This investigation will be the first study assessing genetic modulation of naltrexone's NTX effects upon the abuse liability of a stimulant drug (methamphetamine). The study team will assess the ability of oral NTX to block the reinforcing and positive subjective effects of intranasal (IN) methamphetamine (30mg/70kg). This investigation could identify an important Gene x Pharmacological interaction, contributing to the personalization of stimulant abuse pharmacotherapy.

A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of Naltrexone (NTX) in treating alcohol abuse, increasing the treatment efficacy by over 2-fold among G-allele carriers (AG/GG). The proposed application would be the first to investigate the moderating effect of this genotype in the efficacy of NTX to treat stimulant abuse. More specifically, the study team proposes to investigate the interaction between NTX and intranasal (IN) methamphetamine (30mg/70kg). Participants who meet DSM criteria for mild-to-severe stimulant use disorder (N=up to 70) will complete 4 testing sessions where drug effects are tested following pretreatment with NTX (0, 50 mg). Naltrexone pretreatment effects upon the abuse liability of IN methamphetamine will be assessed using self-report measurements of positive subjective effects and drug self-administration. Medication effects on these validated predictors of abuse potential will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome.

Inclusion Criteria:

1. Male or female age 21 to 50 years
2. DSM-5 criteria for mild-to-severe stimulant use disorder, along with intravenous, intranasal or smoked use of amphetamine-type stimulants in amounts equal to or greater than administered in the current study.
3. Able to give written informed consent to participate.
4. Females must be either post-menopausal, surgically sterilized, or using an acceptable method of contraception (double-barrier method like a condom with a spermicidal lubricant) to participate in this study.
5. Racially Caucasian or of European descent.

Exclusion Criteria:

1. Currently seeking treatment for a substance use disorder.

2. DSM-5 criteria for moderate-to-severe substance use disorders (except those involving cocaine, amphetamines and nicotine).

3. Psychiatric condition that may affect the participants' ability to provide informed consent (e.g., psychotic disorder), or make participation hazardous for the participant or study staff (e.g., severe depression/suicidality, or risk of violence).

4. Uncontrolled neurological, cardiovascular, and hepatic diseases, active tuberculosis, or any other disorder that might make administration of study medications hazardous.

5. Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment.

6. Current treatment with a psychotropic medication that in the physician's judgement would interfere with the study endpoints.

7. History of allergy, adverse reaction, or sensitivity to amphetamines.

8. Medical conditions that may make study participation hazardous:

   • History of seizures or cardiac risk conditions (unstable angina, cardiac arrhythmias, chest pain, strong palpitations (subjectively defined as the feeling that the heart is beating too hard, too fast, skipping a beat, or fluttering).
   • Elevated liver function tests (i.e., AST and ALT > 3 times the upper limit of normal).
   • Impaired renal function (creatinine > 1.2).
   • Hypertension (>140/90).
   • Asthmatic symptoms within the past 3 years.

Baseline data are provided for participants who completed both conditions N=14.

1 Month

Participants and study staff conducting the lab sessions will be blinded to the treatment condition (i.e., naltrexone 0 mg or 50 mg)