A Sad State of Affairs: Psychostimulant Addiction Treatment Leaves Much to be Desired

The authors of a new paper, published ahead of a special issue of Neuropharmacology, give the reader a good look at the current state of psychostimulant substance use disorder treatment - and the results are disappointing. Starting with behavioral treatments and ending with a review of medications, the clear fact remains that there is no single treatment that outperforms most others.

Meta-analyses of behavioral interventions for the treatment of cocaine use disorder have shown modest benefits; while one review found, "there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of" cocaine or amphetamine use disorders. CBT and Contingency Management (CM) remain the mainstay of psychostimulant treatment, and the authors cite data suggesting a combination of CM plus Community Reinforcement Approach might produce the best outcomes.

In terms of pharmacological treatments, researched medications include antagonist therapy, agonist therapy, medications to treat withdrawal symptoms and medications to treat co-occurring psychiatric symptoms or disorders; and the authors of the present paper devote the bulk of their attention to weighing the evidence of such options.

Naltrexone, they note, has shown some promise in laboratory studies, as it has been shown to weaken amphetamine- and cocaine-related effects in some subjects in both human and animal trials. Because it also seems to weaken the subjective euphoric effects of methylphenidate (Ritalin), one area of promise could be in the combination of naltrexone and methylphenidate to limit the abuse potential of an agonist-like treatment.

Disulfiram (aka Antabuse) has also shown some promise in the lab, but mainly in the treatment of cocaine-use disorders. It was shown to increase the brain ratio of dopamine to norepinephrine and to prevent stress-induced cocaine reinstatement. In pilot studies, disulfiram was shown to be effective in reducing cocaine use in patients with cocaine use disorders (CUD), and among buprenorphine-maintained polydrug users. However, in a more recent study, disulfiram showed less promise reducing cocaine use among methadone-maintained patients. The authors of the review point to evidence that disulfiram may only be effective among CUD patients with specific genotypes - and may be more effective among men than women.

Agonist-like treatments are also reviewed by the authors, and appear to offer some of the more exciting, and possibly effective, interventions for psychostimulant addiction. D-amphetamine has been shown to improve treatment retention and reduce illicit cocaine use in early trials; while a later study showed a reduction in withdrawal and craving, but a failure to reduce methamphetamine use. Not mentioned in the review, but a small study we wrote about in 2012 appeared to show promising results in the combination of mixed amphetamine salts (Adderall) and topiramate (Topamax)

For its part, sustained-release methamphetamine has been tested as a maintenance agent for CUD, and appeared to significantly reduce cocaine-positive urine samples and cocaine craving. The familiar medication, methylphenidate, has been shown to be non-superior to placebo in some studies for meth/amphetamine use and cocaine use, but appears to warrant further research at improved dosages. The other agonist-like medication discussed, modafanil, seems to be an interesting candidate for maintenance treatment. Known to be a cognitive enhancer, modafanil may be useful in addressing the impairments in a range of cognitive functions that can result from psychostimulant addiction; but studies have thus far produced more "equivocal" results in most trials as treatments for cocaine or for methamphetamine - even when combined with D-amphetamine. Post-hoc analysis of the available data does, however, suggest efficacy in the less severe cases of addiction.

Additionally, researchers in Latin America have argued in favor oral coca for the treatment of cocaine use disorder. Their "Handbook on Oral Cocaine as Agonist Therapy for Cocaine Dependence" is an intriguing read, and the authors of the review posit that political, cultural and commercial barriers - not scientific ones - are likely to blame for the "lack of follow-up on this line of research".

A host of other medications have been tried and tested for psychostimulant use disorders, with little success. Vaccines, on the other hand, are now gaining momentum in the field and are being used in multiple studies at various phases. A vaccine that that produces antibodies to prevent cocaine from crossing the blood-brain barrier has performed well in Phase I and Phase II trials. A methamphetamine vaccine is still in preclinical development, but initial results have shown good levels of antibodies in animal models and a Phase I  trial is scheduled to begin in 2015.

Considering the vast global toll which is the result of psychostimulant addiction, treatment for these disorders is as desperately needed as ever. If there is one thing that this review makes clear, it's the fact that we still have a long way to go before we can say that we have effective treatment options for the consumer. A question for readers of this blog: what are the techniques and interventions that you have found to be helpful stimulant use disorders? Is there a particular line of research that you feel would be important to investigate further? Do you see the utility of agonist-like medications? Your thoughts are always appreciated.

New Findings in Medication-Assisted Treatment

Some interesting new studies are showing promising results for patients all over the world:

Turns out, Quality of Life improvements aren't just for the wealthy:
Quality of Life (QoL) scores significantly improved in ALL four domains (psychological, physical, social and environmental) of the WHO QoL scale in patients in low and middle income countries, according to the authors of a systematic review of 13 studies involving over 1800 participants. The findings, published online last week in the Journal of Drug and Alcohol Dependence, show that despite the apparent lack of resources in these countries, opiate replacement therapy with methadone or buprenorphine can be an effective treatment tool - with scores increasing along with the length of time at followup - and offering outcomes comparable to those seen in high income countries.
You can read the abstract of the study by Feelemeyer, et al., here: http://www.sciencedirect.com/science/article/pii/S0376871613004225

The methadone of methamphetamine?:
In encouraging news for stimulant users, a small study has shown methylphenidate (Ritalin) to both improve symptoms and reduce use episodes, in a cohort of criminal justice-involved stimulant users with co-occurring ADHD. Similar findings have been published supporting mixed-amphetamine salts (Adderall) plus topiramate (Topamax) for the treatment of cocaine dependence, and more recently topiramate by itself. The authors of the small study note the high prevalence of ADHD among stimulant users in the criminal justice population and in their research used dosages that were high enough to be therapeutically effective for patients with a history of substance use disorders (a flaw, they argue, in previous studies of this kind). Could it be that we are getting closer to an accepted agonist maintenance treatment for stimulant use disorders? Read the results of the Swedish study by Konstenius, et al., published online this month in the journal Addiction:
http://onlinelibrary.wiley.com/doi/10.1111/add.12369/abstract

Groups could improve access to AUD medications:
And finally, in a new study in the Journal of Substance Abuse Treatment, researchers have shown that group pharmacotherapy is an effective intervention for patients on medication-assisted treatment of alcohol use disorders. The authors provide a brief description of this novel approach and their experiences implementing the program. They note that, for many clinicians, providing ongoing monitoring of these effective medications can create a barrier to implementation. What the team found however, was that a "medication group" was not only feasible, but it actually increased their patients' access to meds like disulfiram (Antabuse), naltrexone and acamprosate (Campral). Read the abstract from the report by Dr Shannon Robinson and a team at San Diego's VA Health Care System here: http://www.sciencedirect.com/science/article/pii/S0740547213001347

Most Non-Medication Treatments for ADHD Ineffective: New Study

Hot off the presses (or screen), a new review by the European ADHD Guidelines Group found that non-medication treatments for ADHD are not supported by current evidence. Here's the abstract from The American Journal of Psychiatry.

Nonpharmacological Interventions for ADHD: Systematic Review and Meta-Analyses of Randomized Controlled Trials of Dietary and Psychological Treatments

Edmund J.S. Sonuga-Barke, Ph.D., Daniel Brandeis, Ph.D., Samuele Cortese, M.D., Ph.D., et al.

European ADHD Guidelines Group

Objective: Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments.

Method: Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to nidentify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome.

Results: Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences= 0.21–0.48) and psychological (standardized mean differences=0.40–0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference= 0.16) and artificial food color exclusion (standardized mean difference= 0.42) but were substantially attenuated to nonsignificant levels for other treatments.

Conclusions: Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms.

Am J Psychiatry Sonuga-Barke et al.; AiA:1–15