Abstract
Objective:
To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence.
Method:
A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD (n = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase.
Results:
Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p = .65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = .27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < .0001).
Conclusions:
MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER’s superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time.
Introduction
Attention-deficit hyperactivity disorder (ADHD), characterized by impairing symptoms of hyperactivity-impulsivity and/or inattention, is over-represented among those with substance use disorders, and particularly those with cannabis use disorder (CUD) (Hernandez & Levin, 2022; Soler Artigas et al., 2021; van Emmerick-van Oortmerssen et al., 2014; Zaman et al., 2015). Up to 40% of adolescents entering treatment for their CUD (Tims et al., 2002) have ADHD. Yet there are limited data on how to best treat this comorbid population, despite repeated findings that ADHD is associated with poorer substance use treatment response (Carroll & Rounsaville, 1993; Elkins et al., 2018; Levin et al., 2004; Wise et al., 2001).
While there is substantial literature evaluating medications for child and adolescent and adult ADHD (Catala-Lopez et al., 2017; Elliott et al., 2020), and a growing literature of placebo-controlled randomized pharmacologic trials targeting CUD alone (Brezing & Levin, 2018), there is only a handful of studies that have conducted randomized trials for those with CUD and ADHD. To our knowledge there are four randomized studies that have enrolled adolescents or adults with ADHD and primarily CUD. Two of these studies have evaluated stimulants (e.g., pemoline, OROS-MPH) in adolescents at standard doses (Riggs et al., 2004, 2011) and two have evaluated atomoxetine in adolescents and adults (McRae et al., 2010; Thurstone et al., 2010). Amphetamine formulations have yet to be studied.
Results of these studies have been mixed. In the earliest trial, pemoline, an older, discontinued, stimulant medication, was found to be superior to placebo in reducing ADHD symptoms and drug use among those primarily using cannabis (Riggs et al., 2004). More recently, in a substantially larger multisite trial in which 90% of the sample met criteria for DSM-IV cannabis abuse or dependence, OROS-MPH was not superior to placebo on primary outcome measures (self-reported ratings of ADHD and drug use) (Riggs et al., 2011). However, secondary ADHD and drug use outcomes that included parental ADHD ratings and urine drug tests found that OROS-MPH outperformed placebo in reducing ADHD symptoms and substance use. For the two studies evaluating atomoxetine, ADHD outcomes were mixed; albeit mainly negative, but neither study found that atomoxetine reduced cannabis use. Taken together, these studies suggest that stimulant medications may show greater promise in reducing both ADHD symptoms and cannabis use.
Appropriate dosing is also critical to the success of clinical trials. Earlier work using standard dosing of stimulant medications has produced mixed results in ADHD adults with cocaine and other substance use disorders (Carpentier & Levin, 2017). However, when robust doses of mixed-amphetamine salts extended release (MAS-ER) were used in adults with ADHD and cocaine use disorder, the primary outcomes for ADHD (i.e., 30% reduction in ADHD symptoms) and cocaine use (percentage of abstinent weeks over time) were superior to placebo (Levin et al., 2015). Supporting the notion of using higher dosing are two studies conducted by Konstenius and colleagues. One study found that high doses of OROS-MPH (above FDA-approved dosing) reduced both ADHD symptoms and drug use whereas an earlier study using standard dosing did not improve ADHD symptoms or drug use (Konstenius et al., 2010, 2014).
In the study conducted by Levin et al. (2015) approximately half the sample of adults with ADHD and cocaine use disorder were regular cannabis users. In a secondary analysis of this study, Notzon et al. (2016) found that MAS-ER was more likely to promote abstinence from cannabis than placebo. Therefore, we hypothesized that robust dosing of a commonly used stimulant medication, MAS-ER, would be more likely than placebo to reduce both ADHD symptoms and promote abstinence from cannabis. We chose MAS-ER because we had gained substantial experience using this medication in adults with cocaine use disorders with and without comorbid ADHD (Levin et al., 2015, 2020; Mariani et al., 2011) but there has not been an evaluation of stimulant medication in adults with ADHD and CUD.
This small, feasibility pilot study, to our knowledge, is the first pharmacologic trial evaluating a stimulant medication in adults with CUD who also have ADHD, a group that represents a substantial number of CUD adults seeking addiction treatment. The goal was to demonstrate feasibility, tolerability, and potential utility of MAS-ER in this comorbid population.
Methods
Participants
The pilot study was approved by the Institutional Review Board of the New York State Psychiatric Institute and participants seeking treatment for CUD and/or ADHD were recruited by local advertising or clinical referrals in the New York City area. Participants were enrolled at the Substance Treatment and Research Service (STARS) of Columbia University/New York State Psychiatric Institute (NYSPI). All participants gave informed written consent. We enrolled 33 participants who met Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (American Psychiatric Association, 2013) for CUD and adult ADHD based on the MINI-International Neuropsychiatric Interview (Sheehan et al., 1998) and an amended version of The Diagnostic Interview for ADHD in Adults 2.0 (DIVA 2.0) (Ramos-Quiroga et al., 2019) which utilized DSM-5 criteria. Both were performed as part of a comprehensive psychiatric and medical evaluation.
Study inclusion criteria required participants to be: (1) ages 18 to 65 and capable of giving informed consent and of complying with study procedures; (2) meeting DSM-5 diagnosis for current CUD and adult ADHD; (3) reporting using cannabis at least 5 days per week over the past 28 days and having a positive urine for THC on day of study entry; and (4) having a score >22 on the Adult ADHD Investigator Symptom Rating Scale (AISRS) (Spencer et al., 2010).
Participants were excluded if they: (1) met DSM-5 criteria for schizophrenia, schizoaffective illness, psychotic disorder other than transient psychosis due to drug use, current major depression, bipolar illness, or psychiatric disorders (other than substance use) which would require psychiatric intervention or would interfere with study participation and those with significant current suicidal risk. Individuals with major depression and a HAM-D >17 (Hamilton, 1960) (considered moderate to severe depression) were excluded. Individuals with baseline Clinical Global Impression Rating (CGI) >4 for Other Psychiatric Disorders (Guy, 1976) were excluded (HAM-D and CGI parameters were added after study commencement); (2) were medically unstable that would make participation hazardous; (3) use of synthetic cannabinoids in the past month and meeting CUD diagnosis based on synthetic cannabinoids use alone in the past year; (4) had liver enzyme function tests greater than three times normal; (5) had systolic blood pressure (SBP) > 140; diastolic blood pressure (DBP) >90; pulse >100 (participants who have BP and pulse below these parameters on stable antihypertensive medication were included); (6) were nursing mothers, pregnant women or women of child-bearing age who refused to agree to use an effective method of contraception during the trial; (7) met more than 3 (moderate or severe) DSM-5 criteria for other substance use disorders or were physiologically dependent on any other drugs (excluding nicotine) that would require a medical intervention (symptom criteria added post study commencement); (8) had cognitive impairment that would impede study participation; (9) had a known sensitivity/allergy to MAS-ER or amphetamine analogs; (10) had a history of amphetamine use disorders, including amphetamines such as methamphetamine and MDMA; (11) had current cocaine use disorder; (12) were mandated to treatment; and (13) had a history of seizures. Any history of seizures was excluded because high doses of amphetamine were being administered and amphetamines are associated with greater seizure risk.
Procedures
The pilot study was a two arm, randomized, double-blind, placebo-controlled outpatient 12-week trial, comparing daily doses of MAS-ER 80 mg and placebo. The study started with a 1-week single-blind placebo lead-in phase; participants who were abstinent from cannabis during this week, or noncompliant with study procedures, were not randomized. After completion of the placebo lead-in period (week 1), eligible individuals were randomized to MAS-ER or placebo in a 1:1 ratio. Participants who are randomized to the medication arm had their dose titrated to 80 mg MAS-ER once daily (over 2 weeks) and were maintained on this target dose or the maximum tolerated dose for the subsequent 8 weeks using a fixed-flexible dosing approach. During week 12, participants were tapered off the medication. The purpose of the lead-out was to blind participants to the exact point of medication discontinuation and to provide naturalistic data on the effects of medication discontinuation. MAS-ER was administered in 10 mg and 20 mg capsules; placebo capsules appeared identical to the MAS-ER capsules. Study medication was dispensed weekly in a fixed-flexible dose schedule and participants were provided with medication bottles under double-blind conditions. Dose reductions for tolerability were made based on clinical judgment by the research psychiatrist blinded to the treatment assignment. Regular meetings were conducted with the physicians to discuss their approach to their clinical dosing decisions to ensure they were modifying doses in a consistent fashion.
Medication adherence was assessed by (1) self-report with pill count, (2) from urine quantification of amphetamines (not available to blinded study staff), and (3) urine riboflavin using quantitative fluorometry (available to study staff) (Del Boca et al., 1996; Herron et al., 2013). To accomplish this MAS-ER and placebo were over-encapsulated with riboflavin and staff were trained in the use of the laboratory fluorometer. A timeline followback assessment of study medication compliance accounting for each dose of prescribed study medication was conducted with a weekly financial incentive ($10) for the medication bottle return. Quantitative toxicology for amphetamine (immunoassay-quantitative with cutoff 1,000 ng/ml) was conducted every visit beginning post randomization.
Study visits occurred twice weekly during the study period. Serum pregnancy testing was performed during screening and a urine pregnancy test was performed at study weeks 2, 5, 8, and 12. A complete blood count, comprehensive metabolic profile, TSH and urinalysis was performed during the screening process. Urine samples for cannabis toxicology (quantitative GC/MS with cutoff 15 ng/ml, and qualitative immunoassay with cutoff 50 ng/ml) and creatinine (20–300 mg/dL) were collected twice per week. Creatinine normalized THC concentrations were calculated by dividing the quantitative THC ng/ml by creatinine mg/dL and multiplying by 100 in order to report the results in ng THC per mg of creatinine. Pulse and blood pressure were measured at every study visit, twice weekly. Electrocardiograms (ECGs) were conducted at screening, weeks 4, 8, and 12. The COMBINE Systematic Assessment for Treatment Emergent Events (COMBINE SAFTEE) (Johnson et al., 2005) was performed weekly. Participants earned $10 for travel at each visit during treatment and received an additional $10 weekly when they returned their medication bottles. In addition, participants could earn progressive weekly cash payments if they attended their study appointments. Starting at $2.50 for the first study visit, the value of the cash incentive for each subsequent consecutive visit is doubled to a maximum of $25. Failure to attend study appointments would reset the value of cash incentives back to their initial $2.50 from which the value would escalate again from the same schedule. Participants could earn a maximum of $562.50.
Cannabis use was recorded by the Timeline Followback (TLFB) method (Litten & Allen, 1992) modified for cannabis (Mariani et al., 2011). Besides recording a use day, these data also allowed for an estimate of the amount of cannabis used in dollars per day. The TLFB was conducted at baseline (providing self-reported substance use for the 28 days prior to study) and then at each subsequent visit throughout the study.
ADHD measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS) (T. J. Spencer et al., 2010) (score ranges from 0 to 54) and the Clinical Global Impression (CGI) improvement scale for ADHD (Guy, 1976), both collected at baseline and then weekly throughout the study.
The psychosocial intervention for this study was Medical Management (Anton et al., 2006; Pettinati et al., 2005), modified for cannabis dependence. Participants had a weekly supportive behavioral treatment session with the research psychiatrist. Medical Management facilitates compliance with study medication, study procedures, promotes abstinence from cannabis, and encourages mutual-support group attendance.
Study discontinuation criteria during study period included: (1) development of serious psychiatric symptoms as indicated by a CGI improvement score of 6 (much worse than baseline) or greater for 2 consecutive weeks; (2) continued cannabis use placing participant at risk for self-destructive behavior or other harm as indicated by a CGI improvement score of 6 (much worse than baseline) or greater for 2 consecutive weeks; (3) pregnancy; (4) cardiovascular instability as monitored by vital signs/visit and clinical evaluation defined as pulse at rest >100 or systolic blood pressure (SBP) at rest >140 or diastolic blood pressure (DBP) >90 mm Hg for more than 2 weeks would result in medication discontinuation or SBP > 160, DBP > 110, HR > 110 after sitting quietly for a period of time would result in immediate discontinuation of study medications; of note, if the participant has a pulse >100 or a SBP >140 mm Hg or DBP >90 mm Hg, the participant’s medication would be lowered. If medication adjustments did not result in normalization of pulse or blood pressure within 2 weeks then the medication was discontinued; (5) cardiac risks as defined as cardiovascular chest pain, fainting, or arrhythmias. Any cardiovascular concerns at screening or any cardiac-related adverse events or concerns resulted in a consultation with the study cardiologist. If a participant needed to be discontinued from medication, he or she was given the opportunity to continue with therapy as provided in the study and treated clinically by the study psychiatrist or referred to a more appropriate level of care as needed.
Analysis
All participants were randomized in blocks of two, four, and six with stratification by binarized AISRS (AISRS ≤ 35 vs. AISRS > 35) (Efrid, 2011). The randomized sequence was designed by an independent statistician and utilized by the research pharmacist. Participants and all other study staff were blind to treatment assignment.
Baseline characteristics were summarized by treatment group using means, standard deviations, medians, interquartile range, counts, and percentages as appropriate. Non-efficacy outcomes were retention, medication adherence (self-reported proportion of pills taken of those with pills prescribed the day before, staff recorded urine qualitative riboflavin fluorescence during days 8 to 77, and laboratory-determined urine amphetamine level during days 8–77), and tolerability. Retention was summarized using proportions of those who completed the maintenance phase of the study (Week 11), and time to dropout between treatment groups was compared using the log-rank test and Cox proportional hazards models, adjusting for the covariates of sex and binarized baseline ADHD symptoms. The Wilcoxon rank sum test was used to compare measures of adherence across treatment groups.
The primary cannabis use outcome was defined as abstinence as recorded by the Timeline Followback method, during the last 2 weeks of the participant’s involvement in the 8-week maintenance phase of the trial. Participants who dropped out before 2 weeks were considered non-abstinent. Secondary outcomes were weekly cannabis use in (a) dollar value and in (b) days of use, as well as (c) weekly creatine-normalized THC levels. The total number of positive urine samples, as measured by qualitative THC dip stick tests, was also analyzed and compared between treatment groups using a two-sample t-test.
The primary outcome for ADHD was defined as the percentage of participants who achieved at least a 30% reduction in symptom severity as measured by the adult ADHD Investigator Rating Scale (AISRS), from baseline to the last week of the participant’s involvement in the 8-week maintenance phase of the trial. A 50% reduction in AISRS from baseline to end of study enrollment was also analyzed as a post hoc exploratory outcome. Secondary outcomes included the weekly AISRS score and ADHD symptom improvement from baseline to last measurement assessed using the Clinical Global Impression scale (score of 1 [very much improved] or 2 [much improved]). If participants were missing CGI, they were imputed as not meeting the improvement threshold.
The primary outcome of cannabis use (last 2 weeks of abstinence) and secondary outcome of ADHD symptom improvement (CGI ≤ 2) were analyzed using logistic regression with predictors: treatment group (MAS-ER vs. placebo), binarized baseline ADHD symptoms (AISRS ≤ 35 vs AISRS > 35), sex (male vs. female), and the corresponding baseline, that is, average daily dollar value of cannabis in the 28 days prior to randomization for cannabis use outcome, ADHD ratings at consent (AISRS score), or CGI severity at consent. Because the primary cannabis use outcome, last 2 weeks of abstinence, was not achieved by any subject in the placebo group, logistic regression cannot produce a parameter estimate (odds ratio, OR) and the corresponding standard error for the effect of treatment group. Firth’s penalized approach (Firth, 1993) produces adjusted OR for the association between the primary outcome (with no observed events in placebo group) and treatment, using maximization of penalized likelihood function that guarantees that the parameter estimates are finite. Firth’s penalized approach produces adjusted Firth’s odds ratios and confidence intervals, while adjusting for the above-mentioned covariates. The primary outcome of at least 30% reduction in AISRS was compared between the treatment groups using Fisher’s exact test. The exploratory outcome of at least 50% reduction in AISRS was also compared between the treatment groups using Fisher’s exact test.
In the proposal, the power of the primary outcome was designed as follows: “The primary purpose of the proposed study is to estimate the 95% confidence interval for the effect size of ADHD and CUD measures of ADHD symptoms and marijuana use. The resulting 95% confidence interval provides considerably more information than testing a specific null hypothesis: it gives us a range of plausible parameter estimates for the difference of population proportion of abstinence in the final 2 weeks of the study between the MAS-ER and placebo groups. The following power calculations are only in support of the study proposal: with 20 participants per group, and assuming that the observed proportion meeting the primary outcome in the placebo group ranges from 10% to 25%, we have 80% power, at two-tailed α = .05, to detect an effect as follows: 10% on placebo vs. 48% on MAS-ER; 15% vs. 55%; 20% vs. 63%; or 25% vs. 69%.”
The distributions of all continuous secondary outcomes were checked for normality using histograms and descriptive statistics. Continuous secondary outcomes were analyzed using a generalized linear mixed effect model, with a random intercept to account for the between-subject variances and the appropriate link function using SAS PROC GLIMMIX. The interaction between study week (1–11; treated as continuous) and treatment group (MAS-ER vs. placebo), as well as the same covariates mentioned above, were included. The secondary cannabis use outcomes of weekly (a) dollar value, (b) number of use days, and (c) creatine-normalized THC followed a lognormal distribution.
All analyses were conducted using SAS® 9.4 and figures were made using R version 4.0.3; all hypothesis tests were on the intent-to-treat sample of all randomized participants and were two-sided tests with level of significance 5%.
Results
Participant Progress in Study and Demographics
In all, 451 participants were screened, 33 participants entered the trial, and a total of 28 participants (see CONSORT diagram, Figure 1) were randomized to either MAS-ER (n = 13; 46.4%) or placebo (n = 15; 53.6%). Recruitment began in July 2016 and ended in October 2019. Individuals who initiated screening were assessed for potential eligibility in any one of several ongoing CUD clinical trials. The most common reason for screen failure for this trial was not meeting eligibility criteria for having ADHD (n = 177). Characteristics of the randomized participants are shown in Table 1.
CONSORT Flow Diagram.
Demographic and Clinical Characteristics at Baseline by Treatment Group (n = 28).
Retention
The proportion of dropouts in the MAS-ER group was 46% (6/13) and 27% (4/15) in the placebo group. There was not a significant difference in time to dropout between treatment groups, according to the log-rank test (χ2(1) = 1.04, p = .31). Time to dropout throughout the 11-week trial was not significantly different between the MAS-ER and placebo groups (Hazard Ratio (treatment compared to placebo) = 0.56; 95% CI = 0.15, 2.14; p = .40), while controlling for sex (p = .88) and binarized baseline ADHD symptoms (p = .59).
Safety and Tolerability
There was one serious adverse event reported in the active medication arm of the trial. A participant was hospitalized overnight due to atrial fibrillation. He was given IV cardizem (10 mg) and discharged on metoprolol XR and baby aspirin. The study cardiologist determined that the arrhythmia was probably attributed to the study medication. The participant had been on a reduced dose of 20 mg due to increased anxiety, irritability and decreased appetite since week 2 of the trial. Prior to the hospitalization, as per protocol, all required ECGs for safety were conducted at screening and at weeks 4 and 8. Of note, his ECGs were within normal limits; week 8 ECG noted sinus bradycardia, otherwise normal. This SAE resulted in a protocol change outlining a more specific protocol for dose reductions of medication related AEs. For any AE of moderate intensity related to study medication, there would be a decrease in the dose of MAS-ER by 50%. For any AE of severe intensity related to study medication, the medication would be held and then slowly titrated up to the maximum tolerated dose if there was a resolution of symptoms.
Moderate to severe adverse events are described in Table 2. Fisher’s exact tests were performed and found no significant treatment differences in the proportion of moderate to severe adverse events. Insomnia was the most commonly reported adverse event (14.3%, 4/28), followed by anxiety (10.7%, 3/28) and chest pain, headaches, and nervousness (7.1%, 2/28).
Moderate to Severe Adverse Events.
Cannabis Use Outcomes
The proportion of participants who achieved last 2 weeks of abstinence was 15.4% (2/13) for those receiving MAS-ER and 0% (0/15) for those receiving placebo (see Figure 2B). The treatment effect was not significant (Firth’s odds ratio (F-OR) = 4.7, 95% confidence interval, 95% CI [0.31, 72.1]; p = .27), while adjusted by baseline cannabis use, sex, and binarized baseline ADHD symptoms. Baseline cannabis use (F-OR = 1.0, 95% CI [0.97, 1.0]; p = .94), sex (F-OR = 0.89, 95% CI [0.03, 32.4]; p = .95), and binarized baseline ADHD symptoms (F-OR = 1.1, 95% CI [0.11, 12.2]; p = .91) were not significantly associated with the primary outcome.
(A) Observed proportion of participants with at least 30% AISRS reduction (B) Observed proportion with final 2 weeks abstinent (C) Model-estimated Marijuana Use in dollar value over time ± one standard error (D) Model-estimated Marijuana Use in number of use days ± one standard error (E) Model-estimated Creatine-normalized THC over time ± one standard error.
The longitudinal mixed effect model using lognormal distribution to model the weekly cannabis use in dollars showed a significant treatment by week interaction effect (p = .0016), while adjusting for baseline average daily dollar value, sex, and binarized baseline ADHD symptoms. (see Figure 2C). The MAS-ER group showed a significant decrease in cannabis use dollars with each week in the study by 26.6% (unstandardized beta (b) = −0.31, standard error (SE) = 0.06; p < .0001), compared to the placebo group, which did not change significantly with each week (6.8%; b = −0.07, SE = 0.05; p = .11). Similar results were found for the weekly cannabis use in days. There was a significant treatment by week interaction effect (p = .0005), while adjusting for baseline number of use days, sex, and binarized baseline ADHD symptoms (see Figure 2D). The MAS-ER group showed a significant decrease in cannabis use with each week in the study by 23.3% (b = −0.27, SE = 0.05; p < .0001), compared to the placebo group, which did not change significantly with each week (3.5%; b = −0.04, SE = 0.04; p = 0.39).
Urine THC was assessed twice a week during the 11-week trial. The mean number of positive tests was 15.0 in the placebo group and 10.9 in the MAS-ER group. The median (interquartile range [IQR]) number of positive tests was 13 (7–23) in the placebo group and 11 (3–16) in treatment group. The two-sample t-test under assumption of equal variances shows that the mean number positive urine tests for THC was not significantly different between groups (p = .19). The longitudinal mixed effect model using lognormal distribution to model mean weekly creatine-normalized THC showed no significant treatment by week interaction effect (p = 0.64). When the interaction term was removed from the model, there was no significant difference between treatment groups (p = 0.36), but there was a significant effect of week observed (p = 0.028), with both groups significantly decreasing in creatine-normalized THC with each week in the study by 3.2% (b = −0.03, SE = 0.01; see Figure 2E).
ADHD Outcome
On average, the change in AISRS score was 15.79 (SD = 9.94) in the placebo group and 19.25 (10.97) in the MAS-ER group. The proportion of subjects who achieved at least 30% reduction in AISRS score was not significantly different between the placebo (71.4%, 10/14) and the MAS-ER (83.3%, 10/12) group (Fisher exact test p = .65; see Figure 2A). Under a more stringent definition of improvement, the proportion of subjects who achieved at least 50% reduction in AISRS score was also not significantly different between the placebo (35.7%, 5/14) and the MAS-ER (66.7%, 8/12) group (Fisher exact test p = .64).
Longitudinal mixed effect model of the weekly continuous AISRS score did not show any significant differences between groups during the trial; the arm by week interaction (p = .13) was not significant while adjusting for baseline AISRS (p = .02), gender (p = .91), and binarized baseline ADHD symptoms (p = .27). The model-estimated change in AISRS score from baseline (Week 0) to Week 11 was not significantly different (p = .87) between treatment groups: −21.18 in the placebo group compared to −21.80 in the MAS-ER group.
For the secondary outcome of ADHD symptom improvement, the proportion of participants with improvement (CGI score of 1–2) during the last week of the study (or dropout week) was 50% (7/14) in the placebo group and 53.9% (7/13) in the MAS-ER group. The treatment effect was not significant (OR = 0.43, 95% CI [0.06, 3.08]; p = .40), while adjusted by baseline CGI severity (OR = 2.96, 95% CI [0.53, 16.6]; p = .22), sex (OR = 0.06, 95% CI [0.003, 1.02]; p = .05) and binarized baseline ADHD symptoms (OR = 0.56, 95% CI [0.095, 3.32]; p = .53).
Medication Adherence
Treatment groups also did not significantly differ by the proportion of pills taken. The median average proportion of pills taken in the placebo group (n = 14) was 93.2% compared to 100.0% in the treatment group (n = 13). These proportions were not significantly different (Z = 1.37, p = .17). There was no treatment difference in the proportion of subjects with dose discontinuations (Fisher’s exact test p = .09; placebo: 0%, 0/15; MAS-ER: 23%, 3/13) or dose reductions (Fisher’s exact test p = .37; placebo: 13%, 2/15; MAS-ER: 31%, 4/13).
The final dose (mg/day) following any adjustments or prior to medication discontinuation or final taper was not significantly different between the placebo (median = 80, interquartile range (IQR) = 50–80) and MAS-ER (median = 60, IQR = 20–80) groups (Z = 1.56, p = .12).
Median (interquartile range) percentages of samples that fluoresced for riboflavin were 73% (37%–88%) for the MAS-ER group and 80% (50%–95%) for the placebo group (Z = −1.37; p = .17). Median percentage of samples positive for amphetamine per participant in the treatment group was 55% (IQR = 37%–87%).
Discussion
Extended-release mixed amphetamine salts (MAS-ER) administered in robust doses, was not superior to placebo in reducing ADHD symptoms by at least 30% or promoting abstinence from cannabis; the two primary outcomes of this pilot study. For two secondary outcomes, reduction in weekly days of use and weekly dollar spent over time, the MAS-ER group had a significant reduction over time whereas the placebo arm did not. Notably, there was no clinically concerning increase in problematic use of alcohol or other illicit substances during the course of the trial (data not presented). Overall retention rate was consistent with other similar studies, with no significant difference across the two treatment arms. The medication was well-tolerated without significant differences in moderate or severe adverse events in the two treatment arms. This is consistent with stimulant medication trials conducted in adults with ADHD alone (Groenman et al., 2017; Weisler et al., 2005) or stimulants (e.g., methylphenidate, pemoline) for adolescents with ADHD and CUD (Riggs et al., 2004, 2011).
Similar to our earlier studies with adults with cocaine use disorder with and without ADHD (Levin et al., 2015, 2020; Mariani et al., 2011), we chose to use high dosing of MAS-ER. This methodologic decision was to ensure that there was an adequate exposure of medication given that earlier trials with stimulant medication with low bioavailability and standard dosing were less likely to produce a superior improvement in the ADHD symptoms or stimulant use (Konstenius et al., 2010; Levin et al., 2006, 2007). While the medication was well-tolerated, with a median dose of 60 mg; this did not produce a superior outcome in the primary outcome. In retrospect, we might have considered reduction in frequency of days used or daily amount of use for this pilot study. There is no established primary outcome for treatment trials for cannabis use. At the time this study was initiated, there was a focus on abstinence for substance use disorder trials which may be an unreasonably high bar to assess efficacy. The field has increasingly endorsed reduction in use as a reasonable and potentially clinically meaningful outcome (Brezing & Levin, 2018). This is reflected in more recent studies, including our own (Freeman et al., 2020; Levin et al., 2021; Lintzeris et al., 2019; Mariani et al., 2021).
One question that arose after the pilot study was conducted was whether the 30% improvement was an adequate measure of improvement. While this is a common outcome measure in adult ADHD treatment trials (Spencer et al., 2001; Wilens et al., 2005), it may not be ideal for trials conducted in active substance users. T. E. Wilens et al. (2011) found that ADHD symptoms are exacerbated by alcohol use and reduction of alcohol or perhaps other drug use, may reduce some of the ADHD symptomatology but not substantially. Further, the intensive structure of the study along with medication management with an experienced psychiatrist may have contributed to improvement of ADHD symptoms. Based on this, we conducted an exploratory analysis using 50% reduction in ADHD symptoms comparing baseline to end of study; a common percentage used to assess depressive symptoms in trials evaluating antidepressants (Zhang et al., 2022). We found that 35.7% of the placebo arm and 66.7% of the MAS-ER arm met this criterion. While this is a notable difference in the treatment arms, it was not significant.
An important aim of this study was to assess the tolerability of MAS-ER 80 mg per day in adults with CUD and ADHD. While there have been a number of trials assessing amphetamine formulations for adults with stimulant use disorders with and without ADHD (Tardelli et al., 2020), there has not been, to our knowledge, a randomized clinical trial that has assessed amphetamine formulations as a treatment for adults with CUD and ADHD. Although the protocol was designed to titrate participants up to 80 mg MAS-ER a day, dose reductions due to side effects or protocol-driven requirements in systolic or diastolic blood pressure or heart rate safety parameters resulted in a median dose of 60 mg/day.
Throughout this trial, risks to participants were mitigated by close monitoring of vital signs, assessment of cardiovascular symptoms, and weekly meetings with a psychiatrist to assess psychiatric symptoms. There was one serious adverse event in the active treatment arm (atrial fibrillation) that was deemed study-related. Although we have not had this occur with any of our prior studies with stimulant users where amphetamine or methylphenidate formulations were administered (Levin et al., 2006, 2007, 2015, 2020; Mariani et al., 2011), and this was a singular event in this pilot trial, it emphasizes the need to use these medications cautiously with close cardiovascular monitoring as well as attend to other cardiovascular risk factors prior to initiating stimulant medication.
Another concern of prescribing stimulant medication is the risk of misuse and diversion (Faraone et al., 2020). Nonmedical use is common in young adults in the general population (“National Survey on Drug Use and Health”, 2020). Moreover, among those receiving stimulant medication for ADHD, misuse is greater among those who are simultaneously using alcohol or other psychoactive substances (Wilens et al., 2016). However, the risk of misuse of prescription stimulants among those seeking treatment for both their substance use disorder and ADHD may be low. Whereas adolescents in the Riggs et al. (2011) trial were more likely to lose their medication than adults with ADHD and nicotine use disorder in another trial (Winhusen et al., 2011), lost medication was no different for the active treatment (OROS-MPH) and placebo arms for the two trials. This suggests that adolescents and adults in active treatment for their ADHD and substance use disorder are not typically diverting or misusing their medication. Similarly, we did not have any evidence of participants in this trial misusing or diverting their medication.
In our trial we found that typically, 55% of urine samples were positive for amphetamines for participants in the active treatment arm. Regardless of whether a participant reported that they missed doses or ran out of pills because they missed repeated appointments, urines were tested for amphetamine; thus, this percentage may have underestimated medication adherence in this group. However, lower than optimal adherence may have occurred because participants did not like how the medication “made them feel” or experienced persistent adverse effects. Even so, this percentage is similar or higher than rates found in other pharmacologic treatment trials targeting those with stimulant use disorders when objective measures are used (Coffin et al., 2020; Heinzerling et al., 2014). Despite this, we cannot be sure that most of the participants were taking their medication as prescribed but risk of diversion and misuse was likely to be mitigated by giving our participants a long-acting formulation that has slower absorption and elimination rates compared to immediate release preparations (Heal et al., 2013; Mao et al., 2011; Weisler & Childress, 2011) and that they were closely monitored and only received one-week supply of medication at a time.
Limitations
There are several limitations with this pilot, feasibility trial. The sample size was small which limited the power to detect differences between study groups. Future studies might enhance recruitment by evaluating participants interested in trials targeting ADHD and engage those who have a concomitant CUD. A second limitation is that we enrolled individuals who had an AISRS of >22, which is lower than industry sponsored trials. The lower score may have contributed to the high placebo response; although this is somewhat mitigated in that the mean AISRS score was 33.5 for the placebo arm and 33.9 for the active medication arm. Third, the robust psychotherapeutic platform may have elevated the placebo ADHD response rate. While this was a purported issue with another trial targeting adolescents with substance use disorders (mostly cannabis use disorder) and ADHD (Riggs et al., 2011), we did not find such a high ADHD placebo response rate in a previous trial targeting adults with cocaine use disorder and ADHD (Levin et al., 2015) as we did in this trial.
A fourth limitation was the high drop-out rate. While this is not unique to this trial, retention in the trial might have been enhanced if we provided progressive payments for attendance that continued to escalate over the course of the entire trial. While some may argue that using a low intensity psychosocial intervention might have impacted retention, rates of retention in prior trials using cognitive behavioral interventions do not fare better. Finally, since only a minority of patients with ADHD have a CUD, and similarly only a small percentage of those with CUD have ADHD, the overall generalizability is limited. However, since there are no FDA-approved medications for CUD, focusing on a subpopulation that might benefit from a targeted intervention is a rational approach.
Conclusions
In summary, the present trial finds that: (1) patients with ADHD and CUD tolerated MAS-ER combined with medication enhancement therapy; (2) administration of MAS-ER did not produce higher rates of abstinence or a greater percentage of individuals who had at least a 30% improvement in ADHD symptoms. Future research might want to use more research sites or use other recruitment strategies to engage adults with ADHD and CUD to better assess the potential utility of treating ADHD among adults with CUD.
Footnotes
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Frances R. Levin receives research support from NCATS, SAMHSA, US World Meds, and Aelis Pharmaceuticals. She also receives medication from Indivior for research and royalties from APA publishing. In addition, Dr. Levin served as a nonpaid member of a Scientific Advisory Board for Alkermes, Indivior, Novartis, Teva, and US WorldMeds and is a consultant to Major League Baseball. John J Mariani has served as a consultant to Indivior, Inc. Martina Pavlicova has no conflicts to report. C. Jean Choi has no conflicts to report. Cale Basaraba has no conflicts to report. Amy L. Mahony has no conflicts to report. Daniel J. Brooks has no conflicts to report. Christina A. Brezing has no conflicts to report. Nasir Naqvi has no conflicts to report.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute on Drug Abuse/NIH [NIDA U54DA0378421]. The authors are solely responsible for the collection, analysis, interpretation of data and the content of this manuscript.
