Pharmacogenetics of Naltrexone for Stimulant Abuse

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.