Summary: Lisdexamfetamine (Vyvanse), a medication commonly used to treat ADHD, lowers the risk of hospitalization and death for those with amphetamine use disorder.
Source: Karolinska Institute
The ADHD medication lisdexamfetamine was associated with the lowest risk of hospitalization and death in people with amphetamine addiction, when medications generally used among persons with substance use disorders were compared.
This is shown in a large registry-based study by researchers at Karolinska Institutet in Sweden in collaboration with the University of Eastern Finland and Niuvanniemi Hospital, published in JAMA Psychiatry.
“Our results suggest that lisdexamfetamine is associated with the best outcomes, and encourage the conduction of randomized controlled trials to explore this further,” says Jari Tiihonen, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s last author.
Amphetamines are the second most used illicit drugs in the world and amphetamine-related hospitalizations are increasing substantially.
However, there are currently no approved pharmacological interventions available for treating addiction to amphetamine or the variant methamphetamine. Certain medications have shown promising results, but to date, the studies have often been small and convincing evidence is lacking.
In the present study, the researchers investigated the association between generally used medications among persons with substance use disorder and the risk of two primary outcomes in people with amphetamine or methamphetamine use disorder: 1) hospitalization due to substance use disorder or 2) hospitalization due to any cause, or death.
The study included nearly 14,000 individuals; all residents aged 16 to 64 years living in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder from July 2006 to December 2018. Individuals with schizophrenia or bipolar disorder were excluded.
The patients were followed from the time of diagnosis until the patient died, moved from Sweden, was diagnosed with schizophrenia or bipolar disorder or the study ended. The median follow-up time was 3.9 years.
The researchers looked at how the risk of hospitalization or death for each individual differed depending on whether they were on or off the medication at that time.
Amphetamines are the second most used illicit drugs in the world and amphetamine-related hospitalizations are increasing substantially. Credit: Champlax
“Our results show that lisdexamfetamine, a medication approved for treating ADHD and in some countries also for binge eating, was the only specific medication associated with reduced risk of hospitalization and death,” says the study’s first author Milja Heikkinen, researcher at the University of Eastern Finland and Niuvanniemi Hospital.
The risk of hospitalization due to substance use disorder was 18% lower and the risk of hospitalization due to any cause or death was 14% lower during periods of lisdexamfetamine use, compared to periods without the ADHD medication.
The combination of two or more different medications for substance use disorder was also associated with a lower risk of hospitalization or death.
Use of benzodiazepines was associated with poorer outcomes; 17% higher risk of hospitalization due to substance use disorder and 20% higher risk of hospitalization due to any cause or death, during periods of use compared to periods of non-use. The use of antidepressants was also associated with slightly worse outcomes than non-use.
The researchers note that pharmacological treatments are often discontinued when the clinical state has improved, and are started when the clinical state deteriorates.
Therefore, the results may underestimate the putative beneficial effect of treatments. To control for this phenomenon, the researchers conducted analyses by omitting the first 30 days of use. The results were then in line with the main analyses.
Association of Pharmacological Treatments and Hospitalization and Death in Individuals With Amphetamine Use Disorders in a Swedish Nationwide Cohort of 13 965 Patients
There are no medications approved by authorities for the treatment of amphetamine or methamphetamine dependence, and studies investigating the effectiveness of pharmacological treatments in hard outcomes, such as hospitalization and death, are lacking.
To investigate the association between pharmacotherapies and hospitalization and mortality outcomes in persons with amphetamine or methamphetamine use disorder.
Design, Setting, and Participants
This nationwide register-based cohort study was conducted from July 2006 to December 2018 with a median (IQR) follow-up time of 3.9 (1.0-6.1) years. Data were analyzed from December 1, 2021, to May 24, 2022. All residents aged 16 to 64 years living in Sweden with a registered first-time diagnosis of amphetamine or methamphetamine use disorder and without previous diagnoses of schizophrenia or bipolar disorder were identified from nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension.
Medications for substance use disorders (SUDs) or for attention-deficit/hyperactive disorder, mood stabilizers, antidepressants, benzodiazepines and related drugs, and antipsychotics. Medication use vs nonuse was modeled with the PRE2DUP (from prescription drug purchases to drug use periods) method.
Main Outcomes and Measures
Primary outcomes were hospitalization due to SUD and any hospitalization or death, which were analyzed using within-individual models by comparing use and nonuse periods of 17 specific medications or medication classes in the same individual to minimize selection bias. The secondary outcome was all-cause mortality, studied using between-individual analysis as traditional Cox models.
There were 13 965 individuals in the cohort (9671 [69.3%] male; mean [SD] age, 34.4 [13.0] years). During follow-up, 7543 individuals (54.0%) were taking antidepressants, 6101 (43.7%) benzodiazepines, 5067 (36.3%) antipsychotics, 3941 (28.2%) ADHD medications (1511 [10.8%] were taking lisdexamphetamine), 2856 (20.5%) SUD medications, and 1706 (12.2%) mood stabilizers. A total of 10 341 patients (74.0%) were hospitalized due to SUDs, 11 492 patients (82.3%) were hospitalized due to any cause or died, and 1321 patients (9.5%) died of any cause. Lisdexamphetamine was the only medication in this study that was significantly associated with a decrease in risk of 3 outcomes (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94 for SUD hospitalization; aHR, 0.86; 95% CI, 0.78-0.95 for any hospitalization or death; aHR, 0.43; 95% CI, 0.24-0.77 for all-cause mortality). Methylphenidate use also was associated with lower all-cause mortality (aHR, 0.56; 95% CI, 0.43-0.74). Use of benzodiazepines was associated with a significantly higher risk of SUD hospitalization (aHR, 1.17; 95% CI, 1.12-1.22), any hospitalization or death (aHR, 1.20; 95% CI, 1.17-1.24), and all-cause mortality (aHR, 1.39; 95% CI, 1.20-1.60). Use of antidepressants or antipsychotics was associated with a slight increase in risk of SUD hospitalization (aHR, 1.07; 95% CI, 1.03-1.11 and aHR, 1.05; 95% CI, 1.01-1.09) as well as any hospitalization or death (aHR, 1.10; 95% CI, 1.06-1.14 and aHR, 1.06; 95% CI, 1.03-1.10, respectively).
Conclusions and Relevance
In this study, use of lisdexamphetamine was associated with improved outcomes in persons with amphetamine or methamphetamine use disorders, encouraging the conduct of randomized clinical trials. Prescription benzodiazepine use was associated with poor outcomes.