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Alcohol dependence is a major public health problem. Of all the drugs of abuse, alcohol is estimated to have caused the most harm to human health. This is partly due to the fact that alcohol is widely available and alcohol intoxication is socially acceptable.
Alcohol dependence and abuse is highly comorbid with mental health issues. Identifying drugs that could help mitigate alcohol cravings in substance users is an important area of drug discovery.
One’s susceptibility to alcohol dependence and abuse has been linked to a number of polymorphisms (genetic variations within the population).
The polymorphism Rs1799971 is particularly relevant to alcoholism:
The rs1799971(G) allele in exon 1 of the mu opioid receptor OPRM1 gene causes the normal amino acid at residue 40, asparagine (Asn), to be replaced by aspartic acid (Asp). In the literature this SNP is also known as A118G, N40D, or Asn40Asp
Some of the self-reinforcing effects of alcohol administration stem from the fact that alcohol hijacks the opioid system. Hence, the polymorphism *rs1799971 *results in abnormal mu-opioid activity and confers increased risk of developing alcoholism. The opioid system underlies the euphoriant effects of painkillers like morphine or heroin.
Tianeptine and Alcohol
Tianeptine, an antidepressant drug used in Europe (but not in the US), binds to mu-opioid receptors in the brain. Despite this activity, Tianeptine is not considered a drug of abuse, though in rare cases Tianeptine dependence and abuse has been reported.
Tianeptine has a novel mechanism of action that involves modulation of glutamate receptors and activation of the mu-opioid receptor. Tianeptine also reverses stress-induced synaptic remodeling in animal models.
Since Tianeptine is a full agonist at the mu-opioid receptor, Tianeptine may help alleviate alcohol cravings by behaving as a kind of opioidergic substitute.
It was recently reported that acute Tianeptine administration reduced withdrawal symptoms in alcohol-dependent rodents[ref]Uzbay T, Kayir H, Celik T, Yüksel N. Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats. Progress in neuro-psychopharmacology & biological psychiatry. 30(3):478-85. 2006. [pubmed][/ref]. Specifically, tianeptine treatment attenuated locomotor hyperactivity and agitation in animals withdrawn from ethanol after chronic exposure.
This hypothesis has also been tested in humans. Consider the following abstract[ref]Favre JD, Guelfi-Sozzi C, Delalleau B, Lôo H. Tianeptine and alcohol dependence. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 7 Suppl 3:S347-51. 1997. [pubmed][/ref] (emphasis mine):
Tianeptine has been shown to be active in the treatment of depression in patients with history of alcohol abuse or dependence. In a first double-blind study performed versus amitryptiline, depression after withdrawal was improved by tianeptine, and biological abnormalities usually related to chronic alcohol intake tended to decrease. Similar results were found in an open study carried out on 277 alcoholic patients treated for 1 year. As these patients were depressed, no definite conclusion could be drawn from these results in respect of a specific action of tianeptine on alcohol dependence. Thus, a multicentre double-blind study has been performed which compared tianeptine (12.5 mg t.i.d) and placebo in 342 non-depressed patients fulfilling DSM-III-R criteria for Psychoactive Substance Dependence (alcohol)
Though more research is needed, it may be worth asking whether Tianeptine should be added to the pharmacologic armamentarium for the treatment of alcohol dependence, along with other opioidergic agents like Naltrexone.