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.

Can THC Protect the Brain against Methamphetamine's Toxicity?

A fascinating new study in the journal Neuropharmacology, suggests the brain's endocannabinoid system can be aided in its neuroprotective efforts against the toxicity of methamphetamine by introducing external cannabinoids to increase the system's "endogenous tone". The cannabinoids in question, THC, URB and JZL, appear to inhibit the breakdown of the brain's own endocannabinoids, improving the ability of the brain to protect itself against the "external insult" of overdoses of methamphetamine.

Here is the abstract, via ScienceDirect:

Abstract

Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ⁹-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB₁ and CB₂cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB₂, but not of CB₁, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB₂ receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain.

And here is a table showing levels of two of the major endocannabinoids, AEA and 2-AG,  following doses of methamphetamine:

And finally striatal levels of the cytokine tumor necrosis factor alpha:

Source:
http://www.sciencedirect.com/science/article/pii/S0028390814001099

Prometa or Promota? Hope You Didn't Spring for It

A new study just released found that Prometa, a proprietary combination of currently available drugs and nutrients, was no better than placebo in the treatment of methamphetamine addiction. This parallels the negative finding in treatment of alcohol dependence (although most subjects in the alcohol study did worse on Prometa than placebo.) Prometa contains two drugs widely prescribed among people with alcohol dependence, gabapentin (Neurontin) and hydroxyzine (Vistaril.) The third drug, flumezanil, is widely used to reverse the effects of benzodiazepines (such as alprazolam or lorazepam.) However, it can only be given intravenously so it is primarily used to help wake people up after procedures such as colonoscopy where "conscious sedation" is used instead of putting the patient to sleep. The folks at Hythium, Prometa's parent company devised a series of intravenous infusions of these drugs followed by oral medication. They also added various nutrients. Underwritten by wealthy investor Terren Peizer, Hythium hyped Prometa very successfully and in the complete absence of any credible evidence. Prometa is very costly, in the range of $12,000-15,000 or more per month, but enough people addicted to alcohol, methamphetamine or cocaine coughed it up out of desperation, driving the stock very high initially. Those of use who know something about psychopharmacology always knew this was a bunch of horse manure but that doesn't matter much in the addiction treatment world. Prometa wasn't greeted with universal acclaim to say the least. A headline on MSNBC.com in 2007 read: "Unproven meth, cocaine ‘remedy’ hits market. Researchers debate quick fix: Is it good medicine or just marketing?" It took 4 years, but now high quality studies have debunked any claim to efficacy for alcohol or methamphetamine. The meth study, by Ling et al. (Addiction, published online in advance of print, 11/15/11), randomly assigned 120 meth addicts seeking treatment to either the Prometa protocol or a similar set up (with the iv infusions and all) but using placebo instead. As expected, Prometa was no better than placebo. At least it did better in this study than in the study by Anton et al. (J Clin Psychopharmacol 2009;29:334-342,) where for most study subjects, those receiving Prometa had significantly worse outcomes than those receiving placebo! So does this take the wind out of their sales? Of course not! Hythium has the nerve to quote these studies on their website as though they prove than Prometa works, when they show the opposite. That takes real chutzpah. But then again, it's no different than all the treatment centers who offer nutritional supplements, yoga, life coaching, equine therapy etc. as effective for treating addiction. And people keep flocking to them, and paying for them. So until consumers (and payers) wise up, I guess they'll keep selling their snake oil as long as people are buying it.

More NIDA Hype: Vaccines for Addictions (NYT, 10/4/11)

The New York Times today published a story about research on vaccines to prevent or treat substance addictions. The tantalizing title: "An Addiction Vaccine, Tantalizingly Close." The problem? It's not only not close, it's looking more and more unlikely as time goes on. The article details the research career of Kim Janda, an immunologist at the Scripps Institute. Unfortunately, his dedicated quest to develop an effective vaccine for nicotine, alcohol, cocaine, methamphetamine or even obesity have all been dead ends. Often, research in rodents is tantalizing but then human studies are inevitably disappointing. Yet, he is said to be at the "vanguard of addiction research." No less a luminary than the inevitably quoted Drug War General and Director of the National Institute on Drug Abuse (NIDA) Nora Volkow naturally endorses this research, which they funded. Ummmhhh. What am I missing here? I wish that this research offered more promise than it appears to, but I'm afraid I see it on the back burner more than the vanguard.

 Dr. Janda commented that because there is so little available to help some of these addicts, people are desperate to hear something that gives them hope. I am sympathetic to the suffering of individuals with addiction and their loved ones, and I understand their desperation. I see it every day in my practice. Indeed as a physician I experience it, having to give them some pretty bad news about the dearth of highly effective treatments for stimulant addictions. (Note: contingency management, where patients are given rewards for staying abstinent and attending sessions is effective at improving engagement and retention. Whether those effects last very long is still unclear. Also high quality cognitive behavior therapy given to better prognosis addicts is beneficial. However, neither of these treatments is available in the community. The 12-step rehab widely available in the community probably has little if any long term effectiveness.) My interpretation is that non-treatment factors (legal sanctions, accumulating adverse consequences, pressure from others, growing up) are more important than treatment of any kind in determining whether a person will stop.

 Just to be clear, none of this is to say that funding basic and clinical research which has not yet yielded much in the way of clinical breakthroughs is not unique to addiction, and not a reason to decrease funding for it. For all of the billions of dollars put into research on treating solid cancers, for example, there is not much to show for it. In many cases, like cancer of the pancreas, brain or lung, there have been no significant advances at all. We still have no effective way to prevent or treat obesity or osteoarthritis. And yes, new treatments in these other areas that offer modest if any net benefit are also touted by a press looking for something big. So this type of thing seems pretty common in a society that looks to technological solutions for problems where changes in policy and regulation would arguably yield more. But I am concerned when the importance of research findings for treating addiction are exaggerated. I think giving hope that something new may become available has its place here as it does in other diseases. But I also think we have to be careful so we don't lose credibility among a public that is not accustomed to looking to science for an answer for addiction since the most widespread treatment is based on a spiritual transformation.

 One more quick note: Dr. Janda also made the unfortunate comment about addicts needing to "want to stop." In my experience, all addicts want to stop because being addicted is so miserable. But breaking up with cocaine is hard to do. Changing behavior of any type is very hard to do. We aren't very good at it, and we are overall pretty poor at helping others change health behavior and maintain the change. It's possible, it happens more often than we might even expect, but when it doesn't happen it's just too easy to blame the victim as "not wanting to change." And it's too scary to realize that sometimes it's impossible to change even when your life depends on it. Just ask the smokers inhaling through their tracheostomy tubes after having treatment for throat cancer. How terrifying is it to watch yourself die of a behavioral disorder that you abhor and despise and want desperately to change?

 MW