dronabinol 20 mg showed abuse-related positive, cannabis-like, and sedative effects. Taranabant was not significantly different from placebo on most of the subjective measures other than negative/dysphoric effects at the highest dose, and its effects were significantly less pronounced relative to phentermine and dronabinol on most measures. Phentermine improved cognitive/motor performance and dronabinol impaired motor/cognitive performance on some measures, whereas taranabant 4 and 20 mg had minor impairment effects on manual tracking. CONCLUSIONS: The phentermine and dronabinol results demonstrate the validity and sensitivity of the study. Taranabant did not consistently show stimulant/cannabis-like effects or abuse potential in recreational polydrug users, indicating that cannabinoid 1 receptor inverse agonists/antagonists are unlikely to be recreationally abused.