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EDITORIAL

doi:10.1111/j.1360-0443.2011.03652.x

What can we learn from the failure of yet another miracle cure for addiction?
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The rst long-term double-blind study of PROMETA has demonstrated that this putative miracle cure for methamphetamine addiction is ineffective. Given the vulnerability of addicted people and their desperation for a cure, effective governmental regulation and a shared spirit of skepticism about wonder drugs should always be maintained. In this issue of Addiction, Ling and colleagues [1] rigorous clinical trial concludes that the much-ballyhooed PROMETA protocol is ineffective as a treatment for methamphetamine dependence. Patients receiving the protocol did no better than those on placebo, regardless of whether the outcome was self-reported methamphetamine use, urinanalysis conrmed use or self-reported craving. The story of this miracle cure will, in some ways, be familiar to students of the history of addiction treatment [2], yet warrants analysis because of what it might teach us about the addiction treatment and research enterprise. Like most of the putatively simple cures for addiction that have risen rapidly to prominence through history [2], PROMETA burst onto the public scene during an epidemic, namely the rapid growth of methamphetamine addiction in the western United States in the early 2000s. Treatment professionals, politicians and most of all methamphetamine-addicted people and their families were understandably desperate for a cure. In this environment, a former junk bond trader with no medical background raised US$150 million in capital to market a combination of three medications (gabapentin, umazenil and hydroxyzine) as a treatment for methamphetamine addiction [3]. Normally, introducing a new medication requires approval by the US Food and Drug Administration (FDA), including tests of product safety and an efcacy trial such as that conducted by Ling and colleagues [1]. A loophole in this regulatory system is that 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. The manufacturer of PROMETA was therefore able to

immediately market and sell a new addiction treatment protocol with no federal review or clinical trial evidence. Grateful testimonials from individuals who said that PROMETA had cured them of methamphetamine addiction overnight soon appeared in major media outlets [3]. A drug court-based treatment agency in Pierce County, Washington then reported astounding results from a pilot study: 98% abstinence conrmed by random urine tests [4]. County and state ofcials bestowed an US$900 000 grant to expand the PROMETA program. Meanwhile, a small, open-label single-group study in Texas by Urschel and colleagues [5] reported positive preliminary results on PROMETA (although the studys methods were sharply critiqued [6]), and some well-known clinicians around the country endorsed the treatments value [7]. All these developments were touted by the manufacturer in a massive marketing campaign, bringing further media attention and interest from potential patients. Patients and their families cobbled together the US$12 00015 000 required to purchase the wonder drug, which was made available in franchised for-prot treatment centers. Amid this boomlet of enthusiasm, those who wanted to wait for rigorous research [8] before embracing the miracle cure were largely swept aside as fuddy-duddies who were denying life-saving care to seriously ill people. A subsequent audit of the Pierce County program put the rst needle into the bubble by uncovering that PROMETAs effectiveness had been greatly exaggerated [9]. The incredible 98% rate of clean urines had been calculated only after excluding patients who did not show up for required tests or had dropped out of the treatment program entirely. Equally damaging was the revelation that the Pierce County treatment program manager, and some of the county and state ofcials who had helped arrange the US$900 000 in funding, were stockholders in PROMETAs manufacturer [10]. This was the start of a pattern: sometimes through commendable disclosure by the people concerned [7] and sometimes through investigative journalism, it became evident that a large proportion of the pro-PROMETA voices in the addiction eld had a signicant nancial stake in the products success1. As the reputation of the treatment became

1 Whether nancial conicts of interest clouded any particular individuals judgment about PROMETAs effectiveness is not something I presume to know. Certainly, an individual can have a nancial stake in a proprietary addiction treatment and at the same time believe sincerely that it will benet patients. My sole point here is that PROMETAs standing with addiction professionals and the public was eroded by the unusually high prevalence of potential nancial conicts of interests among its advocates, particularly when such conict of interests came to light through investigation by others rather than being disclosed voluntarily by the individuals concerned.

Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

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tarnished, its manufacturers fortunes declined. The most recent corporate report [11] of the formerly US150million-dollar company projected that it would run out of cash by September 2011. Shares of its once-valuable stock are currently trading at the price of 1 penny (i.e. 1% of 1 US$).

THREE LESSONS FROM THE RISE AND FALL OF PROMETA 1 The wish for a simple, quick cure for addiction is understandably widespread among addicted people, their families, politicians and professionals in the addiction eld. Many serious, good-hearted people will be shocked at Lings [1] negative results because they believed sincerely that PROMETA was a miracle cure for methamphetamine addiction. From this latest disappointment, we should absorb the following lesson: when the next wonder drug for addiction comes along (and it will), 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 miraculousseeming the cure, the greater should be our skepticism. 2 There is a worrisome vulnerability in the US FDAs new drug approval process. As was the case with another would-be miracle cureultra-rapid opiatedetoxication [8]a manufacturer was able to market an untested treatment protocol to addicted patients because the components of the treatment protocol had been previously FDA-approved for the treatment of other disorders. It seems very unlikely that the typical addicted patient understands that all components of this treatment protocol have been FDA-approved does not necessarily imply that the treatment protocol itself has any evidence of being an effective treatment for addiction. Off-label use of medications is well-established in medical practice and has signicant value in many cases, but a balance must be struck with the risk this creates for evasion of the normal safety and efcacy checks by creators of new treatment protocols. The FDA should convene a high-level study group to develop proposals to better trade off these two concerns, using the experience of PROMETA as one of its subjects for analysis. 3 Independent scientic research on addiction is essential for public health and safety. We have a huge advantage at this historical moment which was not available to people in prior eras who could not determine whether Dr. Keeleys Double Chloride of Gold Injections, Dr. Revalys Guaranteed Remedy for the Tobacco Habit and Dr. Meekers Addiction Antidote were effective [2]: a well-developed addiction treat-

ment research enterprise. Those who devote themselves to this calling 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. Society needs more than anecdotes, testimonials and marketing materials to decide which interventions should be allowed a place in our health-care system; treatment research is how to get it. Authors note Dr Humphreys work on this paper was supported by a US Department of Veterans Affairs Senior Research Career Scientist award. The content of this paper do not necessarily reect ofcial positions of the Department of Veterans Affairs. Declarations of interest None. Keywords Clinical trials, drug addiction, methamphetamine, PROMETA protocol, treatment.
KEITH HUMPHREYS

Veterans Affairs and Stanford University Medical Centers, 795 Willow Road, Menlo Park, Palo Alto, CA 94025, USA. E-mail: knh@stanford.edu References
1. Ling W., Shoptaw S., Hillhouse M., Bholat M. A., Charuvastra C., Heinzerling K. et al. Double-blind placebo-controlled evaluation of the PROMETA protocol for methamphetamine dependence. Addiction 2012; 107: 3619. 2. White W. L. Slaying the Dragon: The History of Addiction Treatment and Recovery in America. Bloomington, Illinois: Chestnut Health Systems; 1998. 3. CBS News. Televised Segment of 60 Minutes Titled Prescription for Addiction. 10 December, 2007. Available at: http:// www.cbsnews.com/video/watch/?id=3596421n (accessed 1 September 2011; archived by Webcite at http://www. webcitation.org/634RF7MES). 4. Clarridge C. Pilot Program Helps Ease Drug Addictions. 9 July 2006. Available at: http://seattletimes.nwsource.com/ html/localnews/2003114981_drugtreatment09m.html (accessed 22 August 2011; archived by Webcite at http:// www.webcitation.org/634RXQbBv). 5. Urschel H. C., Hanselka L. L., Gromov I., White L., Baron M. Open-label study of a proprietary treatment program targeting type A g-Aminobutyric acid receptor dysregulation in methamphetamine dependence. Mayo Clin Proc 2007; 82: 11708. 6. Mendelson J., Rawson R., Newton T., Galloway G., de Wit H., Dewey S. L. et al. Treatment of methamphetamine dependence. Mayo Clin Proc 2008; 83: 36873.
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Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

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7. Smith D., Torrington M. Biologic intervention is warranted. California Society for Addiction Medicine News 2006; no volume number: 2. 8. Rawson R., McLellan A. T. Insufcient scientic evidence for Prometa. California Society for Addiction Medicine News 2006; no volume number: 3. 9. Huss K. Setbacks Plague Drug Addiction Remedy. 11 January 2008. Available at: http://www.msnbc.msn.com/id/ 22315918/ (accessed 22 August 2011; archived by Webcite at http://www.webcitation.org/634RGigpa).

10. Otto M. A. Local Ofcials Owned Stock in Company. 24 December 2007. Available at: http://www.thenewstribune.com/ 2007/10/24/186348/local-ofcials-owned-stock-in.html (accessed 22 August 2011; archived by Webcite at http:// www.webcitation.org/634ROkiXg). 11. Hythiam Inc. Reports Operating Results. 16 May 2011. Available at: http://www.gurufocus.com/news/133352/ hythiam-inc-reports-operating-results-10q (accessed 22 August 2011; archived by Webcite at http://www. webcitation.org/634R3qOAa).

Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Addiction, 107, 237239