PROMETA Postmortem

How the latest miracle cure for addiction failed to deliver.

PROMETA™: Last seen going down fast, smoke pouring from all engines.

As reported here at Addiction Inbox, a double-blind placebo-controlled evaluation of PROMETA™ by W. Ling and associates, published online last month in the journal Addiction, found that the much-publicized treatment protocol for meth addiction “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving.” The authors of the journal paper didn’t accuse Hythiam, the company that makes and sells the product, of not telling the truth. They just said that the treatment didn’t work. The study authors did, however, find evidence of “potential financial conflicts of interests among its advocates…”

An earlier CBS News "60 Minutes" news report in 2009 had raised similar questions, but generated a great deal of publicity for PROMETA™. And the only testing available, a small open study from Texas, had shown positive results. Testimonials began mounting, and a few prominent doctors in the addiction field lent their names to the marketing effort. More conservative voices, like Richard Rawson and the University of Pennsylvania’s Tom McClellan, warned that there was insufficient scientific evidence to push forward with the new treatment—but their concerns were swept aside amid the general enthusiasm for a long-sought antidote to the ravages of methamphetamine addiction.

So how did it happen? And what, if anything, does it teach us about the enterprise of addiction research and treatment?

An editorial by Dr. Keith Humphreys of the Stanford University Medical Centers, which  accompanied the report of the clinical trial in Addiction, attempted to analyze the saga of how “a former junk bond trader with no medical background raised $150 million in capital to market a combination of three medications (gabapentin, flumazenil and hydroxyzine) as a treatment for methamphetamine addiction.” Bear in mind that only one of the drugs—gabapentin—had ever been involved in clinical trials against addiction, with decidedly mixed results. As for the other ingredients, a prominent neuroscientist who blogs pseudonymously as Neuroskeptic, commented at the time: “What the hell kind of a cocktail is that? Gabapentin—OK, it might reduce anxiety and stabilize mood, although the evidence is poor and if you wanted to do that, there are better drugs. Ditto for hydroxazine. And why you want both of those is unclear. But flumazenil? That doesn't do much if you haven't taken a benzodiazepine. But if it did do anything it would be to antagonize the gabapentin.”

All in all, not a promising analysis.

The three drugs are approved for various uses by the FDA, and there is the rub: Off-label practices allow physicians to prescribe medications for uses other than those listed on the official package insert. As useful as this practice can be, it creates a situation in which a “combination of previously approved medications can be marketed without review as a new treatment protocol, despite the fact that none of the individual medications had any evidence nor were originally approved as a treatment for the condition the new protocol targets.”

Under this directive, Hythiam was free to promote the combination of approved medications as a new addiction treatment advance without any significant testing, Humphreys contends.

If the treatment, in the end, proved to be no better than placebo for meth addiction, what made it seem like such a successful new thing under the sun at the outset? Wishful thinking, Humphreys believes: “Many serious, good-hearted people will be shocked at Ling’s negative results because they believed sincerely… we must not yield to our powerful collective desire to believe before we have hard evidence of effectiveness from disinterested, respected sources. The simpler, faster and more miraculous-seeming the cure, the greater should be our skepticism.”

Furthermore: "As was the case with another would-be ‘miracle cure’—ultra-rapid opiate-detoxification—a manufacturer was able to market an untested treatment protocol to addicted patients…”

Why? Because “off-label use of medications is well-established in medical practice and has significant value in many cases, but a balance must be struck with the risk this creates for evasion of the normal safety and efficacy checks by creators of new treatment protocols."

"We have a huge advantage at this historical moment which was not available to people in prior eras who could not determine whether ‘Dr. Keeley’s Double Chloride of Gold Injections’, ‘Dr. Revaly’s Guaranteed Remedy for the Tobacco Habit’ and ‘Dr. Meeker’s Addiction Antidote’ were effective,” writes Humphreys. Namely, “a well-developed addiction treatment research enterprise." And because of that, we should “point with pride to Ling et.al.’s work as an example of how high-quality science can inform suffering people about what will help them and what will not; and those who set public research budgets need look no further for an example of return on investment.”

HUMPHREYS, K. (2012). What can we learn from the failure of yet another ‘miracle cure’ for addiction? Addiction, 107 (2), 237-239 DOI: 10.1111/j.1360-0443.2011.03652.x

Photo Credit: http://blog.nebraskahistory.org

The Black Market for Seroquel

Speed freaks, coke heads, and antipsychotics.

Last week, writing on the Daily Beast web site, reporter Jeff Deeney profiled a startling underground market for the antipsychotic medication Seroquel (quetiapine). Deeney described street transactions in North Philadelphia for Quells or Suzie-Qs, as the drug is sometimes called. Seroquel, a drug developed for the treatment of schizophrenia and bipolar disorder, has developed an additional reputation as a “comedown” drug for stimulant abusers.

Seroquel, a so-called atypical antipsychotic, works by altering levels of dopamine. While some addicts have claimed that the drug is perfect for a cocaine or speed comedown, Seroquel has also been studied for its anti-craving properties when used for cocaine abstinence.

Why would a speed freak or a coke addict want to take a drug that might decrease their desire for their stimulant of choice? For the same reason that ecstasy users often take a morning-after dose of Prozac in a misguided attempt to compensate for possible damage to serotonin receptor arrays. Or because the drug is mildly sedating for some users. However, there may be more to it. Perhaps Seroquel is an effective anti-craving medication for cocaine and methamphetamine addicts, who misuse it as a drug to ease them through enforced periods of detox or lack of availability.

One high-traffic drug discussion site has shut down a long-standing thread on Seroquel with the warning: “Do not use Seroquel for a cocaine comedown.”

The fact that prescription Seroquel is available as a street drug, at least in some parts of the country, demonstrates the likelihood that physicians and psychiatrists are increasingly using it for off-prescription purposes—like drug detox. Deeney strongly suggests that this is the case: “Drug dealers, mandated to treatment as a condition of their probation or parole, are given off-label prescriptions for Seroquel, then sent right back to the street, where the pills can be sold for cash to users and other dealers.”

Increasing its appeal is Seroquel’s reputation for combining well with cocaine in a mixture known as a Q-Ball, or Rosemary’s Dolly—a variation on the heroin/cocaine mix known as a Speedball, to which Seroquel can also be added. An anonymous med student on a medical blog noted that “certain people say they love Seroquel when doing a speed-ball. Makes sense, think about it. It heightens the high of the heroin, it eases the crash of the cocaine.”

Seroquel’s ability to modulate the effect of illegal drugs means that the medication can possibly find a market both as a detox drug for stimulant abusers, and as an ingredient in the very stimulants they abuse.

By itself, Seroquel is not considered addictive. Some addicts told Deeney that the drug simply put them to sleep more quickly after a long meth run. Indeed, Seroquel is considered to be more sedating than similar antipsychotics such as Olanzapine and Aripiprazole. The larger issue, as the Daily Beast post makes clear, is that “Seroquel can have serious side effects including diabetes, a permanent Parkinson’s-like palsy called tardive dyskinesia, and sudden cardiac death.”

All of this confusing and sometimes contradictory input is coming well ahead of the clinical data, although a study in 2001, presented at the 4th International Conference on Bipolar disorder, found that quetiapine caused a significant reduction in cocaine use among a small group of cocaine-dependent subjects who also suffered from bipolar disorder. A report last year in the Journal of Clinical Psychopharmacology also showed positive results with cocaine users. Studies of quetiapine for the reduction of cocaine use are currently being undertaken by the Seattle Institute for Biomedical and Clinical Research.

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