A Randomized Controlled Trial of Lorcaserin in Cocaine Use Disorder

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Case Vignette

“Mr Jones” is a 28-year-old Black man with a history of cocaine use disorder (CUD) and cocaine-induced psychotic disorder. He started using cocaine at age 19. At age 20, he required a brief inpatient hospitalization for substance-induced psychosis, believing that he was a deity from the planet Virgon who had been sent to Earth to fulfill the book of Revelations. Mr Jones currently uses 1 to 2 grams of cocaine/week for the past 3 years. He also has a comorbid alcohol use disorder. He is not currently taking any psychotropic medications, but previously failed a trial of naltrexone. At an outpatient appointment, Mr Jones inquires about other potential pharmacologic options for the treatment of his CUD, including investigational agents. As his psychiatrist, how would you respond?

Morbidity and mortality associated with CUD in the United States is increased.¹ However, there are no US Food and Drug Administration-approved medications for the treatment of CUD, and there is little evidence for psychotherapeutic approaches other than contingency management.² Therefore, there is an urgent unmet need for medication development for this disorder.

Preclinical studies suggests that serotonin 5-HT2C agonists such as lorcaserin (marketed in the US from 2012-2020 for weight loss), might have efficacy in CUDs, by blunting the subjective effects of cocaine and decreasing impulsivity.³ Given that alcohol use disorder is a common comorbidity in CUDs,⁴ lorcaserin also decreased alcohol self-administration in rats.⁵

The Current Study

McCann et al performed a 12-site, randomized, parallel arm study of lorcaserin in CUDs.⁶ The study allowed up to 3 weeks for screening, a 13-week treatment phase, and a 3-week follow-up period.

Inclusion criteria were treatment-seeking males and females aged 18 to 65 with DSM-5 cocaine use disorder, weight more than 50 kg and BMI greater than 20. Participants were required to have at least 1 day of cocaine use during the 30 days prior to screening, and at least 1 positive on-site urine test during screening. Exclusion criteria were pregnancy or lactation; use of lorcaserin during the 30 days prior to screening; a substance use disorder for any psychoactive substance other than cocaine, benzodiazepines, alcohol, nicotine, caffeine, or marijuana; a history of methadone or buprenorphine treatment during the year prior to screening; a positive on-site urine drug test for methampheatime, amphetamine, methadone, buprenorphine, oxycodone, or other opioids; alcohol use disorder judged to require medically supervised detoxification; ongoing mandatory drug testing; a Beck Depression Inventory-II score higher than 20; acute suicidality or a history of suicidal behavior; schizophrenia, bipolar disorder, or other psychotic disorder; and participation in a clinical trial of an investigational medication during the previous 6 months.

During the treatment phase, participants received a 1-week, single-blind run-in period of twice daily 15 mg acetazolamide (marker of medication adherence), followed by randomization to twice daily 10 mg lorcaserin or placebo for 12 weeks. Participants visited the clinic once weekly for assessments, urine samples, and individual 1-hour cognitive behavior therapy sessions to facilitation avoidance of cocaine use. Optional sessions were also available to facilitated avoidance of alcohol use. Participants visited the clinic for follow-up on study weeks 14 and 16.

The primary efficacy outcome measure was the proportion of subjects abstinent from cocaine during the last 3 weeks of the treatment phase within the efficacy population. The efficacy population was an enrichment strategy that included patients with a high blood acetazolamide level (indicating adherence) and reported 8 or more days of cocaine use during the 30 days prior to screening (decreased likelihood of placebo response). Abstinence was based on self-report and all urine assay results were negative for cocaine metabolites during the 3-week period. The secondary efficacy endpoint was the proportion of subjects achieving abstinence from cocaine during the last 3 weeks of the treatment phase in a subset of the efficacy population that were either nondrinkers or attempting alcohol abstinence. Data were analyzed using chi-square tests or Fisher’s exact tests for categorical variables, and t-tests for continuous variables.

The investigators screened 593 subjects, and 271 were enrolled in the 1-week, single-blind run-in period while 242 participants were randomized, of whom 183 (76%) qualified for inclusion in the efficacy population (92 randomized to placebo and 91 to lorcaserin). Among randomized subjects, mean age was 50, 72% were male, 66% were Black and 27% White. Among randomized participants, 76% administered cocaine by smoking and 23% nasally.

In the efficacy population, lorcaserin failed to facilitate achievement of cocaine abstinence (1.1% vs 4.3%). A similar pattern of findings was observed in all randomized study participants. Concordantly, there was no difference in craving severity between lorcaserin and placebo groups. Amongst the 30 participants who met DSM-5 criteria for alcohol use disorder and attempted to achieve abstinence during the trial, there was no difference in abstinence rates between lorcaserin and placebo (6.3% vs 7.1%), again with a similar pattern of findings for all randomized participants.

The average medication adherence was 77%. Lorcaserin was generally well tolerated. Approximately 56% of randomized participants reported adverse events in both study groups. The only statistically significant difference in adverse events was more weight loss in the lorcaserin group (7% vs 0%), consistent with its other indication. There were no deaths during the trial. All serious adverse events were considered not related to study medication or procedures.

Study Conclusions

The authors concluded that although medication adherence and sample size were sufficient to detect a significant effect, lorcaserin failed to facilitate abstinence from cocaine in in individuals with CUD (and alcohol in participants with comorbid CUD and alcohol use disorder). Given the 10 mg twice daily dose, the authors could not rule out the possibility that higher doses of lorcaserin may have shown efficacy. However, further evaluation of lorcaserin in CUD is unlikely due to its withdrawal from the market.⁷

The Bottom Line

Lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Becker S, Spiller HA, Badeti J, et al. Cocaine exposures reported to United States poison control centers, 2000- 2020. Clin Toxicol (Phila). 2022;60(7):827-837.

2. Farrell M, Martin NK, Stockings E, et al. Responding to global stimulant use: challenges and opportunities. Lancet. 2019;394(10209):1652-1667.

3. Howell LL, Cunningham KA. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharm Rev. 2015;67(1):176-197.

4. Carroll KM, Rounsaville BJ. Contrast of treatment-seeking and untreated cocaine abusers. Arch Gen Psychiatry. 1992;49(6):464-471.

5. Rezvani AH, Cauley MC, Levin ED. Lorcaserin, a selective 5-HT2C receptor agonist, decreases alcohol intake in female alcohol preferring rats. Pharmacol Biochem Behav. 2014;125:8-14.

6. McCann DJ, Chen HG, Devine EG, et al. Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder. Drug Alcohol Depend. 2024;255(2024):111063.

7. Sharretts J, Galescu O, Gomatam S, et al. Cancer risk associated with lorcaserin – The FDA’s review of the CAMELLIA-TIMI 61 trial. N Engl J Med. 2020;383(11):1000-1002.