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 Pharmacokinetics of Speed

Meth lingers longer than coke, targets different brain areas.

Scientists at the Brookhaven National Laboratory, already famous for their work on positron emission tomography (PET) scans, have traced the pathways by which methamphetamine lingers in the brain longer than cocaine. The Brookhaven Lab, managed by the U.S. Department of Energy (DOE) tested non-drug abusing volunteers. The results will be published in the November 1 issue of Neuroimage.

The researchers injected the 19 volunteers with radioactively tagged doses of the drugs. Scanning cameras then recorded the concentration and distribution of the tagged molecules. Both cocaine and methamphetamine enter the brain quickly—part of the reason why the two drugs are so reinforcing. However, cocaine clears the brain just as quickly, while meth does not. Moreover, the study demonstrated that methamphetamine is much more widely distributed throughout the brain than cocaine, which tends to exclusively target the dopamine-rich limbic reward pathways. “This slow clearance of methamphetamine from such widespread brain regions may help explain why the drug has such long-lasting behavioral and neurotoxic effects,” said Joanna Fowler, lead author of the study.

The researchers also looked at a more controversial hypothesis—widespread reports that methamphetamine abuse among African Americans is markedly lower than it is among Caucasians. These reports lead Fowler and her colleagues to question “whether biological or pharmacokinetic differences might explain this difference.”

The answer? Evidently not. According to a Brookhaven press release, “Surprisingly, the researchers found significant differences in cocaine pharmacokinetics between African Americans and Caucasians, with the African Americans exhibiting higher uptake of cocaine, a later rise to peak levels, and slower clearance.” When it came to speed, however, the scientists failed to detect any racial differences in uptake.

Fowler’s conclusion: “Variables other than pharmacokinetics and bioavailability account for the lower prevalence of methamphetamine abuse in African Americans.”

She added that “the differences observed for cocaine pharmacokinetics are surprising considering there are no differences in cocaine abuse prevalence between these two ethnic groups.”

This may come as a surprise to people who have been taught by news coverage and crime dramas to think of the crack problem as a “black problem.” But it may also indicate an inherent physiological preference for cocaine among African Americans, regardless of stated levels of abuse prevalence. As usual, more studies are needed.

Image Credit: Brookhaven National Laboratory News

dopamine

Amphetamine Blues

How meth addiction happens.

If alcohol’s impact on brain cells is wide-ranging and diffuse, and marijuana’s impact is selective and subtle, the impact of cocaine and amphetamine is much more straightforward. “There is certainly lots of evidence for common neurological mechanisms of reward across a wide variety of drugs,” said Dr. Robert Post, chief of the biological psychiatry branch at NIMH.

Animals will readily administer cocaine and amphetamine, Dr. Post once explained to me, but when researchers surgically block out areas of the brain that are dense with dopamine receptors, the picture changes dramatically. “The evidence definitely incriminates dopamine in particular,” said Dr. Post. “In animal models, if you make selective lesions in the dopamine-rich areas of the brain, particularly the nucleus accumbens in the limbic system, the animals won’t self-administer either amphetamine or cocaine.”

When you knock out large slices of the nucleus accumbens, animals no longer want the drugs. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain won’t do, of course.

At the heart of the meth high is a chemical paradox. The entire range of stimulative effects hits the limbic system within seconds of being inhaled or inject, and the focused nature of the impact yields an astonishingly pleasurable high.

But the long-term result is exactly the opposite. The body’s natural stock of these neurotransmitters starts to fall as the brain, striving to compensate for the artificial flooding of the reward center, orders a general cutback in production. At the same time, the receptors for these neurotransmitters become excessively sensitive due to the frequent, often unremitting nature of the stimulation.

The release of dopamine and serotonin in the limbic structure called the nucleus accumbens lies at the root of active drug addiction. It is the chemical essence of what it means to be addicted. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” Dopamine is more than a primary pleasure chemical—a “happy hormone,” as it has been called. Dopamine is also the key molecule involved in the memory of pleasurable acts. Dopamine is part of the reason why we remember how much we liked getting high yesterday.

One reason why amphetamine addicts will continue to use, even in the face of rapidly diminishing returns, is simply to avoid the crushing onset of withdrawal. Even though the drug may no longer be working as well as it once did, the alternative--the psychological and physical cost of withdrawal--is even worse. When addicts talk about “chasing a high,” the metaphor can be extended to the losing battle of neurotransmitter levels. In the jargon used by Alcoholics Anonymous, addicts generally have to get worse before they can get better.

Speed, then, is diabolically well suited to the task of artificially stimulating the limbic reward pathway. Molecules of amphetamine displace dopamine and norepinephrine in the storage vesicles, squeezing those two neurotransmitters into the synaptic gap, and keeping them there, where they repeatedly stimulate their receptors. By mechanisms less well identified, cocaine accomplishes the same feat. Speed also interferes with the return of dopamine, norepinephrine, and serotonin molecules to their storage sacs, a procedure known as reuptake blocking—the same mechanism by which the so-called selective serotonin reuptake inhibitors (SSRI) antidepressants increase the availability of serotonin in the brain.

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

addiction drugs