Recently, TSM was attacked on the Forum with the claim "there is no proof - none - that TSM works at all in a clinical setting". I sent the note to Dr. David Sinclair, the scientist behind TSM. He felt that perhaps it was time to set the record straight, and provided me with this reply.

Roy Eskapa, PhD


From:

David Sinclair, Ph.D.
National Institute for Health and Welfare (THL)
Helsinki, Finland

We first need to clarify what TSM really is. (I usually call it “pharmacological extinction”, but actually this is a bit too narrow a term.)

TSM is taking naltrexone (or other opioid antagonists) in such a way that the medicine is in the brain when alcohol is drunk. This is the method I proposed in the 1980s: Having a subject suffering from alcoholism drink alcohol while sufficient quantities of naltrexone, nalmefene or naloxone are present in the brain to block the reinforcement from the alcohol.

Logically, the only alternative (the only way to use naltrexone other than TSM), is taking naltrexone or another antagonist in a way so that the medicine is only present when no alcohol is being drunk; during complete abstinence.
The scientific evidence is unequivocal: it supports TSM. In contrast, there is essentially no scientific support for opioid antagonists producing significant benefits without TSM.

Preclinical

Back in the 1980s, when the first studies came out showing that opioid antagonists reduced alcohol intake by rats and monkeys, our laboratory embarked on long series of preclinical studies, nearly 50 experiments, designed to determine the mechanism or mechanisms producing the effect. As one does in science, we test one hypothesis after another, eliminating those that were inconsistent with the results. After we had gone through all the hypotheses we could think of, I presented our results at other laboratories and asked for their suggestions of possible hypotheses.

When we were done, there were only two mechanisms left that were consistent with all of the data. The more important was extinction (also known as Pavlovian extinction): learned behaviors that are emitted and then do not get reinforcement are weakened, progressively with each trial. More recently, I have compared the rate at which drinking goes down over trials with the formula for extinction: it is almost a perfect match for both our preclinical and clinical data. Consequently, I am quite confident that opioid antagonists are producing extinction.

The other mechanism that survived all of the tests was that the antagonists may decrease the “first drink effect”, i.e., the increase in craving produced by the first drink of alcohol after abstaining. The total amount drunk on one occasion was decreased in rats and humans after even the first administration of an antagonist. This binge-limiting effect is less consistent and less powerful than extinction, but it does appear to be a second mechanism through which the antagonists produce benefits. Again, however, the binge-limiting effect only occurs after alcohol is drunk while on the medication. This, like extinction, it is part of TSM.

Clinical

The scientific evidence from clinical trials can be seen best in the database of trials using naltrexone and nalmefene included as Appendix A in Eskapa’s 2008 book, The Cure for Alcoholism. And earlier version of the database was published in 2004 (Sinclair and Fantozzi). The database currently contains 84 human studies (63 with alcoholism, 19 with other addictions) with conditions making extinction was possible: 82 of these studies (97.6%) reported significant benefits. 40 studies (38 with alcohol) had conditions making extinction impossible (e.g. naltrexone given in a hospital with no alcohol available, or during abstinence prior to the first drink after detoxification): 1 of these studies (2.5%) reported significant benefits. (Three other studies in the database did not describe their methods sufficiently to allow them to be classified as TSM or non-TSM). The Heinälä et al. 2001 dual double-blind placebo-controlled clinical trial should be given particular mention because it was specifically designed to test whether pairing with drinking was needed for naltrexone to be clinically effective. In addition, naltrexone was given without prior detoxification to alcoholics who were currently drinking. Naltrexone produced significant results with TSM; in contrast, naltrexone with abstinence tended to be worse than placebo. The naltrexone results with TSM were significantly better than with abstinence.

The conclusion that naltrexone works through extinction was reached long ago in research on heroin addiction. The first naltrexone clinical trial was with heroin addicts (Renault, 1978). This was a large double blind placebo-controlled clinical trial run by NIDA. The patients were told not to use any opiates while on the medication, and told that if they used a small dose of opiates they would feel no pleasure; if they used a large dose they might die. All together, naltrexone had no significant benefits over placebo. Some of the patients, however, disobeyed the instructions and used heroin or methadone. Naltrexone produced significant benefits in these patients. It was concluded that naltrexone works by extinction: consequently, naltrexone produced benefits when taken in a way so that the medicine is present when the person takes opiates but naltrexone does not work when taken so that the medicine is only present when the addict is not taking opiates. The study was published a second time in 1980 as a NIDA monograph. Nevertheless, the package insert today still says addicts should be told not use any opiates while on naltrexone, that if they take a small dose they will feel no pleasure, and that they will die if they take a large dose. It fails to state that the scientific evidence shows naltrexone only works if the patient disobeys these instructions. The conclusion that naltrexone causes extinction was published by Abram Wikler in the addiction field, long before I suggested it in the case of alcohol drinking. Perhaps TSM should be called TWM (The Wikler Method).

Logic

There is ample evidence that naltrexone can be effective, not only against alcoholism, but also in the treatment of opiate addiction, amphetamine addiction, pathological gambling, binge eating of foods that release endorphins, and kleptomania. It also can suppress various other behaviors including sexual interest, exercise, and maternal responses.
When a person first takes a naltrexone pill and the medication has reached the nervous system, how does it know which of these behaviors to block?

In fact, naltrexone alone does not block any of these behaviors. It only blocks the reinforcement produced after the person had drunk alcohol, taken heroin, amphetamine, gambled, binged on chocolate, looked at pornography, jogged, or cuddled a baby. The mechanism of extinction then weakens whichever response was made and then failed to produce the expected reinforcement, just like extinction weakened the salivation of Pavlov’s dogs to the bell, after they had made that learned response and failed to get the expected reinforcement.

So what difference does it make, knowing how naltrexone works?

First, knowing the mechanisms tells us how to make naltrexone be more effective. Currently, naltrexone has a reputation in the alcoholism field for having only modest efficacy. I believe a major reason for this is that naltrexone is being prescribed along with instructions to abstain. Some of the patients, sometimes, happen – intentionally or accidently - to do the right thing by drinking while the medication is present in the brain. When this happens they experience benefits. . As in the heroin clinical trial, only those alcoholics who disobey the instructions to abstain while on naltrexone receive benefits from the medication. This, by the way, was the conclusion in the first naltrexone-alcoholism clinical trial (Volpicelli et al., 1992): the significant benefits of naltrexone were seen in those patients who drank alcohol while on the medication.

Under these circumstances, the medicine demonstrates only modest efficacy. At least partly for this reason, few doctors are prescribing naltrexone for treating alcoholism. A great opportunity for helping the majority of alcoholics is being lost.

Second, knowing how naltrexone works prevents needless suffering, danger, and expense to the patients from the practice of detoxification. The standard naltrexone protocol is to subject alcoholics first to detoxification before starting the naltrexone in the false hope that it will help maintain abstinence. Knowing that naltrexone works only when paired with drinking, however, makes it obvious that prior detoxification should be eliminated: naltrexone should be given to patients who are currently drinking and thus will benefit from the medication – as a result of pharmacological extinction. Most patients then show a gradual reduction in drinking month after month. By four months, most of the patients are, in fact, detoxified: they no longer are physiologically dependent upon alcohol. The detoxification was done, however, slowly and safely, and without the use of addictive detoxification medicines. Indeed, TSM can be seen as an alternative means of detoxification, but with the added benefit that the subjects lose their interest in alcohol.


David Sinclair, Ph.D.
National Institute for Health and Welfare (THL)
Helsinki, Finland


Note from Roy Eskapa -

The COMBINE study did not set out to test TSM - pharmacological extinction. It did however conclude that naltrexone - previously only prescribed by specialists - could now be made available in general medical settings. COMBINE was published in May 2006 in the Journal of the American Medical Association (JAMA) - the significance is that family practitioners can now safely prescribe naltrexone for addictive drinking under basic medical management. Prior to this, doctors could be reluctant to prescribe naltrexone unless the patient were seen by a specialist.

I will soon post the updated database for the clinical trials on humans.

Thank you, Dr. Eskapa for making an appearance. I am very thankful you posted the response from Dr. Sinclair along with your personal comments.

Personally, I am tired of defending and promoting this very successful alcoholism treatment method that has cured me beyond the doubt of any rational mind. I keep my weekly "unit" numbers in my signature line for all to analyze. They are real-life genuine numbers of a real person (me) for which I could produce scanned written notes from my planning book if I had to back them up in a court of law.

Yet, people come on here and continually dispute TSM. I understand some skepticism. I understand why people have some questions. But this forum just burns out moderators. Currently, there is no moderator. I will not be one. I have exactly 10 weeks and 5 days left before I leave this forum just as I have promised my wife, and I can hardly wait.

So N101CS and DrRoyEskapa, please please please rise to the occasion, keep TSM and this website alive, and continually popularize TSM until it becomes the self-sustaining treatment of choice for alcoholism treatment.

Bob

EDIT: I have removed the following statement I made yesterday because I exhibited AA/12stepper behavior: "And for all you nay-sayers, recoverism addicts and 12-stepping drones, if you don't like the treatment then get the hell out of here and leave these recovering people alone." There is no place for this emotionally charged statement when we are debating science. I apologize.

It'll be good to see the updated database. Personally, I'm glad of this opportunity to thank you, because even though I'm only <2 months in, I already have "significant benefits". Its good not to have to worry about alcoholism anymore, and its great that I found this cure when I'm relatively young (25).

I have since passed on your book to at least two other people.

I wouldn't worry too much about people say online- if they are saying it anonymously, they surely must lack integrity and therefore it can be largely discounted.

Well said, Bob!

Hi Dr. Eskapa,

Thanks for the response, and for making this treatment available for so many of us. After 4 months, I am seeing results after so many pathetic and demoralizing years of struggling. For that I am immeasurably grateful!

I would love to see you sponsor either this site, or one like it, to help people along the way, and help move TSM more into the mainstream. My understanding is that this site is all volunteer and that we may need a moderator (a thankless job, as I hear it.)

Is there any chance you could hire someone to be a moderator, in support of your book? And maybe you and your organization could host conferences of TSM doctors (and any cured folks who don't mind being public) to share information, spread the word and publicize their success stories?

I think your book is a great start, but we have too many unsupported people out here flying solo. I think a worldwide effort to advertize and organize would greatly help this cause!

I, too am tired of this. I expressed my scientific reservations about TSM, but it is apparent that this is basically a support forum for true-believers. I don't want to discourage anyone from pursuing TSM, since the evidence is that NAL works.

Drs. Sinclair and Eskapa's answer adds nothing to my original discussions. In brief, I believe that the rat model (again these rats were bred for alcoholism) shows extinction behavior. There is no question here. But this only points the way to human study, and you can't use these rat studies as support for or against TSM.

The vast majority of the clinical studies quoted have no relevance to TSM at all, except that NAL was used. The 78% success rate is from one clinic study - non-peered reviewed and not even repeated by that same clinic. There is nothing close to a DBPS for TSM.

I repeat, there is *no* good support for TSM. Yes, some users will get cured, just as some self-remitters (folks who just decide to cut down drinking on their own without any meds or groups) get cured. Anedoctal reports prove nothing, but can suggest formal studies. I am sorry if I can not get this basic scientific point across.

Obviously, as a skeptic and "nay-sayer" among the cured and soon-to-be-cured, I am outsider here. Neither I nor the rest of the group benefits from further discussions along these lines, so I will sign off.

I wish everyone the best in dealing with his/her AL problems.

I CAME , I SAW , I PISSED EVERYBODY OFF THEN NONCHALENTLY WALKED AWAY FROM

THE WRECKAGE .

Jeez folks

cut the guy a break. He is here, he is doing TSM the same as us. He has simply asked some questions based on the reading he has done of the quoted material. He isn't dismissing TSM. He isn't knocking it. He is asking legitmate questions which if/when resolved will help strengthen the case for the method. How many people have done as he has, and gone back to source? A few, me included, and guess what - he has a point!
That doesn't mean there aren't good reasons why this is the case, but he is entitled (and should be encouraged) to ask questions - that is the way we all progress.

We're in danger of becoming as dogmatic as those we often mock/scorn in AA/SoberRecovery etc

that's ALL you ever did, and you were constantly saying the evidence was opposite of what you say here (see below) unless you mean the evidence is that Nal works in conunction with abstinence and not with TSM, which is not true.


this quote either contradicts your above statement, or is implying that Nal works better while abstaining. Maybe you don't have enough evidence that TSM works to satisfy you (why the hell are you, a friggin genius know it all, doing TSM then?) but we don't have enough evidence that Nal works without TSM, and some of the studies even showed a negative effect of Nal with abstinence. and since the last sentence here implies that TSM is placebo effect, why the hell would you be on TSM? I still don't think you are.


Good riddance! You were offered the opportunity to question all you liked, even encouraged to do so. and that's ALL you ever did here. You bristled every time anybody disagreed with you and took offense to everything, even insulting those on the TSM path by comparing us to 12 steppers. You made yourself an outsider with your snotty, condescending, know it all attitude, The fact that you question and research was never an issue, but now that Sinclair and Eskapa have entered the conversation, you're turning tail and running and blaming it on those who disagree with you or those who you have insulted. I'm not surprised. This was your chance to get answers, but you didn't want answers. Eskapa said he would post the studies later, but you didn't even stick around did you? seems such a curious mind as yours would want to look into that.
I know a TROLL when I see one



I don't think you do. I don't think you are doing TSM. If someone is SO down on a method, why would they be practicing said method. It is obvious you came here with some sort of axe to grind, and I'm thinking maybe you are a 12 stepper who thinks he's fighting the good fight by discouraging people from trying TSM so maybe they'll end up being "saved" in AA by the "sunlight of the spirit"

I tried to give you the benefit of the doubt but you have now proven that you were only here to stir up a shitstorm,