Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial
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| Title: | Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial |
|---|---|
| Language: | English |
| Authors: | Frances R. Levin (ORCID |
| Source: | Journal of Attention Disorders. 2024 28(11):1467-1481. |
| Availability: | SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com |
| Peer Reviewed: | Y |
| Page Count: | 15 |
| Publication Date: | 2024 |
| Document Type: | Journal Articles Reports - Research |
| Descriptors: | Comorbidity, Attention Deficit Hyperactivity Disorder, Marijuana, Drug Abuse, Drug Therapy, Stimulants, Randomized Controlled Trials, Outcomes of Treatment, Sample Size, Symptoms (Individual Disorders), Pilot Projects, Compliance (Psychology) |
| Geographic Terms: | New York |
| DOI: | 10.1177/10870547241264675 |
| ISSN: | 1087-0547 1557-1246 |
| 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: [greater than or equal to] 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 = 0.65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = 0.27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < 0.0001). 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. |
| Abstractor: | As Provided |
| Entry Date: | 2024 |
| Accession Number: | EJ1436085 |
| Database: | ERIC |
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| FullText | Links: – Type: pdflink Url: https://content.ebscohost.com/cds/retrieve?content=AQICAHj0k_4E0hTGH8RJwT4gCJyBsGNe_WN95AvKlDbXJGqwxwFOmr5bGJPkxGioMtqmiEQjAAAA4TCB3gYJKoZIhvcNAQcGoIHQMIHNAgEAMIHHBgkqhkiG9w0BBwEwHgYJYIZIAWUDBAEuMBEEDMg_srtPy1AI-1YgBQIBEICBmQMhit5OIv0jnuG53pTCvfv4hv9trux0LIyR_-iIIZtgYkhtHlE1nHiJw77FH8KAfeLpoo4e4uMJ8nIT0o00EVrHlrBhyx34WpRruZqzG1ZT2bDmmOHW044GF7FrdBpB7Yc5Hv1719VsXImRfmpAiCr8-75_ucZtFNV7Na50GJ8WTftHcPQVcot-GK_-E0S_JOAp1uqK14S_Xg== Text: Availability: 1 Value: <anid>AN0179022151;gs001sep.24;2024Aug19.05:24;v2.2.500</anid> <title id="AN0179022151-1">Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial </title> <p>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 &lt;.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.</p> <p>Keywords: cannabis use disorder; adult ADHD; adult ADHD treatment; substance abuse</p> <hd id="AN0179022151-2">Introduction</hd> <p>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) ([<reflink idref="bib20" id="ref1">20</reflink>]; [<reflink idref="bib44" id="ref2">44</reflink>]; [<reflink idref="bib50" id="ref3">50</reflink>]; [<reflink idref="bib58" id="ref4">58</reflink>]). Up to 40% of adolescents entering treatment for their CUD ([<reflink idref="bib49" id="ref5">49</reflink>]) 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 ([<reflink idref="bib5" id="ref6">5</reflink>]; [<reflink idref="bib10" id="ref7">10</reflink>]; [<reflink idref="bib27" id="ref8">27</reflink>]; [<reflink idref="bib57" id="ref9">57</reflink>]).</p> <p>While there is substantial literature evaluating medications for child and adolescent and adult ADHD ([<reflink idref="bib6" id="ref10">6</reflink>]; [<reflink idref="bib11" id="ref11">11</reflink>]), and a growing literature of placebo-controlled randomized pharmacologic trials targeting CUD alone ([<reflink idref="bib3" id="ref12">3</reflink>]), 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 ([<reflink idref="bib41" id="ref13">41</reflink>], [<reflink idref="bib42" id="ref14">42</reflink>]) and two have evaluated atomoxetine in adolescents and adults ([<reflink idref="bib36" id="ref15">36</reflink>]; [<reflink idref="bib48" id="ref16">48</reflink>]). Amphetamine formulations have yet to be studied.</p> <p>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 ([<reflink idref="bib41" id="ref17">41</reflink>]). 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) ([<reflink idref="bib42" id="ref18">42</reflink>]). 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.</p> <p>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 ([<reflink idref="bib4" id="ref19">4</reflink>]). 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 ([<reflink idref="bib30" id="ref20">30</reflink>]). 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 ([<reflink idref="bib23" id="ref21">23</reflink>], [<reflink idref="bib24" id="ref22">24</reflink>]).</p> <p>In the study conducted by [<reflink idref="bib30" id="ref23">30</reflink>] approximately half the sample of adults with ADHD and cocaine use disorder were regular cannabis users. In a secondary analysis of this study, [<reflink idref="bib38" id="ref24">38</reflink>] 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 ([<reflink idref="bib30" id="ref25">30</reflink>], [<reflink idref="bib29" id="ref26">29</reflink>]; [<reflink idref="bib34" id="ref27">34</reflink>]) but there has not been an evaluation of stimulant medication in adults with ADHD and CUD.</p> <p>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.</p> <hd id="AN0179022151-3">Methods</hd> <p></p> <hd id="AN0179022151-4">Participants</hd> <p>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 ([<reflink idref="bib1" id="ref28">1</reflink>]) for CUD and adult ADHD based on the MINI-International Neuropsychiatric Interview ([<reflink idref="bib43" id="ref29">43</reflink>]) and an amended version of The Diagnostic Interview for ADHD in Adults 2.0 (DIVA 2.0) ([<reflink idref="bib40" id="ref30">40</reflink>]) which utilized DSM-5 criteria. Both were performed as part of a comprehensive psychiatric and medical evaluation.</p> <p>Study inclusion criteria required participants to be: (<reflink idref="bib1" id="ref31">1</reflink>) ages 18 to 65 and capable of giving informed consent and of complying with study procedures; (<reflink idref="bib2" id="ref32">2</reflink>) meeting DSM-5 diagnosis for current CUD and adult ADHD; (<reflink idref="bib3" id="ref33">3</reflink>) 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 (<reflink idref="bib4" id="ref34">4</reflink>) having a score &gt;22 on the Adult ADHD Investigator Symptom Rating Scale (AISRS) ([<reflink idref="bib46" id="ref35">46</reflink>]).</p> <p>Participants were excluded if they: (<reflink idref="bib1" id="ref36">1</reflink>) 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 &gt;17 ([<reflink idref="bib17" id="ref37">17</reflink>]) (considered moderate to severe depression) were excluded. Individuals with baseline Clinical Global Impression Rating (CGI) &gt;4 for Other Psychiatric Disorders ([<reflink idref="bib16" id="ref38">16</reflink>]) were excluded (HAM-D and CGI parameters were added after study commencement); (<reflink idref="bib2" id="ref39">2</reflink>) were medically unstable that would make participation hazardous; (<reflink idref="bib3" id="ref40">3</reflink>) use of synthetic cannabinoids in the past month and meeting CUD diagnosis based on synthetic cannabinoids use alone in the past year; (<reflink idref="bib4" id="ref41">4</reflink>) had liver enzyme function tests greater than three times normal; (<reflink idref="bib5" id="ref42">5</reflink>) had systolic blood pressure (SBP) &gt; 140; diastolic blood pressure (DBP) &gt;90; pulse &gt;100 (participants who have BP and pulse below these parameters on stable antihypertensive medication were included); (<reflink idref="bib6" id="ref43">6</reflink>) 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; (<reflink idref="bib7" id="ref44">7</reflink>) 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); (<reflink idref="bib8" id="ref45">8</reflink>) had cognitive impairment that would impede study participation; (<reflink idref="bib9" id="ref46">9</reflink>) had a known sensitivity/allergy to MAS-ER or amphetamine analogs; (<reflink idref="bib10" id="ref47">10</reflink>) had a history of amphetamine use disorders, including amphetamines such as methamphetamine and MDMA; (<reflink idref="bib11" id="ref48">11</reflink>) had current cocaine use disorder; (<reflink idref="bib12" id="ref49">12</reflink>) were mandated to treatment; and (<reflink idref="bib13" id="ref50">13</reflink>) 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.</p> <hd id="AN0179022151-5">Procedures</hd> <p>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.</p> <p>Medication adherence was assessed by (<reflink idref="bib1" id="ref51">1</reflink>) self-report with pill count, (<reflink idref="bib2" id="ref52">2</reflink>) from urine quantification of amphetamines (not available to blinded study staff), and (<reflink idref="bib3" id="ref53">3</reflink>) urine riboflavin using quantitative fluorometry (available to study staff) ([<reflink idref="bib8" id="ref54">8</reflink>]; [<reflink idref="bib21" id="ref55">21</reflink>]). 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.</p> <p>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) ([<reflink idref="bib22" id="ref56">22</reflink>]) 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.</p> <p>Cannabis use was recorded by the Timeline Followback (TLFB) method ([<reflink idref="bib32" id="ref57">32</reflink>]) modified for cannabis ([<reflink idref="bib34" id="ref58">34</reflink>]). 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.</p> <p>ADHD measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS) ([<reflink idref="bib46" id="ref59">46</reflink>]) (score ranges from 0 to 54) and the Clinical Global Impression (CGI) improvement scale for ADHD ([<reflink idref="bib16" id="ref60">16</reflink>]), both collected at baseline and then weekly throughout the study.</p> <p>The psychosocial intervention for this study was Medical Management ([<reflink idref="bib2" id="ref61">2</reflink>]; [<reflink idref="bib39" id="ref62">39</reflink>]), 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.</p> <p>Study discontinuation criteria during study period included: (<reflink idref="bib1" id="ref63">1</reflink>) development of serious psychiatric symptoms as indicated by a CGI improvement score of 6 (much worse than baseline) or greater for 2 consecutive weeks; (<reflink idref="bib2" id="ref64">2</reflink>) 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; (<reflink idref="bib3" id="ref65">3</reflink>) pregnancy; (<reflink idref="bib4" id="ref66">4</reflink>) cardiovascular instability as monitored by vital signs/visit and clinical evaluation defined as pulse at rest &gt;100 or systolic blood pressure (SBP) at rest &gt;140 or diastolic blood pressure (DBP) &gt;90 mm Hg for more than 2 weeks would result in medication discontinuation or SBP &gt; 160, DBP &gt; 110, HR &gt; 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 &gt;100 or a SBP &gt;140 mm Hg or DBP &gt;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; (<reflink idref="bib5" id="ref67">5</reflink>) 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.</p> <hd id="AN0179022151-6">Analysis</hd> <p>All participants were randomized in blocks of two, four, and six with stratification by binarized AISRS (AISRS ≤ 35 vs. AISRS &gt; 35) ([<reflink idref="bib9" id="ref68">9</reflink>]). 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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>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 &gt; 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 ([<reflink idref="bib13" id="ref69">13</reflink>]) 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.</p> <p>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%."</p> <p>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.</p> <p>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%.</p> <hd id="AN0179022151-7">Results</hd> <p></p> <hd id="AN0179022151-8">Participant Progress in Study and Demographics</hd> <p>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 (<emph>n</emph> = 13; 46.4%) or placebo (<emph>n</emph> = 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 (<emph>n</emph> = 177). Characteristics of the randomized participants are shown in Table 1.</p> <p>Graph: Figure 1. CONSORT Flow Diagram.</p> <p>Table 1. Demographic and Clinical Characteristics at Baseline by Treatment Group (n = 28).</p> <p>Graph</p> <p> <ephtml> &lt;table&gt;&lt;colgroup&gt;&lt;col align="left" /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;/colgroup&gt;&lt;thead&gt;&lt;tr&gt;&lt;th align="left" rowspan="2"&gt;Characteristic&lt;/th&gt;&lt;th align="center" colspan="2"&gt;Total sample (&lt;italic&gt;n&lt;/italic&gt; = 28)&lt;/th&gt;&lt;th align="center" colspan="2"&gt;Placebo (&lt;italic&gt;n&lt;/italic&gt; = 15)&lt;/th&gt;&lt;th align="center" colspan="2"&gt;MAS-ER (&lt;italic&gt;n&lt;/italic&gt; = 13)&lt;/th&gt;&lt;/tr&gt;&lt;tr&gt;&lt;th align="center"&gt;&lt;italic&gt;n&lt;/italic&gt;&lt;/th&gt;&lt;th align="center"&gt;Mean (&lt;italic&gt;SD&lt;/italic&gt;) or %&lt;/th&gt;&lt;th align="center"&gt;&lt;italic&gt;n&lt;/italic&gt;&lt;/th&gt;&lt;th align="center"&gt;Mean (&lt;italic&gt;SD&lt;/italic&gt;) or %&lt;/th&gt;&lt;th align="center"&gt;&lt;italic&gt;n&lt;/italic&gt;&lt;/th&gt;&lt;th align="center"&gt;Mean (&lt;italic&gt;SD&lt;/italic&gt;) or %&lt;/th&gt;&lt;/tr&gt;&lt;/thead&gt;&lt;tbody&gt;&lt;tr&gt;&lt;td colspan="7"&gt;Demographics&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Strata&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; AISRS &amp;#8804; 35&lt;/td&gt;&lt;td&gt;16&lt;/td&gt;&lt;td&gt;57.1%&lt;/td&gt;&lt;td&gt;9&lt;/td&gt;&lt;td&gt;60.0%&lt;/td&gt;&lt;td&gt;7&lt;/td&gt;&lt;td&gt;53.8%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; AISRS &amp;#62; 35&lt;/td&gt;&lt;td&gt;12&lt;/td&gt;&lt;td&gt;42.9%&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;40.0%&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;46.2%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Age&lt;/td&gt;&lt;td&gt;28&lt;/td&gt;&lt;td&gt;32.9 (10.2)&lt;/td&gt;&lt;td&gt;15&lt;/td&gt;&lt;td&gt;33.3 (9.5)&lt;/td&gt;&lt;td&gt;13&lt;/td&gt;&lt;td&gt;32.4 (11.2)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Gender&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Male&lt;/td&gt;&lt;td&gt;22&lt;/td&gt;&lt;td&gt;78.6%&lt;/td&gt;&lt;td&gt;10&lt;/td&gt;&lt;td&gt;66.7%&lt;/td&gt;&lt;td&gt;12&lt;/td&gt;&lt;td&gt;92.3%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Female&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;21.4%&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;33.3%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;7.7%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Race&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Black&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;17.9%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;15.4%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Native Hawaiian&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;7.1%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;6.7%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;7.7%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; White&lt;/td&gt;&lt;td&gt;13&lt;/td&gt;&lt;td&gt;46.4%&lt;/td&gt;&lt;td&gt;8&lt;/td&gt;&lt;td&gt;53.3%&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;38.5%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Multiracial&lt;/td&gt;&lt;td&gt;8&lt;/td&gt;&lt;td&gt;28.6%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;38.5%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Ethnicity&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Hispanic/Latino&lt;/td&gt;&lt;td&gt;11&lt;/td&gt;&lt;td&gt;39.3%&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;33.3%&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;46.2%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Not Hispanic/Latino&lt;/td&gt;&lt;td&gt;17&lt;/td&gt;&lt;td&gt;60.7%&lt;/td&gt;&lt;td&gt;10&lt;/td&gt;&lt;td&gt;66.7%&lt;/td&gt;&lt;td&gt;7&lt;/td&gt;&lt;td&gt;53.8%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Education&lt;/td&gt;&lt;td&gt;28&lt;/td&gt;&lt;td&gt;14.4 (1.8)&lt;/td&gt;&lt;td&gt;15&lt;/td&gt;&lt;td&gt;14.8 (1.6)&lt;/td&gt;&lt;td&gt;13&lt;/td&gt;&lt;td&gt;14 (2.0)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Marital status&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Single&lt;/td&gt;&lt;td&gt;18&lt;/td&gt;&lt;td&gt;64.3%&lt;/td&gt;&lt;td&gt;10&lt;/td&gt;&lt;td&gt;66.7%&lt;/td&gt;&lt;td&gt;8&lt;/td&gt;&lt;td&gt;61.5%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Married/living w partner&lt;/td&gt;&lt;td&gt;8&lt;/td&gt;&lt;td&gt;28.6%&lt;/td&gt;&lt;td&gt;4&lt;/td&gt;&lt;td&gt;26.7%&lt;/td&gt;&lt;td&gt;4&lt;/td&gt;&lt;td&gt;30.8%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Separated&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;3.6%&lt;/td&gt;&lt;td&gt;0&lt;/td&gt;&lt;td&gt;0.0%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;7.7%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Divorced&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;3.6%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;6.7%&lt;/td&gt;&lt;td&gt;0&lt;/td&gt;&lt;td&gt;0.0%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; Employment status&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Full time&lt;/td&gt;&lt;td&gt;11&lt;/td&gt;&lt;td&gt;39.3%&lt;/td&gt;&lt;td&gt;7&lt;/td&gt;&lt;td&gt;46.7%&lt;/td&gt;&lt;td&gt;4&lt;/td&gt;&lt;td&gt;30.8%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Part time&lt;/td&gt;&lt;td&gt;8&lt;/td&gt;&lt;td&gt;28.6%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;38.5%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Student&lt;/td&gt;&lt;td&gt;4&lt;/td&gt;&lt;td&gt;14.3%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;13.3%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;15.4%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Temporarily out of work&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;10.7%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;6.7%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;15.4%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Unemployed&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;3.6%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;6.7%&lt;/td&gt;&lt;td&gt;0&lt;/td&gt;&lt;td&gt;0.0%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Other&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;3.6%&lt;/td&gt;&lt;td&gt;1&lt;/td&gt;&lt;td&gt;6.7%&lt;/td&gt;&lt;td&gt;0&lt;/td&gt;&lt;td&gt;0.0%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt; ADHD diagnosis&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Combined type&lt;/td&gt;&lt;td&gt;12&lt;/td&gt;&lt;td&gt;42.9%&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;40.0%&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;46.2%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Predominantly hyperactive-impulsive&lt;/td&gt;&lt;td&gt;6&lt;/td&gt;&lt;td&gt;21.4%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;23.1%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Predominantly inattentive&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;17.9%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;15.4%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Other Specified&lt;/td&gt;&lt;td&gt;5&lt;/td&gt;&lt;td&gt;17.9%&lt;/td&gt;&lt;td&gt;3&lt;/td&gt;&lt;td&gt;20.0%&lt;/td&gt;&lt;td&gt;2&lt;/td&gt;&lt;td&gt;15.4%&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td colspan="7"&gt;Cannabis Use in the past 28 days&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Total using days&lt;/td&gt;&lt;td&gt;28&lt;/td&gt;&lt;td&gt;27.1 (1.4)&lt;/td&gt;&lt;td&gt;15&lt;/td&gt;&lt;td&gt;26.9 (1.7)&lt;/td&gt;&lt;td&gt;13&lt;/td&gt;&lt;td&gt;27.3 (1.1)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Median (IQR)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;28 (26.5, 28.0)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;28 (26, 28)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;28 (27, 28)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Average daily dollars&lt;/td&gt;&lt;td&gt;28&lt;/td&gt;&lt;td&gt;29.9 (35.2)&lt;/td&gt;&lt;td&gt;15&lt;/td&gt;&lt;td&gt;25.2 (25)&lt;/td&gt;&lt;td&gt;13&lt;/td&gt;&lt;td&gt;35.3 (44.7)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Median (IQR)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;19.2 (8.9, 35.5)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;17.3 (7.8, 30.0)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;21.0 (10.0, 45.0)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Average daily grams&lt;/td&gt;&lt;td&gt;26&lt;/td&gt;&lt;td&gt;2.3 (2.6)&lt;/td&gt;&lt;td&gt;14&lt;/td&gt;&lt;td&gt;1.7 (1.5)&lt;/td&gt;&lt;td&gt;12&lt;/td&gt;&lt;td&gt;3.0 (3.4)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt; Median (IQR)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;1.4 (0.54, 2.8)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;1.4 (0.5, 2.4)&lt;/td&gt;&lt;td /&gt;&lt;td&gt;1.4 (0.83, 4.6)&lt;/td&gt;&lt;/tr&gt;&lt;/tbody&gt;&lt;/table&gt; </ephtml> </p> <hd id="AN0179022151-9">Retention</hd> <p>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(<reflink idref="bib1" id="ref70">1</reflink>) = 1.04, <emph>p</emph> =.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; <emph>p</emph><emph>=</emph>.40), while controlling for sex (<emph>p</emph> =.88) and binarized baseline ADHD symptoms (<emph>p</emph> =.59).</p> <hd id="AN0179022151-10">Safety and Tolerability</hd> <p>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.</p> <p>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).</p> <p>Table 2. Moderate to Severe Adverse Events.</p> <p>Graph</p> <p> <ephtml> &lt;table&gt;&lt;colgroup&gt;&lt;col align="left" /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;col align="char" char="." /&gt;&lt;/colgroup&gt;&lt;thead&gt;&lt;tr&gt;&lt;th align="left"&gt;Adverse event&lt;/th&gt;&lt;th align="center"&gt;Total (&lt;italic&gt;N&lt;/italic&gt; = 28) &lt;italic&gt;n&lt;/italic&gt; (%)&lt;/th&gt;&lt;th align="center"&gt;Placebo (&lt;italic&gt;n&lt;/italic&gt; = 15) &lt;italic&gt;n&lt;/italic&gt; (%)&lt;/th&gt;&lt;th align="center"&gt;MAS-ER (&lt;italic&gt;n&lt;/italic&gt; = 13) &lt;italic&gt;n&lt;/italic&gt; (%)&lt;/th&gt;&lt;th align="center"&gt;Fisher's exact test &lt;italic&gt;p&lt;/italic&gt;-value&lt;/th&gt;&lt;/tr&gt;&lt;/thead&gt;&lt;tbody&gt;&lt;tr&gt;&lt;td&gt;Insomnia&lt;/td&gt;&lt;td&gt;4 (14.3)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;3 (23.1)&lt;/td&gt;&lt;td&gt;.311&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Anxiety&lt;/td&gt;&lt;td&gt;3 (10.7)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;2 (15.4)&lt;/td&gt;&lt;td&gt;.583&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Chest pain&lt;/td&gt;&lt;td&gt;2 (7.1)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;2 (15.4)&lt;/td&gt;&lt;td&gt;.206&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Headache&lt;/td&gt;&lt;td&gt;2 (7.1)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;1.000&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Nervousness&lt;/td&gt;&lt;td&gt;2 (7.1)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;1.000&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Anorexia&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Arm numbness&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Atrial fibrillation&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Backache&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Cramps&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1.000&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Dizziness&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Erectile dysfunction&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Increased blood pressure&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Irritable&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Jittery&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Psychomotor agitation&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1.000&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Shortness of breath&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Tremor&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Upper respiratory infection&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;1 (6.7)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1.000&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Weight decrease&lt;/td&gt;&lt;td&gt;1 (3.6)&lt;/td&gt;&lt;td&gt;0 (0.0)&lt;/td&gt;&lt;td&gt;1 (7.7)&lt;/td&gt;&lt;td&gt;.464&lt;/td&gt;&lt;/tr&gt;&lt;/tbody&gt;&lt;/table&gt; </ephtml> </p> <hd id="AN0179022151-11">Cannabis Use Outcomes</hd> <p>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]; <emph>p</emph> =.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]; <emph>p</emph> =.94), sex (F-OR = 0.89, 95% CI [0.03, 32.4]; <emph>p</emph> =.95), and binarized baseline ADHD symptoms (F-OR = 1.1, 95% CI [0.11, 12.2]; <emph>p</emph> =.91) were not significantly associated with the primary outcome.</p> <p>Graph: Figure 2. (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.</p> <p>The longitudinal mixed effect model using lognormal distribution to model the weekly cannabis use in dollars showed a significant treatment by week interaction effect (<emph>p</emph><emph>=</emph>.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; <emph>p</emph> &lt;.0001), compared to the placebo group, which did not change significantly with each week (6.8%; b = −0.07, SE = 0.05; <emph>p</emph> =.11). Similar results were found for the weekly cannabis use in days. There was a significant treatment by week interaction effect (<emph>p</emph><emph>=</emph>.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; <emph>p</emph> &lt;.0001), compared to the placebo group, which did not change significantly with each week (3.5%; b = −0.04, SE = 0.04; <emph>p</emph> = 0.39).</p> <p>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 (<emph>p</emph> =.19). The longitudinal mixed effect model using lognormal distribution to model mean weekly creatine-normalized THC showed no significant treatment by week interaction effect (<emph>p</emph> = 0.64). When the interaction term was removed from the model, there was no significant difference between treatment groups (<emph>p</emph> = 0.36), but there was a significant effect of week observed (<emph>p</emph> = 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).</p> <hd id="AN0179022151-12">ADHD Outcome</hd> <p>On average, the change in AISRS score was 15.79 (<emph>SD</emph> = 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 <emph>p</emph> =.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 <emph>p</emph> =.64).</p> <p>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 (<emph>p</emph> =.13) was not significant while adjusting for baseline AISRS (<emph>p</emph> =.02<emph>)</emph>, gender (<emph>p</emph> =.91<emph>)</emph>, and binarized baseline ADHD symptoms (<emph>p</emph> =.27<emph>)</emph>. The model-estimated change in AISRS score from baseline (Week 0) to Week 11 was not significantly different (<emph>p</emph> =.87) between treatment groups: −21.18 in the placebo group compared to −21.80 in the MAS-ER group.</p> <p>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]; <emph>p</emph> =.40), while adjusted by baseline CGI severity (OR = 2.96, 95% CI [0.53, 16.6]; <emph>p</emph> =.22), sex (OR = 0.06, 95% CI [0.003, 1.02]; <emph>p</emph> =.05) and binarized baseline ADHD symptoms (OR = 0.56, 95% CI [0.095, 3.32]; <emph>p</emph> =.53).</p> <hd id="AN0179022151-13">Medication Adherence</hd> <p>Treatment groups also did not significantly differ by the proportion of pills taken. The median average proportion of pills taken in the placebo group (<emph>n</emph> = 14) was 93.2% compared to 100.0% in the treatment group (<emph>n</emph> = 13). These proportions were not significantly different (<emph>Z</emph> = 1.37, <emph>p</emph> =.17). There was no treatment difference in the proportion of subjects with dose discontinuations (Fisher's exact test <emph>p</emph> =.09; placebo: 0%, 0/15; MAS-ER: 23%, 3/13) or dose reductions (Fisher's exact test <emph>p</emph> =.37; placebo: 13%, 2/15; MAS-ER: 31%, 4/13).</p> <p>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 (<emph>Z</emph> = 1.56, <emph>p</emph> =.12).</p> <p>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 (<emph>Z</emph> = −1.37; <emph>p</emph> =.17). Median percentage of samples positive for amphetamine per participant in the treatment group was 55% (IQR = 37%–87%).</p> <hd id="AN0179022151-14">Discussion</hd> <p>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 ([<reflink idref="bib15" id="ref71">15</reflink>]; [<reflink idref="bib51" id="ref72">51</reflink>]) or stimulants (e.g., methylphenidate, pemoline) for adolescents with ADHD and CUD ([<reflink idref="bib41" id="ref73">41</reflink>], [<reflink idref="bib42" id="ref74">42</reflink>]).</p> <p>Similar to our earlier studies with adults with cocaine use disorder with and without ADHD ([<reflink idref="bib30" id="ref75">30</reflink>], [<reflink idref="bib29" id="ref76">29</reflink>]; [<reflink idref="bib34" id="ref77">34</reflink>]), 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 ([<reflink idref="bib23" id="ref78">23</reflink>]; [<reflink idref="bib26" id="ref79">26</reflink>], [<reflink idref="bib25" id="ref80">25</reflink>]). 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 ([<reflink idref="bib3" id="ref81">3</reflink>]). This is reflected in more recent studies, including our own ([<reflink idref="bib14" id="ref82">14</reflink>]; [<reflink idref="bib28" id="ref83">28</reflink>]; [<reflink idref="bib31" id="ref84">31</reflink>]; [<reflink idref="bib35" id="ref85">35</reflink>]).</p> <p>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 ([<reflink idref="bib45" id="ref86">45</reflink>]; [<reflink idref="bib54" id="ref87">54</reflink>]), it may not be ideal for trials conducted in active substance users. [<reflink idref="bib53" id="ref88">53</reflink>] 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 ([<reflink idref="bib59" id="ref89">59</reflink>]). 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.</p> <p>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 ([<reflink idref="bib47" id="ref90">47</reflink>]), 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.</p> <p>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 ([<reflink idref="bib26" id="ref91">26</reflink>], [<reflink idref="bib25" id="ref92">25</reflink>], [<reflink idref="bib30" id="ref93">30</reflink>], [<reflink idref="bib37" id="ref94">37</reflink>]; [<reflink idref="bib34" id="ref95">34</reflink>]), 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.</p> <p>Another concern of prescribing stimulant medication is the risk of misuse and diversion ([<reflink idref="bib12" id="ref96">12</reflink>]). 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 ([<reflink idref="bib55" id="ref97">55</reflink>]). 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 [<reflink idref="bib42" id="ref98">42</reflink>] trial were more likely to lose their medication than adults with ADHD and nicotine use disorder in another trial ([<reflink idref="bib56" id="ref99">56</reflink>]), 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.</p> <p>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 ([<reflink idref="bib7" id="ref100">7</reflink>]; [<reflink idref="bib19" id="ref101">19</reflink>]). 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 ([<reflink idref="bib18" id="ref102">18</reflink>]; [<reflink idref="bib33" id="ref103">33</reflink>]; [<reflink idref="bib52" id="ref104">52</reflink>]) and that they were closely monitored and only received one-week supply of medication at a time.</p> <hd id="AN0179022151-15">Limitations</hd> <p>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 &gt;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 ([<reflink idref="bib42" id="ref105">42</reflink>]), we did not find such a high ADHD placebo response rate in a previous trial targeting adults with cocaine use disorder and ADHD ([<reflink idref="bib30" id="ref106">30</reflink>]) as we did in this trial.</p> <p>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.</p> <hd id="AN0179022151-16">Conclusions</hd> <p>In summary, the present trial finds that: (<reflink idref="bib1" id="ref107">1</reflink>) patients with ADHD and CUD tolerated MAS-ER combined with medication enhancement therapy; (<reflink idref="bib2" id="ref108">2</reflink>) 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.</p> <ref id="AN0179022151-17"> <title> References </title> <blist> <bibl id="bib1" idref="ref28" type="bt">1</bibl> <bibtext> American Psychiatric Association. (2013). 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The Journal of Clinical Psychiatry, 83(4), 21m14239. https://doi.org/10.4088/JCP.21m14239</bibtext> </blist> </ref> <ref id="AN0179022151-18"> <title> Footnotes </title> <blist> <bibtext> 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.</bibtext> </blist> <blist> <bibtext> 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.</bibtext> </blist> <blist> <bibtext> Frances R. Levin</bibtext> </blist> <blist> <bibtext>Graph https://orcid.org/0000-0003-4209-1329</bibtext> </blist> </ref> <aug> <p>By Frances R. Levin; John J. Mariani; Martina Pavlicova; C. Jean Choi; Cale Basaraba; Amy L. Mahony; Daniel J. Brooks; Christina A. Brezing and Nasir Naqvi</p> <p>Reported by Author; Author; Author; Author; Author; Author; Author; Author; Author</p> <p></p> <p>Frances R. Levin is the Kennedy-Leavy Professor of Psychiatry at the Columbia University Vagelos College of Physicians and Surgeons and Director of the Division on Substance Use Disorders at New York State Psychiatric Institute. She has a long-standing interest in developing pharmacologic interventions for individuals with a range of substance use disorders and in particular those with additional psychiatric comorbidities. She has conducted research focused on those with ADHD and substance use disorders for nearly 3 decades.</p> <p>John J. Mariani is a Professor of Clinical Psychiatry and the Director of the Substance Treatment and Research Service (STARS) at the Columbia University Irving Medical Center. Dr. Mariani's research interest has been focused on the development of novel psychopharmacological treatments for substance use disorders and related conditions.</p> <p>Martina Pavlicova is an Associate Professor of Biostatistics at the Columbia University Medical Center and Director of the Statistics, Data Science, and Data Management Core at the HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute and Columbia University. Martina's interests are longitudinal mixed effect modeling, machine learning, and statistics education.</p> <p>C. Jean Choi is an experienced biostatistician with expertise in advanced longitudinal analyses within the field of mental health research.</p> <p>Cale Basaraba is a data scientist in the Mental Health Data Science division at the New York State Psychiatric Institute. His interests include causal inference methods, machine learning, and statistical programming.</p> <p>Amy L. Mahony has been working at the New York State Psychiatric Institute in the Substance Use Disorder Division as a therapist and administrative director at one of the outpatient research clinics. Her interests include assessment, diagnosis, and ADHD.</p> <p>Daniel J. Brooks is a Project Manager and therapist at the New York State Psychiatric Institute. His interests include pharmacologic and behavioral health interventions for substance use disorders.</p> <p>Christina A. Brezing is an Assistant Professor at Columbia University Irving Medical Center and Research Scientist in the Division on Substance Use Disorders at New York State Psychiatric Institute. Her research has focused on medication development and the use of technology to better understand and manage care for substance use disorders.</p> <p>Nasir Naqvi is an Associate Professor of psychiatry at Columbia University. His research is focused on mechanisms of behavior change in treatments for alcohol use disorders, combining clinical and neuroimaging methods.</p> </aug> <nolink nlid="nl1" bibid="bib20" firstref="ref1"></nolink> <nolink nlid="nl2" bibid="bib44" firstref="ref2"></nolink> <nolink nlid="nl3" bibid="bib50" firstref="ref3"></nolink> <nolink nlid="nl4" bibid="bib58" firstref="ref4"></nolink> <nolink nlid="nl5" bibid="bib49" firstref="ref5"></nolink> <nolink nlid="nl6" bibid="bib10" firstref="ref7"></nolink> <nolink nlid="nl7" bibid="bib27" firstref="ref8"></nolink> <nolink nlid="nl8" bibid="bib57" firstref="ref9"></nolink> <nolink nlid="nl9" bibid="bib11" firstref="ref11"></nolink> <nolink nlid="nl10" bibid="bib41" firstref="ref13"></nolink> <nolink nlid="nl11" bibid="bib42" firstref="ref14"></nolink> <nolink nlid="nl12" bibid="bib36" firstref="ref15"></nolink> <nolink nlid="nl13" bibid="bib48" firstref="ref16"></nolink> <nolink nlid="nl14" bibid="bib30" firstref="ref20"></nolink> <nolink nlid="nl15" bibid="bib23" firstref="ref21"></nolink> <nolink nlid="nl16" bibid="bib24" firstref="ref22"></nolink> <nolink nlid="nl17" bibid="bib38" firstref="ref24"></nolink> <nolink nlid="nl18" bibid="bib29" firstref="ref26"></nolink> <nolink nlid="nl19" bibid="bib34" firstref="ref27"></nolink> <nolink nlid="nl20" bibid="bib43" firstref="ref29"></nolink> <nolink nlid="nl21" bibid="bib40" firstref="ref30"></nolink> <nolink nlid="nl22" bibid="bib46" firstref="ref35"></nolink> <nolink nlid="nl23" bibid="bib17" firstref="ref37"></nolink> <nolink nlid="nl24" bibid="bib16" firstref="ref38"></nolink> <nolink nlid="nl25" bibid="bib12" firstref="ref49"></nolink> <nolink nlid="nl26" bibid="bib13" firstref="ref50"></nolink> <nolink nlid="nl27" bibid="bib21" firstref="ref55"></nolink> <nolink nlid="nl28" bibid="bib22" firstref="ref56"></nolink> <nolink nlid="nl29" bibid="bib32" firstref="ref57"></nolink> <nolink nlid="nl30" bibid="bib39" firstref="ref62"></nolink> <nolink nlid="nl31" bibid="bib15" firstref="ref71"></nolink> <nolink nlid="nl32" bibid="bib51" firstref="ref72"></nolink> <nolink nlid="nl33" bibid="bib26" firstref="ref79"></nolink> <nolink nlid="nl34" bibid="bib25" firstref="ref80"></nolink> <nolink nlid="nl35" bibid="bib14" firstref="ref82"></nolink> <nolink nlid="nl36" bibid="bib28" firstref="ref83"></nolink> <nolink nlid="nl37" bibid="bib31" firstref="ref84"></nolink> <nolink nlid="nl38" bibid="bib35" firstref="ref85"></nolink> <nolink nlid="nl39" bibid="bib45" firstref="ref86"></nolink> <nolink nlid="nl40" bibid="bib54" firstref="ref87"></nolink> <nolink nlid="nl41" bibid="bib53" firstref="ref88"></nolink> <nolink nlid="nl42" bibid="bib59" firstref="ref89"></nolink> <nolink nlid="nl43" bibid="bib47" firstref="ref90"></nolink> <nolink nlid="nl44" bibid="bib37" firstref="ref94"></nolink> <nolink nlid="nl45" bibid="bib55" firstref="ref97"></nolink> <nolink nlid="nl46" bibid="bib56" firstref="ref99"></nolink> <nolink nlid="nl47" bibid="bib19" firstref="ref101"></nolink> <nolink nlid="nl48" bibid="bib18" firstref="ref102"></nolink> <nolink nlid="nl49" bibid="bib33" firstref="ref103"></nolink> <nolink nlid="nl50" bibid="bib52" firstref="ref104"></nolink> |
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| Items | – Name: Title Label: Title Group: Ti Data: Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial – Name: Language Label: Language Group: Lang Data: English – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Frances+R%2E+Levin%22">Frances R. Levin</searchLink> (ORCID <externalLink term="https://orcid.org/0000-0003-4209-1329">0000-0003-4209-1329</externalLink>)<br /><searchLink fieldCode="AR" term="%22John+J%2E+Mariani%22">John J. Mariani</searchLink><br /><searchLink fieldCode="AR" term="%22Martina+Pavlicova%22">Martina Pavlicova</searchLink><br /><searchLink fieldCode="AR" term="%22C%2E+Jean+Choi%22">C. Jean Choi</searchLink><br /><searchLink fieldCode="AR" term="%22Cale+Basaraba%22">Cale Basaraba</searchLink><br /><searchLink fieldCode="AR" term="%22Amy+L%2E+Mahony%22">Amy L. Mahony</searchLink><br /><searchLink fieldCode="AR" term="%22Daniel+J%2E+Brooks%22">Daniel J. Brooks</searchLink><br /><searchLink fieldCode="AR" term="%22Christina+A%2E+Brezing%22">Christina A. Brezing</searchLink><br /><searchLink fieldCode="AR" term="%22Nasir+Naqvi%22">Nasir Naqvi</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="SO" term="%22Journal+of+Attention+Disorders%22"><i>Journal of Attention Disorders</i></searchLink>. 2024 28(11):1467-1481. – Name: Avail Label: Availability Group: Avail Data: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com – Name: PeerReviewed Label: Peer Reviewed Group: SrcInfo Data: Y – Name: Pages Label: Page Count Group: Src Data: 15 – Name: DatePubCY Label: Publication Date Group: Date Data: 2024 – Name: TypeDocument Label: Document Type Group: TypDoc Data: Journal Articles<br />Reports - Research – Name: Subject Label: Descriptors Group: Su Data: <searchLink fieldCode="DE" term="%22Comorbidity%22">Comorbidity</searchLink><br /><searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Marijuana%22">Marijuana</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+Abuse%22">Drug Abuse</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+Therapy%22">Drug Therapy</searchLink><br /><searchLink fieldCode="DE" term="%22Stimulants%22">Stimulants</searchLink><br /><searchLink fieldCode="DE" term="%22Randomized+Controlled+Trials%22">Randomized Controlled Trials</searchLink><br /><searchLink fieldCode="DE" term="%22Outcomes+of+Treatment%22">Outcomes of Treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Sample+Size%22">Sample Size</searchLink><br /><searchLink fieldCode="DE" term="%22Symptoms+%28Individual+Disorders%29%22">Symptoms (Individual Disorders)</searchLink><br /><searchLink fieldCode="DE" term="%22Pilot+Projects%22">Pilot Projects</searchLink><br /><searchLink fieldCode="DE" term="%22Compliance+%28Psychology%29%22">Compliance (Psychology)</searchLink> – Name: Subject Label: Geographic Terms Group: Su Data: <searchLink fieldCode="DE" term="%22New+York%22">New York</searchLink> – Name: DOI Label: DOI Group: ID Data: 10.1177/10870547241264675 – Name: ISSN Label: ISSN Group: ISSN Data: 1087-0547<br />1557-1246 – Name: Abstract Label: Abstract Group: Ab Data: 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: [greater than or equal to] 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 = 0.65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = 0.27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < 0.0001). 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. – Name: AbstractInfo Label: Abstractor Group: Ab Data: As Provided – Name: DateEntry Label: Entry Date Group: Date Data: 2024 – Name: AN Label: Accession Number Group: ID Data: EJ1436085 |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1177/10870547241264675 Languages: – Text: English PhysicalDescription: Pagination: PageCount: 15 StartPage: 1467 Subjects: – SubjectFull: Comorbidity Type: general – SubjectFull: Attention Deficit Hyperactivity Disorder Type: general – SubjectFull: Marijuana Type: general – SubjectFull: Drug Abuse Type: general – SubjectFull: Drug Therapy Type: general – SubjectFull: Stimulants Type: general – SubjectFull: Randomized Controlled Trials Type: general – SubjectFull: Outcomes of Treatment Type: general – SubjectFull: Sample Size Type: general – SubjectFull: Symptoms (Individual Disorders) Type: general – SubjectFull: Pilot Projects Type: general – SubjectFull: Compliance (Psychology) Type: general – SubjectFull: New York Type: general Titles: – TitleFull: Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Frances R. Levin – PersonEntity: Name: NameFull: John J. Mariani – PersonEntity: Name: NameFull: Martina Pavlicova – PersonEntity: Name: NameFull: C. Jean Choi – PersonEntity: Name: NameFull: Cale Basaraba – PersonEntity: Name: NameFull: Amy L. Mahony – PersonEntity: Name: NameFull: Daniel J. Brooks – PersonEntity: Name: NameFull: Christina A. Brezing – PersonEntity: Name: NameFull: Nasir Naqvi IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 09 Type: published Y: 2024 Identifiers: – Type: issn-print Value: 1087-0547 – Type: issn-electronic Value: 1557-1246 Numbering: – Type: volume Value: 28 – Type: issue Value: 11 Titles: – TitleFull: Journal of Attention Disorders Type: main |
| ResultId | 1 |
