In this study, the investigators will measure affective, neurocognitive and behavioral outcomes related to chronic use of opioids and benzodiazepines (screening phase), and in response to the administration of the opioid morphine, the benzodiazepine alprazolam, morphine then alprazolam, alprazolam then morphine, morphine+alprazolam simultaneously, and placebo (laboratory pharmacology experiment). The latter will enable the investigators to assess the effects of an opioid alone, benzodiazepine alone, concurrent and simultaneous administration of opioid+benzodiazepine, relative to a placebo control.

The investigators propose that benzodiazepine/opioid polysubstance abuse is perpetuated by a dual-deficit in affective/hedonic regulation (difficulties modulating emotional reactions relative to the context and the person's long-term goals). Furthermore, the investigators propose that this dual-deficit biases neurocognition (interferes with executive function) and behaviors (guided by negative reinforcement processes such that polysubstance use acutely blunts aversive states and directs actions away from natural rewards). The scientific premise for this project builds on George Koob's foundational concept that addiction is a 'reward-deficit/stress-surfeit disorder'. There is an urgent need to obtain clinical pharmacology and mechanistic data to test this hypothesis of dual-deficit in affective/hedonic regulation. This study will use human laboratory methods to test affective, neurocognitive and behavioral mechanisms that maintain benzodiazepine/opioid polysubstance abuse.

The screening phase of this human laboratory study will include measures of affective dysregulation related to benzodiazepine/opioid polysubstance use behaviors. These include distress tolerance, pain sensitivity and nocebo responding, and biomarkers (e.g. plasma cortisol). Also, the investigators will include behavioral measures of drug and non-drug reinforcement (e.g. economic simulations of price elasticity of alprazolam and morphine) and neurocognition (e.g. drug attentional bias, response inhibition, cognitive flexibility).

During the pharmacology study the investigators will administer oral placebo, morphine alone and alprazolam doses alone, as well as morphine and alprazolam sequentially (in counterbalanced order) and simultaneously. Following each drug administration, the investigators will measure responses in affective (e.g. anxiety levels, distress tolerance), neurocognitive (e.g. executive function, learning) and behavioral domains (e.g. impulsivity, psychomotor function, reinforcer preferences). The lab study is highly significant because we lack prospective, controlled, dose-response studies that identify whether opioids, benzodiazepines, and their combination modulate core phenotypes that underlie this harmful polysubstance abuse. Testing effects of both sequential and simultaneous benzodiazepine/opioid administration within the same individuals will establish a firm foundation for understanding which phenotypes are sensitive to disruption and may respond to treatment.

Findings from this study will help to focus clinical assessment and identify mechanisms that maintain benzodiazepine/opioid polysubstance abuse, toward the development of novel medication-assisted, evidence-based psychosocial interventions.

Inclusion Criteria:

• must self-report past 10-year experience taking opioid and sedative drugs (for therapeutic or non-therapeutic reasons), but not necessarily at the same time. As an alternative to the sedative drug exposure requirement, participants must have used alcohol on at least 3 separate days during the past month. Participants may have current mild- or moderate-severity Opioid Use Disorder or current mild- or moderate-severity Sedative Use Disorder;
• must not be seeking treatment for their substance use problems;
• must be in current good overall health

Exclusion Criteria:

• meet DSM-5 criteria for current psychosis, bipolar disorder, or severe depression (i.e. severe psychiatric disorder);
• meet DSM-5 criteria for severe substance use disorder for any substance (e.g. Sedative, Opioid, Alcohol);
• past-month benzodiazepine or opioid prescription (which would suggest daily use, tolerance, or withdrawal upon cessation);
• report of past-year any-drug overdose or suicide attempt/ideation;
• exhibit cognitive impairment (IQ < 80 on the Shipley Institute of Living Scale);
• neurological, cardiovascular, pulmonary, or systemic diseases (see specific exclusionary conditions under Protection of Human Subjects);
• body mass index > 38 kg/m2;
• females who are pregnant (urine), lactating or heterosexually active (self-report) and not using medically approved birth control;
• treatment with methadone, buprenorphine or naltrexone;
• past 30-day use of contraindicated medications;
• alcohol-positive breath sample (>.02% breath alcohol concentration);
• urine sample positive for methadone, cocaine, amphetamines, or barbiturates (<300 ng/ml)
• intolerance of lactose

Individual participant data will not be shared.

drug doses will be encapsulated, and placebo is included in the design