Vincent Dole was one of the three physicians who originated methadone as a maintenance drug treatment for heroin addiction in the 1960s. Rather unexpectedly, he was asked to serve as a Class A, non-alcoholic, trustee for the General Service Board of Alcoholics Anonymous. He thought they had made a mistake so before accepting the position, he discussed his research into “chemotherapy for narcotic addiction” with executives of the A.A. Fellowship. They didn’t see any problem or conflict of interest with his appointment and Dr. Dole served as a trustee for A.A. for eleven years, from April of 1965 until April of 1975.

At one point in his tenure as a trustee, he served as a co-chair for the General Service Board. In his farewell letter to the A.A. GSO, printed in the August-September issue of Box 4-5-9, the newsletter from the General Service Office of A.A., he said he would always remain identified with A.A. “My heart is with the Fellowship.”

Like most in A.A., I have gained more in the association than I have been able to give. Especially, it has been a privilege to witness the power of love when focused and unsentimental. I have seen that: Salvation is found in helping others; help stems from knowledge, humility, compassion, and toughness; success is possible.My greatest concern for the future of A.A. is that the principle of personal service might be eroded by money and professionalism. Fortunately, most of the membership of A.A., especially the oldtimers, know that A.A. cannot be commercialized. It is not a trade union of professional counselors or an agency hustling for a budget. The mysterious wisdom of A.A. will discover how to cooperate in reaching out to sick alcoholics while maintaining its Traditions.

In a 1991 article he wrote for the journal Alcoholism, “Addiction as a Public Health Problem,” Dr. Dole said that throughout his time as a trustee he was puzzled by why he specifically was asked to serve. He ended by assuming he had been “brought in as a smoke alarm, a canary in the mine” to guard against “the Fellowship being distorted by aggressive person with dogmatic opinions.” Then, in the late 1960s, he believed a more specific reason emerged, not long before Bill W.’s death. An excerpt from that article is available here: “The Methadone/AA Link.”

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research I should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Dr. Dole went on to say he unsuccessfully sought to find that analogue in his laboratory until it closed in 1991. But he thought the work had just begun. Other laboratories and investigators would continue to work on the analogue problem. “With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.”

Since Dr. Dole made that optimistic prediction, several different medications have been used as a harm reduction strategy for individuals with alcohol dependence or alcohol use disorders. Two opioid antagonists, nalmefene and naltrexone and three drugs acting on the gamma-aminobutyric acid (GABA)ergic system (baclofen, acamprosate and toprimate) has been used formally or informally to reduce alcohol consumption or maintain abstinence. Recently in the journal Addiction, Palpacuer et al. did a meta-analysis of 32 double-blind randomized controlled trials of these five medications. The studies were published between 1994 and 2015, and had a combination of 6,036 patients between them. They concluded:

There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.

There was no evidence of any significant reduction in serious adverse events or mortality. Studies that sought to assess the efficacy of these medications as maintenance drugs, similar to how methadone is used, “were inadequate to investigate” whether they reduced serious adverse events. “In addition, any pharmacological approach that might benefit patients by reducing their alcohol consumption might also harm them because of safety issues.” As a result, the researchers advocated for long-term mega-trials exploring health outcomes.

To conclude, our results suggest that no treatment currently has high-grade evidence for pharmacologically controlled drinking in the treatment of patients suffering from alcohol dependence or alcohol use disorders. At best, some showed low to medium efficacy in reducing drinking, but across a range of studies with a high risk of bias. Although based on all available data in the public domain, this meta-analysis found no evidence of any benefit of the use of drugs aiming for a controlled drinking strategy on health outcomes. We invite researchers and stakeholders to set up a coherent agenda to demonstrate that pharmacologically controlled drinking can be translated into genuine harm reduction for patients. From the clinical perspective, while this new approach is often presented as a ‘paradigm shift’ in terms of therapeutics, doctors and patients should be informed that the critical examination of the pros and cons of the evidence clearly questions the current guidelines that promote drugs in this indication.

Reporting for The Guardian, Sarah Boseley further noted that one of the reasons for the inconclusive findings in Palpacuer et al. was because of the high drop out rates in the studies. “So many people dropped out of the trials that 26 of the 32 studies – 81% of them – had unclear or incomplete outcome data.” The lead author for the study, Clément Palpacuer, said the report did not mean the drugs weren’t effective. “It means we don’t yet know if they are effective. To know that, we need more studies.” There have also been concerns raised about the drugs by some studies already.

Bosley cited Fitzgerald et al., a review of the trial evidence used to approve nalmefene for use in the NHS. The researchers said at best, there was only modest evidence of efficacy in reducing alcohol consumption. This was despite stacking the deck in how the data was analyzed for approval of the drug.

Important weaknesses in nalmefene trial registration, design, analysis and reporting hamper efforts to understand if and how it can contribute to treating alcohol problems in general practice or elsewhere. The efficacy of nalmefene appears uncertain; a judgement of possible limited efficacy in an unusually defined and highly specific post‐hoc subgroup should not provide the basis for licensing or recommending a drug.

There are issues noted with baclofen as well. A co-author of Fitzgerald et al. noted one French study raised concerns with the safety of baclofen, with more deaths in the treatment group (7 of 162) than the placebo group (3 of 158). A further study by France’s medicines safety agency drew attention to additional adverse effects: “In particular, the risk of intoxication, epilepsy and unexplained death [on the death certificate] increases with the dosage of baclofen.” See “Sure Cure for Drunkenness” and “A ‘Cure’ for Alcoholism” and “The End of Alcoholism?” Part 1, Part 2 and Part 3 for more concerns with baclofen and nalmefene.

Vincent Dole’s search for a methadone analogue or adjunctive chemotherapy for alcoholism is unlikely to be successful. As Carleton Erickson pointed out in The Science of Addiction, alcohol is different than other drugs. He said: “Unlike other drugs, alcohol has no specific receptor to activate in the brain.” Cocaine works on the dopamine transporter. Heroin and other opioids work on the opioid receptor; and marijuana works on the cannabinoid receptor. “Alcohol is known to affect the GABA receptor, the NMDA receptor, and probably others.”

There isn’t a hand-in-glove fit between a receptor and alcohol as there is with the opioid receptor and heroin or other opioids. So there isn’t a medication that can single handedly block alcohol as there is with heroin and other opioids. As Bill W. knew from personal experience, alcohol is cunning, baffling and powerful.