Promoter region variant C-824T in the TH gene modulates the subjective effects of cocaine.

BACKGROUND AND OBJECTIVES: This study examined how a promoter variant of TH (rs10770141) affects subjective effects of cocaine in 65 nontreatment-seeking individuals with cocaine dependence. METHODS: Participants received cocaine/saline intravenously, and TH genotypes were evaluated. RESULTS: Homozygous individuals for the minor T allele reported greater "good" and "bad" subjective effects to cocaine than those with the major C allele. DISCUSSION AND CONCLUSIONS: TH rs10770141 modulates subjective effects of cocaine in participants with cocaine dependence. SCIENTIFIC SIGNIFICANCE: These results are among the first to indicate that homozygosity of the T allele of rs10770141 modulates greater sensitivity to cocaine.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an alpha-1 adrenoreceptor subtype D genetic variant.

Background: The α1 antagonist doxazosin reduces cocaine use in individuals with cocaine use disorder (CUD) through a functional polymorphism of the α1 adrenoreceptor. The regulatory role of the α1adrenoreceptor subtype D (ADRA1D) gene polymorphism in CUD is uncharacterized.Objectives: To study how the genetic variant of ADRA1D gene (T1848A, rs2236554) may affect the treatment efficacy of doxazosin in reducing cocaine use.Methods: This 12-week pilot trial included 76 participants with CUD with ADRA1D (T1848A, rs2236554) AA (N = 40) or AT/TT genotype (N = 36). Participants were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29), and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy.Results: The AA and the AT/TT groups had comparable baseline rates of cocaine positive urines at weeks 1-2 (~ 76%). In the placebo group, an increase of cocaine positive urines in the AT/TT group was found as compared to the AA group (24% vs. 9%). In the doxazosin group, a greater decrease in cocaine positive urines was found in the AT/TT group relative to the AA group. The difference between the doxazosin and placebo groups in cocaine negative urines became evident at weeks 5-6 and peaked at weeks 9-10 (~35% difference). The AT/TT group demonstrated a significant medication and time by medication effect (p < .001), whereas the AA group did not.Conclusion: The T-allele carriers showed a greater reduction of cocaine use after treatment with doxazosin in participants with the ADRA1D gene polymorphism (T1848A), suggesting that this SNP may serve as a pharmacogenetic marker in pharmacotherapy of CUD.

Pharmacogenetics of Dopamine ß-Hydroxylase in cocaine dependence therapy with doxazosin.

The α1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine ß-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DßH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DßH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DßH levels from the DBH CC genotype and 27 with lower DßH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DßH and NE levels, as compared with no net reduction in the CC genotype group with normal DßH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

Pharmacogenetic role of dopamine transporter (SLC6A3) variation on response to disulfiram treatment for cocaine addiction.

BACKGROUND AND OBJECTIVES: Disulfiram has been beneficial in treating cocaine addiction in several studies. Patients with two SLC6A3 (DAT1) rs28363170 10-repeat alleles who have with genetically high dopamine transporter (DAT) levels may benefit from increased dopamine levels resulting from disulfiram treatment. METHODS: After stabilization for 2 weeks on methadone, 70 cocaine and opioid codependent patients were randomized into disulfiram and placebo groups for 12 weeks of treatment. We genotyped the SLC6A3 (DAT1) 40 bp 3'-untranslated region variable number tandem repeat variant and evaluated its role in moderating disulfiram efficacy for cocaine dependence. RESULTS: Among the 10,10-repeat genotype group, cocaine-positive urines dropped from 78% to 48% and from 80% to 75% among the 9-repeat carrier group in the disulfiram group (P = 0.0001, with an effect size of 0.09). No difference was observed in cocaine-positive urines in the placebo group between the 10,10-repeat genotype and the 9-allele carrier patients. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We found that patients with genetically higher DAT levels had better treatment outcomes with disulfiram pharmacotherapy of cocaine dependence than those with lower DAT levels. (Am J Addict 2019;28:311-317).

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

OBJECTIVES: We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. METHODS: This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. RESULTS: Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P<0.0001), 'high' (P<0.0001), 'any drug effect' (P<0.0001), 'like cocaine' (P<0.0001), and 'likely to use cocaine if given access' (P<0.05) with experiment-wise significance. CONCLUSION: This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine.

Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

OBJECTIVE: The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure. METHODS: Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats. RESULTS: Participants were mostly male (∼80%) and African American (∼70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values<0.001) compared with individuals homozygous for the 10-allele. For the intron 8 polymorphism, individuals homozygous for the 6-allele exhibited greater responses for 'anxious' compared with carriers of the 5-allele (P<0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to 'good effects', 'bad effects', 'depressed', and 'anxious' (all P-values<0.01). CONCLUSION: The data presented here show for the first time support for the hypothesis that genetic differences in DAT1 contribute to the variation in subjective responses to cocaine among participants with cocaine use disorders.

Is hospitalization a missed opportunity to intervene on tobacco cessation?

BACKGROUND: Although tobacco use is associated with elevated morbidity and mortality, its use remains widespread among adults within the United States. Nicotine Replacement Therapy (NRT) products are effective aids that improve rates of tobacco cessation. Many smokers interact with the medical system, such as during hospitalization, without their tobacco use addressed. Hospitalization is a teachable moment for patients to make health-related changes, including tobacco cessation. METHODS: Retrospective cohort study of adult patients in a university-based patient-centered medical home from 2012 to 2021 evaluating the proportion of adults who smoke who received at least one prescription for NRT. Logistic regression models were used to analyze the association of being hospitalized and receipt of a NRT prescription. RESULTS: Of the 4,072 current smokers identified, 1,182 (29%) received at least one prescription for NRT during the study period. Hospitalization was associated with increased odds of receiving a NRT prescription (OR 1.68). Of 1,844 current smokers with a hospitalization during the study period, 1,078 (58%) never received a prescription for NRT at any point. Only 87 (5%) of the smokers received a prescription for NRT during hospitalization or at the time of hospital discharge. CONCLUSIONS: Despite hospitalization being associated with NRT prescribing, most patients who use tobacco and are hospitalized are not prescribed NRT. Hospitalization is an underutilized opportunity for both hospitalists and primary care physicians to intervene on smoking cessation through education and prescription of tobacco cessation aids.

Hospitalization as an opportunity to improve lung cancer screening in high-risk patients.

BACKGROUND: Lung cancer screening with annual low-dose computed tomography (LDCT) in high-risk patients with exposure to smoking reduces lung cancer-related mortality, yet the screening rate of eligible adults is low. As hospitalization is an opportune moment to engage patients in their overall health, it may be an opportunity to improve rates of lung cancer screening. Prior to implementing a hospital-based lung cancer screening referral program, this study assesses the association between hospitalization and completion of lung cancer screening. METHODS: A retrospective cohort study of evaluated completion of at least one LDCT from 2014 to 2021 using electronic health record data using hospitalization as the primary exposure. Patients aged 55-80 who received care from a university-based internal medicine clinic and reported cigarette use were included. Univariate analysis and logistic regression evaluated the association of hospitalization and completion of LDCT. Cox proportional hazard model examined the time relationship between hospitalization and LDCT. RESULTS: Of the 1935 current smokers identified, 47% had at least one hospitalization, and 21% completed a LDCT during the study period. While a higher proportion of patients with a hospitalization had a LDCT (24%) compared to patients without a hospitalization (18%, p<0.001), there was no association between hospitalization and completion of a LDCT after adjusting for potentially confounding covariates (95%CI 0.680 - 1.149). There was an association between hospitalization time to event and LDCT completion, with hospitalized patients having a lower probability of competing LDCT compared to non-hospitalized patients (HR 0.747; 95% CI 0.611 - 0.914). CONCLUSIONS: In a cohort of patients at risk for lung cancer and established within a primary care clinic, only 1 in 4 patients who had been hospitalized completed lung cancer screening with LDCT. Hospitalization events were associated with a lower probability of LDCT completion. Hospitalization is a missed opportunity to refer at-risk patients to lung cancer screening.

Statin prescribing patterns in patient-centered medical home patients with NAFLD.

OBJECTIVES: Cardiovascular disease is the leading cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD), and statins play a pivotal role in the primary prevention of cardiovascular events. This study investigates statin prescribing in primary care patients with NAFLD to identify opportunities to address cardiovascular disease risk in this cohort. STUDY DESIGN: Retrospective cohort study of primary care electronic health record data from 2012-2018. METHODS: This cohort included 652 patients with radiographic evidence of hepatic steatosis and no evidence of competing chronic liver disease. A statin prescription identified at any time during the study period was the primary outcome. Univariate and multivariable analyses were performed to evaluate the association of clinical signals and comorbidities with statin prescribing. RESULTS: Of the 652 patients in the NAFLD cohort, 56% received a statin prescription during the study period. Elevations in aminotransferases were not associated with statin prescribing (adjusted odds ratio [AOR], 1.17; 95% CI, 0.78-1.76), whereas older patients (AOR, 1.06; 95% CI, 1.05-1.08) and those with diabetes (AOR, 2.61; 95% CI, 1.73-3.92), hypertension (AOR, 2.76; 95% CI, 1.70-4.48), and a BMI greater than or equal to 30 kg/m2 (AOR, 1.49; 95% CI, 1.01-2.22) had higher odds of having a statin prescribed. Of the 288 patients without a statin prescription, 49% had an indication for statin therapy by atherosclerotic cardiovascular disease risk. In total, 16% of included patients did not have lipid panel results during the study period. CONCLUSIONS: This study showed no association between NAFLD and statin prescribing, and the findings highlight opportunities to improve primary prevention of cardiovascular disease in these at-risk patients.

The OPRD1 rs678849 variant influences outcome of disulfiram treatment for cocaine dependency in methadone-maintained patients.

OBJECTIVE: Prior research demonstrated that the δ-opioid receptor (OPRD1) rs678849 variant influences opioid use in African Americans treated with methadone. We examined whether this variant moderated cocaine and opioid use in our clinical cohort of methadone and disulfiram treated recipients. METHODS: Cocaine and opioid codependent patients were stabilized for 2 weeks on methadone and subsequently randomized into groups treated with either methadone + placebo (n = 37) or methadone + disulfiram (250 mg/day; n = 33) for 12 weeks. RESULTS: A drop in cocaine-positive urine was found in the OPRD1 CC genotype group compared to T-allele carrier patients treated with methadone + disulfiram (P < 0.0001), but not in the methadone + placebo group. No difference in opioid-positive urines was found among each genotype group in either treatment group. CONCLUSION: These findings suggested that rs678849 genotype may predict treatment response of disulfiram for cocaine use in patients with co-occurring opioid and cocaine dependence.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

OBJECTIVE: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. METHODS: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. RESULTS: Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. CONCLUSION: These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Pharmacogenetics of addiction therapy.

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies. For several addiction pharmacotherapies, response to treatment varies based on individual genetic makeup. In this chapter, we discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.