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What can we learn from the failure of yet another

miracle cure for addiction?add_3652 237..239

The first long-term double-blind study of PROMETA

has demonstrated that this putative miracle cure formethamphetamine 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] rigor-

ous 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 methamphet-amine use, urinanalysis confirmed 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 allmethamphetamine-addicted people and their families

were understandably desperatefor a cure. In this environ-

ment, a former junk bond trader with no medical back-

ground raised US$150 million in capital to market a

combination of three medications (gabapentin, flumaze-

nil and hydroxyzine) as a treatment for methamphet-

amine addiction [3]. Normally, introducing a new

medication requires approval by the US Food and Drug

Administration (FDA), including tests of product safety

and an efficacy 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 pro-

tocol, despite the fact that none of the individual medica-

tions 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 confirmed

by random urine tests [4]. County and state officials

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 develop-

ments were toutedby themanufacturer in a massive mar-

keting campaign, bringing further media attention and

interest from potential patients. Patients and their fami-

lies cobbled together the US$12 00015 000 required to

purchase the wonder drug, which was made available

in franchised for-profit 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 first needle into the bubble by uncovering that

PROMETAs effectiveness had been g reatly exagger-

ated [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 outof thetreat-

ment program entirely. Equally damaging was the revela-

tion that the Pierce County treatment program manager,

andsome of thecounty andstate officials who hadhelped

arrange the US$900 000 in funding, were stockholders

in PROMETAs manufacturer [10]. This was thestart 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

field had a significant financial stake in the products

success1. As the reputation of the treatment became

1Whether financial conflicts of interest clouded any particular individuals judgment about PROMETAs effectiveness is not some-

thing I presumeto know. Certainly, an individual can havea financial stake in a proprietary addiction treatment and at the same time

believe sincerely that it will benefit patients. My sole point here is that PROMETAs standing with addiction professionals and the

publicwas erodedby the unusuallyhigh prevalence of potential financial conflictsof interests among itsadvocates,particularlywhen

such conflict of interests came to light through investigation by others rather than being disclosed voluntarily by the individuals

concerned.

EDITORIAL doi:10.1111/j.1360-0443.2011.03652.x

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tarnished, its manufacturers fortunes declined.The most

recent corporate report [11] of the formerly US150-

million-dollar company projected that it would run out

of cash by September 2011. Shares of its once-valuable

stock arecurrently trading at the price of 1 penny (i.e. 1%

of 1 US$).

THREE LESSONS FROM THE RISE AND

FALL OF PROMETA

1 Thewish fora simple, quick cure foraddiction is under-

standably widespread among addicted people, their

families, politicians and professionals in the addic-

tion field. 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 foraddiction 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, res-

pected sources. The simpler, faster and more miraculous-

seeming 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 opiate-

detoxification [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 thetreatment 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 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. The FDA should

convene a high-level study group to develop proposalsto better trade off these two concerns, using the

experience of PROMETA as one of its subjects for

analysis.

3 Independent scientific 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 deter-

mine 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 them-

selves to this calling should point with pride to

Linget 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 reflect official positions of the Department

of Veterans Affairs.

Declarations of interest

None.

Keywords Clinical trials, drug addiction, metham-

phetamine, PROMETA protocol, treatment.

KEI TH HUMPHREYS

Veterans Affairs and Stanford University Medical Centers,

795 Willow Road, Menlo Park, Palo Alto, CA 94025, USA.

E-mail: knh@stanford.edu

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