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 Report Sheds Light on Global Epidemiology of Stimulant-Use Disorders

A brand new study by researchers at the Australia National Health and Medical Research Council estimates the global burden of disease due to cocaine and amphetamine. Based on large systematic reviews of epidemiological data, disease models and global prevalence estimates, the authors present comorbidity-adjusted years of life lost to disability (YDL), years of life lost (YLL) and disability-adjusted life years (DALY) estimates. The authors note that their estimates include only the disease burdens attributable directly to amphetamine- and cocaine-use disorders, leaving out the likely considerable HIV- and HCV-attributable costs and burden.

via ScienceDirect:

Abstract

Aims

To estimate the global prevalence of cocaine and amphetamine dependence and the burden of disease attributable to these disorders.

Methods

An epidemiological model was developed using DisMod-MR, a Bayesian meta-regression tool, using epidemiological data (prevalence, incidence, remission and mortality) sourced from a multi-stage systematic review of data. Age, sex and region-specific prevalence was estimated for and multiplied by comorbidity-adjusted disability weightings to estimate years of life lost to disability (YLDs) from these disorders. Years of life lost (YLL) were estimated from cross-national vital registry data. Disability-adjusted life years DALYs) were estimated by summing YLDs and YLLs in 21 regions, by sex and age, in 1990 and 2010.

Results

In 2010, there were an estimated 24.1 million psychostimulant dependent people: 6.9 million cocaine and 17.2 million amphetamines, equating to a point prevalence of 0.10% (0.09-0.11%) for cocaine, and 0.25% (0.22-0.28%) for amphetamines. There were 37.6 amphetamine dependence DALYs (21.3-59.3) per 100,000 population in 2010 and 15.9 per 100,000 (9.3-25.0) cocaine dependence DALYs. There were clear differences between amphetamines and cocaine in the geographic distribution of crude DALYs. Over half of amphetamine dependence DALYs was in Asian regions (52%), whereas almost half of cocaine dependence DALYs was in the Americas (44%, with 23% in North America High Income).

Conclusion

Dependence upon psychostimulants is a substantial contributor to global disease burden; the contribution of cocaine and amphetamines to this burden varies dramatically by geographic region. There is a need to scale up evidence-based interventions to reduce this burden.

Figure 1 compares the DALYs of amphetamines and cocaine between genders:

Fig. 2 shows the distribution of "crude estimated DALYs" due to either substance:

And Fig. 3 shows "Country-level DALYs per 100,000 population due to amphetamine dependence, age-standardized, for persons in 2010":

Source:
http://www.sciencedirect.com/science/article/pii/S0376871614000234

Do Adverse Childhood Experiences Make Amphetamine More Pleasurable?

In a fascinating new study, researchers from the University of Maryland and Johns Hopkins University observed the way amphetamine affects the brain, comparing subjects who reported adverse childhood experiences (ACE) with those who did not. They found significant differences between groups in the way the drug impacted the dopamine (DA) neurotransmitter in the ventral striatal (VS) region of the brain, finding a significant positive correlation between early childhood trauma and VS DA release.

The results, published online in the journal, Psychopharmacology, suggest that adverse childhood experiences may enhance vulnerability to amphetamine-use disorders later in life by changing the way the brain transmits dopamine. Interestingly, a positive association between childhood trauma and amphetamine-induced pleasure was suggested for men, but vice versa for women.

Here's the abstract via SpringerLink, and an interesting image from the article:

Abstract

Rationale

Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear.

Objectives

This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans.

Methods

Following intake assessment, 28 healthy male and female adults, aged 18–29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg).

Results

Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress.

Conclusions

Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

http://link.springer.com/article/10.1007%2Fs00213-013-3407-z