TABLE 1.

Off-label and investigational drugs in the treatment of alcohol use disorder: overview.

Medication	Results	Data	Recommendation	Mechanism of action	Medication group	Advantage	Disadvantage
Baclofen	Conflicting (promising, but serious safety concerns)	Good	Second-line therapy	GABA-B agonist	Muscle relaxant	Renal excretion	Dosing 3–4x/day
							Overdose risk with severe sedation and coma
Gabapentin	Conflicting (promising)	Good	Additional therapy	Inhibition of Na+ and Ca2+ cannels	Anticonvulsant	Reduction of heavy drinking	Overdose risk
			Reduction of heavy drinking
Topiramate	Promising	Intermediate	Additional therapy	GABAergic inhibition	Anticonvulsant	Mainly renal excretion	Moderate effect
			Second-line therapy
Ondansetron	Highly promising	Good	Combined therapy	Serotonin antagonist	Antiemetic	Especially for early onset alcoholism	Pharmacogenetic differences
Varenicline	Highly promising	Good	Combined therapy, especially for comorbid nicotine abuse	nAChR agonist	Smoking cessation	Nearly no hepatic metabolism	Not for maintaining abstinence, more for drinking reduction
Aripiprazole	Conflicting (promising)	Good	Second-line therapy for high-impulsivity and low self-control	Dopamine receptor agonist, serotonin receptor agonist and antagonist	Antipsychotic	For high-impulsivity	Pharmacogenetic differences
							Adverse events
Quetiapine	Highly disappointing	Intermediate	Not useful for treatment of alcohol use disorder	Serotonin and dopamine antagonist	Antipsychotic	Craving reduction only in patients with insomnia	Risk of misuse
Clozapine	Disappointing	Poor	Not useful for treatment of alcohol use disorder	Multiple neurotransmission pathways	Antipsychotic	Limited evidence for craving reduction	Risk of misuse
Antidepressants	Disappointing (except SSRI)	Limited	Further preclinical and clinical testing	Multiple mechanism of action depending on the drug	Antidepressants	Small reduction of alcohol consumption with SSRI.	Risk of misuse
							Possible pharmacogenetic differences
Lithium	Highly disappointing	Limited	Not useful for treatment of alcohol use disorder	Unknown mechanism of action	Mood stabilizer	No benefits for alcohol use disorder	Adverse events
Neuropeptide Y	Promising	Only preclinical studies	Further preclinical and clinical testing	G-protein coupled Y1-Y6 receptors	Neuropeptide	Preventing progression to addiction	Possible pharmacogenetic differences
Neuropeptide S	Conflicting (promising)	Only preclinical studies	Further preclinical and clinical testing	G-protein coupled neuropeptide S receptor	Neuropeptide	Anxiolytic effect	Possible diverse pharmacogenetic differences
CRF antagonists	Conflicting (promising)	Poor	Further preclinical and clinical testing and development of slow-offset antagonists	CRF1 and CRF2 receptors	Neuropeptide	Promising effect in preclinical studies	Poor translation from rodent studies to clinical human studies
Oxytocin	Highly promising (in rodent studies)	Poor	Further preclinical and clinical testing	Inhibition of growth hormone-releasing factor interactions with GABAergic interneurons in amygdala	Neuropeptide	Very good safety profile and mainly positive side effects	Very short half-life of intranasal oxytocin
			Perhaps as needed use				Poor translation from rodents to humans
PF-05190457	Highly promising	Poor	Further preclinical and clinical testing	Ghrelin receptor inverse agonist	Gastrointestinal peptide hormone system	Good safety profile	Dosage 3–4x per day
Memantine	Disappointing	Limited	Not useful as an anti-craving drug in treatment of alcohol use disorder	Non-competitive NMDA receptor antagonist	Treatment of Alzheimer disease	Maybe useful for alcohol-cue stimuli deconditioning	No effect on craving
Ifenprodil	Promising	Poor	Further preclinical and clinical testing	Non-competitive NMDA receptor antagonist	NMDA receptor modulator	Reduction of alcohol consumption in preclinical and clinical trials	Very limited data
Samidorphan	Promising	Poor	Further preclinical and clinical testing	μ-opioid receptor antagonist	Opioid system modulator	Favorable side effect profile	Somnolence and small risk of abuse
Ondelopran	Promising	Poor	Further preclinical and clinical testing	Selective opioid receptor antagonist	Opioid system modulator	Reduction of alcohol consumption	Very high interindividual pharmacokinetic variability
ABT-436	Conflicting (disappointing)	Poor	Probably not useful for treatment of alcohol use disorder	V1B antagonist	Vasopressin receptor antagonist	Favorable results for patients with high stress levels	Conflicting results within the study
SSR149415	Promising	Only preclinical studies	Further preclinical and clinical studies	V1B antagonist	Vasopressin receptor antagonist	Synergetic effect with naltrexone	Very limited preclinical data
Mifepristone	Conflicting (promising, but with very high misuse, risk of illegal abortion)	Limited	Not recommended in treatment of alcohol use disorder	Progesterone and type II glucocorticoid receptor antagonist	Medical abortion of pregnancy	Reduction of alcohol-induced neuro-degeneration	Very high risk of misuse for illegal abortion
Ibudilast	Conflicting (disappointing)	Poor	Further clinical testing	Non-selective phosphodiesterase inhibitor	Anti-inflammatory and treatment of asthma	Reduction of craving with depressive comorbidity	No craving reduction in general alcohol use disorder
Citicoline	Highly disappointing	Poor	Not useful for treatment of alcohol use disorder	Cell-membrane phospholipid intermediate product	Neuronal cell-membrane modulator	Reduction of cocaine consumption but with habituation effect	No effect at all on alcohol consumption and craving
Rimonabant	Highly disappointing	Poor	Not useful for treatment of alcohol use disorder	Selective CB1 receptor blocker	Endocannabinoid-system modulator	Treatment of tobacco smoking, obesity and cardiometabolic risk factors	Depression-related adverse events, anxiety and suicidal tendencies
Surinabant	Inconclusive	Only preclinical studies	Not useful for treatment of alcohol use disorder	CB1 receptor antagonist	Endocannabinoid-system modulator	Reduction of alcohol consumption in rats	No clinical data due to severe adverse events of rimonabant
AM4113	Promising	Only preclinical studies	Further preclinical and clinical testing	CB1 receptor neutral antagonist	Endocannabinoid-system modulator	In preclinical tests no anxiety and depression-like effects	No clinical data
Gamma-hydroxybutyrate (GHB)	Highly promising (but high risk of abuse)	Good	Not recommended by WHO for treatment of alcohol use disorder due to high abuse risk	GHB receptor and partial GABA-B receptor agonist	Treatment of narcolepsy and cataplexy	Very promising results for reduction of alcohol consumption	High abuse risk and misuse as rape drug. High risk of neuro-depression in case of co-ingestion with alcohol