Nalmefene is the first medication approved for alcoholism with the primary goal of reducing alcohol intake in an as needed approach. Nalmefene received a marketing authorization valid throughout the European Union on February 25, 2013 and is under development in Asia. Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile. In vitro studies have demonstrated that Nalmefene is a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor. In vivo studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions. In the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name Revex. The product was discontinued by its manufacturer around 2008. Currently Nalmefene is sold under the trade name Selincro. Selincro is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking-risk level, without physical withdrawal symptoms and who do not require immediate detoxification.

Dexoxadrol is a sigma receptor agonist. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. Dexoxadrol was developed as analgesics for use in humans, however, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol. Dexoxadrol is a NMDA receptor antagonist, which possesses high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel.

DOV-102,677 is a “Triple” Monoamine Neurotransmitter Uptake Inhibitor being developed by Merck for treating the major depressive disorder. In preclinical studies, DOV 102,677 increased extracellular levels of DA and 5-HT in the prefrontal cortex at 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. However, phase I clinical trials for treatment Depression in the USA was discontinued. Instead of being developed for depression, DOV-102,677 is being developed for the treatment of alcoholism.

PF-670462 is a selective inhibitor of the δ- and ε-isoforms of casein kinase I, with IC50 values of 7.7 and 14 nM respectively, and >30 selectivity relative to 42 other kinases tested. Casein kinase Iε phosphorylates PER proteins, which are involved in setting the period of the circadian pacemaker or clock. PF-670462 is potent (IC50 7.7 nM) and effective in vivo (i.e. it induces profound phase delays in circadian periodicity). PF-670462 has being shown to have an ability to induce phase delays in circadian rhythms in rats, in which it is rapidly metabolized, and in monkeys. A potential pharmacological use of the compounds like PF-670462 could be for therapy of cognitive deficits in shift workers, mood changes in bipolar disorders, and phase advances in the sleep–wake cycle in elderly people. It has also being shown that Inhibition of the casein-kinase-1-ε/δ/ with PF-670462 prevents relapse-like alcohol drinking in rats, suggesting that CK1 inhibitors may be candidates for drug treatment development for alcoholism.

BIIE-0246 is a highly potent, high affinity antagonist selective for the Y2 receptor subtype. BIIE-0246 is a drug used in scientific research, it was one of the first non-peptide Y2-selective antagonists developed, and remains among the most widely used tools for studying this receptor. It has been used to demonstrate a role for the Y2 subtype as a presynaptic autoreceptor limiting further neuropeptide Y release, as well as modulating dopamine and acetylcholine release. Blockade of central neuropeptide Y (NPY) Y2 receptors by BIIE-0246 has being shown to reduce ethanol self-administration in rats.

SB-206606 (better known as BRL-37344) was developed by Beecham Pharmaceuticals and is currently licensable from GlaxoSmithKline. SB-206606 is an agonist for the Beta-3 adrenergic receptor with an EC 50 value of 17 nM (human B3AR expressed in CHO cells). SB-206606 was in pre-clinical development as a potential treatment of Diabetes Mellitus, although such efforts have been discontinued. Recently it has also garnered some interest as a potential treatment for alcoholism.

Norharman or beta-carboline (9H-pyrido[3,4-b]indole) is a neuroactive alkaloid first isolated from Peganum harmala L. It is implicated in a number of human diseases including Parkinson's disease, tremor, addiction and cancer. Norharman formed endogenously but external sources have been identified (among others fried meat and fish, meat extracts, alcoholic drinks, coffee brews, tobacco smoke). It inhibits monoamine oxidase and indoleamine 2,3-dioxygenase. In addition norharman binds with high affinity to imidazoline I2B receptors. Plasma norharman levels are elevated in chronic alcoholics and Parkinson's disease patients.

Picamilon (also known as N-nicotinoyl-GABA, Pycamilon, and Pikamilon) is a drug formed by a synthetic combination of niacin and GABA. It was developed in the Soviet Union in 1969 and further studied in both Russia and Japan as a prodrug of GABA. Picamilon permeated the blood-brain barrier and then is hydrolyzed into GABA and niacin. The released GABA, in theory, would activate GABA receptors potentially producing an anxiolytic response. The second released component, niacin, is a vasodilator. Today picamilon is sold in Russia as a prescription drug and is used for the treatment of a variety of illnesses and disorders, ranging from depression to a migraine, neuro infections, senile psychosis, certain types of glaucoma, and even acute alcohol intoxication. As of 2015, the FDA classified picamilon as a substance that does not meet the requirements of a dietary supplement and is therefore no longer permitted to be sold in the United States.

Lithium orotate consists of lithium, an alkali metal, and orotic acid, a compound produced naturally in the body. Lithium orotate is marketed as a dietary supplement. It has a “GRAS” status. The chronic administration of lithium helps to support healthy mood by modulating NMDA receptors in the brain. Lithium also alters sodium transport and interferes with other ion exchange mechanisms, altering nerve conduction. Lithium can replace sodium in extracellular fluid. Recommended applications are: supports balanced mood; modulates polarization of cell membranes; ameliorates headaches; reduces alcohol cravings; supports healthy brain aging. Typical side effects are muscle weakness, apathy, loss of appetite (from all of one human trial).

Nitrefazole (2-methyl-4-nitro-1-(4-nitro-phenyl)imidazole, Altimol) is a strong and long lasting inhibitor of aldehyde dehydrogenase, an enzyme involved in the metabolism of alcohol. It was used for the treatment of alcoholism as an alcohol-sensitizing agent (alcohol deterrent). Nitrefazole was introduced in the early 1980s. By 1984 its use had been associated with hepatotoxic reactions, some of which were fatal. This lets to its withdrawal. WHO has no information to suggest that preparations containing nitrefazole remain commercially available.