Drug Liking Research Articles

Comparative pharmacology and abuse potential of oral dexamphetamine and lisdexamfetamine-A literature review.

To compare the pharmacology and abuse potential of oral dexamphetamine and lisdexamfetamine (LDX). A search of Medline and Embase was conducted to identify relevant articles for this literature review. Dexamphetamine and LDX, a prodrug of dexamphetamine, are indicated for the treatment of attention-deficit/hyperactivity disorder. It has been suggested that LDX may have a reduced potential for oral abuse compared to immediate-release dexamphetamine. As a prodrug, LDX has the same pharmacodynamic properties as dexamphetamine. A study in healthy adults showed that the pharmacokinetic profile of dexamphetamine following oral administration of LDX is essentially identical to that of an equimolar dose of dexamphetamine administered 1h later. In addition, dexamphetamine produced subjective drug liking effects comparable to those produced by LDX. LDX showed linear dose proportional pharmacokinetics up to a dose of 250mg, indicating a lack of overdose protection at supratherapeutic doses. Furthermore, the exposure to dexamphetamine released from LDX may be prolonged by the consumption of alkalizing agents. The available evidence from pharmacodynamic, pharmacokinetic and abuse liability studies suggests a comparable potential for oral abuse of dexamphetamine and LDX.

Evaluating the Abuse Potential of Lenabasum, a Selective Cannabinoid Receptor 2 Agonist.

Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings. SIGNIFICANCE STATEMENT: This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder.

Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis. Effects of single-dose oral THC (15mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed. Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory. In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-‍linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Shared decision-making and client-reported dose satisfaction in a longitudinal cohort receiving injectable opioid agonist treatment (iOAT)

BackgroundAcross different types of oral Opioid Agonist Treatment for people with Opioid Use Disorder, receiving a dose that meets their needs is associated with better outcomes. Evidence also shows patients are more likely to receive an “adequate dose” when their prescribers are involving them in decision making. Neither of these findings have been studied in the context of injectable Opioid Agonist Treatment, which is the purpose of this study.MethodsThis study was a retrospective analysis of an 18-month prospective longitudinal cohort study of 131 people receiving injectable Opioid Agonist Treatment. In the 18-month study, observations were collected every two months for one year, and then once more at 18 months. At 6 months, participants were asked whether their dose was satisfactory to them (outcome variable). Generalized Estimating Equations were used, to account for multiple observations from each participant. The final multivariate model was built using a stepwise approach.ResultsFive hundred forty-five participant-observations were included in the analysis. Participant-observations were grouped by “dose is satisfactory” and “wants higher dose”. From unadjusted analyses, participants were less likely to report being satisfied with their dose if they: were Indigenous, had worse psychological or physical health problems, had ever attempted suicide, were younger when they first injected any drug, were a current smoker, felt troubled by drug problems, gave their medication a lower “drug liking” score, and felt that their doctor was not including them in decisions the way they wanted to be. In the final multivariate model, all previously significant associations except for “current smoker” and “troubled by drug problems” were no longer significant after the addition of the “drug liking” score.ConclusionsPatients in injectable Opioid Agonist Treatment who are not satisfied with their dose are more likely to: be troubled by drug problems, be a current smoker, and report liking their medication less than dose-satisfied patients. Prescribers’ practicing shared decision-making can help patients achieve dose-satisfaction and possibly alleviate troubles from drug problems. Additionally, receiving a satisfactory dose may be dependent on patients being able to access an opioid agonist medication (and formulation) that they like.

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.

Does childhood adversity alter opioid drug reward? A conceptual replication in outpatients before surgery

Introduction Opioid analgesic treatment during surgery entails the risk of persistent use. Experiences of childhood adversity have been shown to increase opioid reward in preclinical models, a finding recently extended to healthy humans. We tested whether childhood adversity similarly increased opioid reward, operationalized as drug-induced feeling good and drug liking, in outpatients receiving opioids on the operating table. Methods This observational study recruited patients entering a Norwegian hospital for an outpatient surgical procedure. An opioid intravenous opioid analgesic (remifentanil [Minto model, effect-site concentration: 5 ng/ml], or oxycodone [5 mg]) was administered in the minutes before general anesthesia. Verbal numerical ratings of feeling good and anxious were collected 1 min before, and 1–3 min after opioid infusion. Ratings of drug liking, disliking, and feeling high were also collected after infusion. Patients (n = 151) completed measures of childhood adversity at a later date. Results Regression analyses revealed a modest yet significant negative association between childhood adversity and post-opioid liking (b = −0.06, p = 0.046) but no significant effect on feeling good (b = 0.01, p = 0.690) after the pre-operative opioid dose. Exploratory analyses showed that more childhood adversity was significantly associated with higher reports of anxiety, depression, loneliness, and pain catastrophising, however not with alcohol or other drug use, or with any other subjective drug effects. Discussion Ratings of feeling good and drug liking of medically prescribed opioids given before surgery were not higher after childhood adversity, and previous findings were not conceptually replicated. The discrepancy between current and prior results may be due to the context and stress related to the impending surgery, the short duration of drug exposure, and the relatively limited levels of high childhood adversity in the current sample compared to the original study. Exploratory analysis was consistent with the possibility of a nonlinear relationship between positive opioid effects and childhood adversity scores. Future research should assess the link between childhood adversity, subjective effects, and use of the prescribed opioids after surgery.

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.

A survey of drug liking and cravings in patients using sublingual or intranasal ketamine for treatment resistant depression: A preliminary evaluation of real world addictive potential.

Ketamine has gained rapid popularity as a treatment option for treatment resistant depression (TRD). Though seen only in limited contexts, ketamine is a potential drug of abuse, addiction and diversion. Clinical ketamine studies to date have not systematically evaluated factors relevant to addiction risk in patients with TRD, but in treating patients with ketamine, risks of potential harms related to addiction must be considered. As clinical access to intravenous ketamine programs is limited in much of Canada, these considerations become even more important for clinicians who elect to offer patients less supervised, non-parenteral forms of ketamine treatment. This study explores factors relevant to addiction risk in a real-world sample of 33 patients with TRD currently or previously treated with sublingual (SL) or intranasal (IN) ketamine in the community. First, patients were surveyed using a Drug Liking and Craving Questionnaire (DLCQ) to assess their level of drug liking and craving for ketamine, and to screen for symptoms of a ketamine use disorder. Second, the pharmacy records of these patients were reviewed for red flags for addiction such as dose escalation or early refills. Third, surveys were administered to the treating psychiatrists of patients who had discontinued ketamine to determine if abuse concerns contributed to reason for discontinuation. Though limited to a small sample, results indicate that ketamine is not a universally liked or craved substance in patients with TRD. Prescribers of non-parenteral ketamine should monitor patients and prescribe cautiously. Factors related to addiction (as in the DLCQ) should be explored for clinicians to consider individual risk/benefit for judicious use of ketamine in patients with TRD.

FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment—a pharmacokinetic-pharmacodynamic study

BackgroundTreatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone.MethodsOpiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing.DiscussionStudy outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence.Trial registrationClinicaltrials.gov NCT05161351. Registered on 16 December 2021.

Gabapentin increases the abuse liability of alcohol alone and in combination with oxycodone in participants with co-occurring opioid and alcohol use disorder

BackgroundPeople who have co-occurring Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) carry a higher risk of adverse outcomes, including drug overdose. Early clinical and preclinical studies suggested that gabapentin may be effective in treating both disorders. The present study was designed to assess the effects of gabapentin on the subjective and physiological effects of oxycodone (OXY) and alcohol (ALC), alone and in combination. MethodsDuring an 8-week, inpatient, within-subject, randomized, double-blind, placebo-controlled crossover study, non-treatment seeking participants (N = 13; 12 M/1F; 44.1 ± 3 years of age) with OUD and AUD were maintained on oral morphine (120 mg daily). Under gabapentin (1800 mg/day) and placebo (0 mg/day) maintenance, participants completed nine separate test sessions (three sessions per week) during which they received an oral solution containing 0, 15, or 30 mg/70 kg OXY in combination with 0, 0.5, or 0.75 g/kg ALC. During test sessions, subjective effects and physiological responses were assessed repeatedly on 100-mm visual analog scales (VAS). The primary outcome variable was the VAS rating of drug liking after receiving the drug challenge. ResultsAlcohol alone (but not oxycodone alone) produced dose-related increases in several positive subjective responses, including drug liking. Gabapentin significantly increased drug liking when given in combination with ALC and OXY + ALC (p < 0.05). Gabapentin did not clinically compromise respiration or other vital functions. ConclusionsGabapentin may increase the abuse liability of ALC and OXY + ALC in those with co-occurring OUD and AUD.

Association between ABCB1 rs2235048 Polymorphism and THC Pharmacokinetics and Subjective Effects following Smoked Cannabis in Young Adults

Genetic influences on acute responses to psychoactive drugs may contribute to individual variability in addiction risk. ABCB1 is a human gene that encodes P-glycoprotein, an ATP-dependent efflux pump that may influence the pharmacokinetics of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. Using data from 48 young adults (aged 19–25 years) reporting 1–4 days of cannabis use per week who completed a placebo-controlled human laboratory experiment, we tested the hypothesis that the rs2235048 polymorphism of ABCB1 would influence acute responses to smoked cannabis. C-allele carriers reported on average greater frequency of weekly cannabis use compared to the TT genotype carriers (TC/CC mean ± SEM = 2.74 ± 0.14, TT = 1.85 ± 0.24, p = 0.004). After smoking a single cannabis cigarette to their desired high, C-allele carriers had higher area-under-the-curve (AUC) of both THC metabolites (11-OH-THC TC/CC = 7.18 ± 9.64, TT = 3.28 ± 3.40, p = 0.05; THC-COOH TC/CC = 95.21 ± 116.12, TT = 45.92 ± 42.38, p = 0.043), and these results were impact by self-reported ethnicity. There were no significant differences in self-reported subjective drug effects except for a greater AUC of visual analogue scale rating of drug liking (TC/CC = 35,398.33 ± 37,233.72, TT = 15,895.56 ± 13,200.68, p = 0.017). Our preliminary findings suggest that further work in a larger sample should investigate whether human ABCB1 influences cannabis-related phenotypes and plays a role in the risk of developing a cannabis use disorder.

Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate

Objectives Serdexmethylphenidate (SDX) chloride (Cl) is a novel prodrug of d-methylphenidate (d-MPH). These studies evaluated the abuse potential of SDX Cl when administered orally, intranasally (IN), and intravenously (IV). Methods Three randomized, double-blind, placebo- and active-controlled crossover studies were conducted in recreational drug users to evaluate the abuse-related effects of oral SDX (120 and 240 mg) vs. extended-release (ER) d-MPH (80 mg) and phentermine (60 mg); IN SDX (80 mg) vs. d-MPH (40 mg), and IV SDX (30 mg) vs. d-MPH (15 mg). Abuse-related subjective measures, pharmacokinetics, and safety were assessed. Results The primary endpoint of maximum (Emax) Drug Liking (DL) (0–100-point scale) was significantly higher following d-MPH vs. placebo, validating the studies. In the oral study, DL Emax was significantly higher following 80 mg ER d-MPH (Emax = 81.5) than 120 mg SDX (Emax = 62.8, p < .001) and 240 mg SDX (Emax = 63.8, p = .006); and following 60 mg phentermine (Emax = 80.2) than 120 mg SDX (p = .0195), but not 240 mg SDX (p = .0665). DL Emax scores were significantly higher following IN d-MPH vs SDX (Emax = 93.2 vs. 71.0, p < .0001) and following IV d-MPH vs. SDX (Emax = 84.3 vs. 56.6, p = .001). Intravenous SDX was non-inferior to placebo (p = .001) for DL Emax. Secondary endpoints (e.g. Take Drug Again) were generally consistent with the primary endpoint. Maximal and overall d-MPH exposure was lower for SDX than d-MPH for all routes. Adverse events typical of stimulants were more frequent with d-MPH than SDX. Conclusions These findings indicate that the novel d-MPH prodrug, SDX, has lower abuse potential than d-MPH and support its classification as a C-IV controlled substance.

The drug liking and craving questionnaire (DLCQ) to evaluate addiction risk for ketamine and esketamine

Ketamine and esketamine (SPRAVATO) are rapid acting antidepressants that have gained evidence and popularity in recent years in treating depression, and are under investigation for other psychiatric indications. Ketamine is a potential drug of abuse and the addiction potential of these medications has been repeatedly cautioned in the psychiatric literature. However, no studies have included a systematic evaluation of addiction potential in their research so risk of this harm remains theoretically and has not been quantified to place in properly in a risk/benefit perspective. There is currently no easily accessible and ready to use tool for this purpose, which poses a barrier to including measures of addiction potential in ketamine and esketamine research. Based on review of the literature and a recently suggested comprehensive Ketamine Side Effect Tool (KSET), as well as the United States Food and Drug Administration recommendations for evaluation addictive potential of a drug, we created a simple, patient rated visual analog scale specifically for assessing ketamine/esketamine drug likeability, cravings and temptation to misuse. While this scale is not validated, in the absence of other accessible tools, use of this questionnaire would provide researchers and clinicians a simple and easy to use tool to begin monitoring addictive potential in patients taking ketamine or esketamine, and better inform future research, clinical practice and publicy policy regarding these substances. • Ketamine and Esketamine are rapid acting antidepressants thought to have potential for abuse or misuse, but this has not been studied in clinical trials. • There is need for a simple tool to screen for predictors of addictive potential of ketamine and esketamine in psychiatric practice and research use in clinical ketamine/esketamine programs or associated clinical research. • Based on United States Food and Drug Administration recommendation to screen for drug likeability using a visual analog scale, a simple questionnaire was developed and is shared.

Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse.

To understand the correlation between oxycodone concentration and drug liking response for immediate-release formulations as they relate to different doses and different routes of administration following manipulation involved in opioid misuse and nontherapeutic use. Concentration-response and noncompartmental analyses of drug liking and plasma oxycodone data from Category 3 human abuse potential studies (n = 15-29 per study) were conducted, using Phoenix 6.0 software. Time to onset of a set threshold of subjective effects (Tonset) and offset of subjective effects (Toffset) were estimated based on a baseline pharmacodynamic response set at 50 on a bipolar Drug Liking visual analog scale of 0-100 and the threshold for drug liking set at ≥65, based on study qualification criteria. Partial Area Under the Concentration (AUCTonset-Toffset) and Effect (AUETonset-Toffset) profiles were calculated and their correlation with individual partial AUE vs partial AUC was assessed. The oxycodone concentration-response (drug liking) was best described by a sigmoidal-effect Emax model (S-shaped). Using a defined threshold, drug liking was closely associated with the rate of rise in concentration and the onset of action for oxycodone administered via oral or intranasal route. Partial AUCTonset-Toffset and AUETonset-Toffset showed a strong linear correlation. Results indicate that oxycodone concentration-response and duration of drug liking following manipulation via different routes of administration may be an approach for further exploring drug liking effects of opioids.

Acute objective and subjective intoxication effects of legal-market high potency THC-dominant versus CBD-dominant cannabis concentrates.

As the market for cannabis concentrate products grows, the lack of research regarding the effects of concentrated THC and CBD becomes more glaring. The present study analyzes cannabinoid blood levels and subjective outcomes of physical sensation and affective state after ad libitum use of legal-market concentrate products. Recreational cannabis users were randomly assigned to THC- or CBD-dominant concentrate products, completing a baseline session, and an experimental mobile laboratory session consisting of timepoints before, immediately after, and one-hour after concentrate use. THC-dominant concentrates induced higher intoxication, and higher ratings of drug effect and drug liking than the CBD-dominant concentrate. Both products induced immediate feelings of elation, diminishing over the subsequent hour. Subjective outcomes in the CBD-dominant group revealed immediate decreases in tension and anxiety relative to pre-use, while the THC-dominant group only saw significant decreases in anxiety after one hour. Paranoia spiked immediately post-use in THC-dominant concentrate users, returning to baseline within an hour. Overall, the CBD-dominant concentrate invoked positive mood effects, lower intoxication and an absence of undesirable effects experienced with the THC-dominant concentrate, potentially mitigating negative effects when combined. Results support the need for further investigation into harm-reduction potential of concentrated CBD when used alone and with THC.

Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users.

Difelikefalin, a selective kappa‐opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double‐blind, active‐ and placebo‐controlled, four‐way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu‐opioid partial agonist and kappa‐opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [Emax]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject‐rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS Emax, and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose‐dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end‐of‐session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well‐tolerated. This study indicates that difelikefalin presents a low potential for abuse.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BackgroundOver the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of “drug liking,” “take drug again”), which are referred to as ‘pharmacodynamic (PD)’ responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs.MethodsExtensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data.FindingsFollowing oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65.InterpretationOur assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs.FundingThe study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Relative potency of intravenous oxymorphone compared to other µ opioid agonists in humans - pilot study outcomes.

Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.

Investigating sex differences in acute intoxication and verbal memory errors after ad libitum cannabis concentrate use

BackgroundAn innovative naturalistic at-home administration procedure was used to investigate sex differences in subjective drug effects and verbal memory errors after ad libitum use of high potency state legal market Δ9-tetrahydrocannabinol (THC) concentrate. MethodsRegular concentrate users were randomly assigned to ad libitum administration of one of two cannabis concentrate products (70 % or 90 % THC) that they purchased from a dispensary. 65 participants (N = 34 men, N = 31 women) were assessed in a mobile pharmacology lab before, immediately after, and 1 -h after ad libitum concentrate use. Plasma cannabinoids (THC, 11-OH-THC, CBD), subjective drug effects, and verbal memory errors were assessed at all three time points. ResultsAlthough men and women exhibited similar plasma 11-OH-THC levels across time (p = .10), sex differences were found in plasma THC and CBD after legal market concentrate use, with men displaying significantly higher levels of plasma THC and CBD immediately after cannabis concentrate use (plasma THC [ng/mL]: Mmen = 489.88, Mwomen = 135.08, p < .001; plasma CBD [ng/mL]: Mmen = 1.14, Mwomen = 0.53, p = .04). Despite this, sex differences in subjective effects and verbal memory errors did not emerge, although women reported a steeper decrease in drug liking after use (p = .04). ConclusionThese data provide the first look at sex differences after acute naturalistic cannabis concentrate use, and suggest much higher THC exposure in men versus women, but similar acute drug and impairment effects across the sexes. Further studies are needed to determine the mechanisms (e.g. tolerance, cannabinoid metabolism, smoking topography) behind these findings.