Alcohol craving is an uncontrollable desire to take alcohol and symptoms including anxiety, asthenia, anorexia and insomnia, when this desire is not fulfilled (1). There are several counterparts of the term “craving”, which is described as “a strong desire” in Oxford Dictionary, in Turkish, such as “arzu”, “istek” and “aşerme”; we preferred the last one since we believe it is more appropriate. When the individual start drinking alcohol, a very strong desire to use alcohol develops and this desire continues for a long time. This results in continued use of alcohol by the individual in spite of serious side effects and important negative outcomes (1,2). 

Brain reward system, reinforcing effect of the substance and craving forms the trivet of dependence neurobiology (3). First of all, a substance has to induce euphoria in order to cause dependence. Therefore, it has been hypothesized that dependence equals to brain reward system. Indeed, research has shown that nucleus accumbens and dopamine as a neurotransmitter have a role in emergence of dependence, but this hypothesis is insufficient to explain all processes associated with dependence (4). Following this, it has been argued that reward can not be the only reason for dependence since non-dependent individuals experience same level of pleasure when using these substances. In this context, need to focus on processes other than reward have been increasingly stressed. Concept of craving came in this process; first it was taken on as a symptom of withdrawal, later, it was reported in patients who stopped using the substance several years ago and it has been taken on as a separate phenomenon. Thus, during 1990s and 2000s, different aspects of craving became a research topic. In the recent years, with the advent of technology, it has become possible to study changes leading to craving at cell nucleus and DNA levels (5,6). 

In parallel to these developments in the world, by 2000s articles investigating different aspects of craving have begun to be published in our country. In those articles, different models explaining craving were described and their reflections in treatment were discussed (1,7,8), and reliability and validity of scales which have been used widely in the world, such as obsessive compulsive desire to drink and Penn alcohol craving scale, were investigated (9-11).

In this article, our aim was to review new developments in this field by searching for full text articles in Pubmed and Turkish Psychiatric Index data bases by using craving, neurobiology, genetics, epigenetics and different drug names as key words. 

Neurobiology of Alcohol Craving

Dopamine has an important role in regulation of brain reward system and is also closely associated with craving. Association of dopaminergic system and craving was first shown in animal studies. Brain imaging and drug studies following these found that dopamine has a role in craving. In brain imaging studies, mesolimbic dopaminergic alterations resulting from chronic use of several different substances, from nicotine to cocaine, are shown to be associated with craving. Besides, there are several studies and case series which indicates that antidopaminergic drugs decrease craving while dopaminergic agents increase it (12,13).

Since every neurotransmitter system in the brain is interrelated, serotonorgic, glutamatergic, noradrenergic, GABAergic, and endogen opioid systems are also related with craving. Anton grouped craving into three. He argued that, GABAergic and glutamatergic systems were responsible for abstinance related craving, while dopaminergic, glutamatergic and endogen opioid systems were responsible for craving related with memories on rewarding effects of alcohol and serotonergic system was responsible for stress related craving (14). 

Along with neurotransmitters, association of craving with molecules like leptin, ghrelin, adiponectin and BDNF (brain derived neurotrophic factor) have been investigated. It has been reported that particularly peptides, which effect appetite, such as leptin and ghrelin, are connected with craving (15). Hillemacher et al. (16), reported an association between leptin level and craving in both male and female patients with alchohol dependence; Addolorato et al. (17) compared ghrelin level and obsessive compulsive drinking scale scores and found that in those with high ghrelin level craving was more severe. On the other hand, Hilburn et al. (18) found association between serum BDNF and alcohol, cocaine and metaphetamine craving. Hillemacher et al. (19), investigated the relation of adiponectin, resistin and craving and found decreased adiponectin level during craving periods and that adiponectin was associated with craving while resistin was not. All these findings suggest that neuroendocrinological mechanisms are effective to a large degree in craving and that more detailed investigations are necessary. 

Genetics of Alcohol Craving 

In recent years, a significant part of the studies on craving are genetic studies. In these studies, findings from neurobiology of craving have been utilized and effects of genetic variations among people on craving have been investigated. Particularly, the effects of genetic variations of dopaminergic, serotonergic and opioid systems on craving have been studied along with other genetic variations observed in genes that were thought to be related with craving (5,20).

Genetic polymorphisms of enzymes related with dopamine synthesis and degradation have been shown to be associated with alcohol dependence (20). Researchers also investigated the relation of craving and genetic polymorphisms in dopaminergic system. Agrawal et al. (5), investigated the association of DRD1, DRD2, DRD3 and DRD4 dopamine receptor gene polymorphisms and dopamine transporter gene (DAT) SLC6A3 polymorphism with craving and found an association between some polymorphisms in DRD3 gene and craving. Serotonergic system has also been investigated. In serotonergic system, particular attention has been paid to genetic polymorphisms in the serotonin transporter (5HTT) gene. Association of 5HTT gene long-short (l/s) polymorphism and craving has been examined and individuals with l allele were found to show more severe craving (21). Individuals with TT genotype of rs1042173 polymorphism on the same gene show higher craving (22). On the other hand, Thompson et al. (23) did not find any association between 5HTT gene polymorphisms and craving. In a study investigating the association between Asn40Asp polymorphism on opiad 1 receptor (OPRM) and craving, individuals carrying Asp40 allelle showed more craving (24). There are also other studies which reported associations between sex steroids, alpha synuclein, cannabinoid receptors and GABAergic system genes and craving (25-27). 

In all of these studies, which investigated single nucleotide polymorphisms, indicated that craving is associated with genetic factors in general. However, a single nucleotide polymorphism is not expected to explain whole craving pathophysiology. This is because results are controvertial and craving is a very complex process, which can not be explained with a single neurotransmitter or receptor gene polymorphism. Therefore, studies, which investigate the whole genome simultaneously, have begun to come forward. Agrawal et al. (5) reported that Integrin alpha D (ITGAD) gene on cromozome 7 was associated with craving. However, this is a new technique and more studies in this field are necessary. 

Epigenetic Studies

With technological progress, it is now possible to observe changes, which take place in nucleus of the cells. Epigenetics studies changes in gene activation with mechanisms such as methylation, acetylation, phosphorylation, which do not change DNA code in cell nucleus (28). Best example to understand epigenetics comes from functional differences of cells localized in different parts of the body, although the genetic structure is the same (27). In all psychiatry, most of the epigenetics studies have been conducted in dependence field. Epigenetic changes including histon acetylation, demethylation are shown to be evident both during acute effects of the substance and abstinence periods (29). Particularly, Eric Nestler and his team’s studies on change of transcription factors, which effect RNA synthesis from DNA in cell nucleus, during substance use, are quite interesting. Cocaine was given to rats and effects of cocaine on transcription factors in cell nucleus were investigated. When cocaine was given to animals, changes in transcription factors such as CREB (cAMP response element binding protein) and ΔfosB are detected. In the first days of exposure to cocaine, CREB increases extremely and return to normal in a short time. But increased ΔfosB activity continues long after exposure to cocaine. Maintainance of increased ΔfosB levels even after cessation of the substance after chronic exposure to substance is important to show change in gene expression due to long term substance use. It has been argued that this may also be useful to explain craving. In some substances, individuals show craving symptoms long after cessation of the substance (30,31). All these studies stress the importance of epigenetics on substance-induced conditions including withdrawal, intoxication and craving. Thus, researchers have begun studies targeting treating impaired epigenetic mechanisms and these give hope for future treatment of craving. 

Treatment of Craving

Along with studies on neurobiology and genetics, treatment studies form an important aspect of studies on craving. Effects of both currently available pharmacological agents and new agents developed with information from neurobiology and genetic studies on craving have been investigated (32). 

Treatment of alcohol withdrawal (detoxification) has been done with success in the whole world by using fluids, vitamin support, and benzodizapines. However, detoxification treatment is never sufficient alone and effective drugs are necessary to prevent recurrence. Since craving is an important factor for recurrence, if drugs used for maintainance decrease craving, that will be an important contribution to prevention (33). 

Drugs currently indicated for alcohol maintainance treatment are disulfiram, naltrexone and acamprosate. Long acting injectable form of naltrexone is available in some countries. Phase 2 and 3 studies are continuing for several drugs, but only one antiepilectic drug, topiramate, is currently in approval stage by Food and Drug Administration (FDA) (34). Disulfiram has been used to avert alcohol use. While there are some results in the recent years suggesting that disulfiram might be effective in decreasing cocaine craving by inhibiting beta hydroxylase, it has been accepted that it has no effect on alcohol craving (35). Naltrexone is an opioid antagonist; it decreases alcohol related pleasure, positive reinforcement and craving by blocking endorphine receptors. Evidence for naltrexone related decrease in craving include longer periods of abstinence in patients taking naltrexone when compared with placebo, fewer sudden impulse to drink alcohol in people taking naltrexone and statement of individuals taking naltrexone that they enjoy less when they drink. Studies also showed that, opiad antagonist nalmefene, which is structurally similar to naltrexone, is effective in decreasing craving (36). 

Acamprosate is a NMDA receptor modulator, which has calcium acetylhomotaurinate structure, and structural analogue of the neurotransmitter taurin, which has an inhibitor effect in CNS. It modulates the impaired balance between glutamate and GABA (37). Experimental studies showed that craving is with glutamatergic system hyperactivity in animals and that acamprosate decreases this hyperactivity. After strong effect of acamprosate on craving was shown in experimental models, clinical studies also indicated effectiveness (38). Relations between craving protection effects of drugs, which are used to treat recurrence in alcohol dependence and hypothalamus-hypophysis-adrenal axis, have been investigated. In one study, adrenocorticotropic hormone (ACTH) and cortisole levels were lower in the placebo group than the naltrexone and acamprosate groups during early abstinence period. Kieferet al. (39) argued that naltrexone and acamprosate decreased craving by inhibiting the decrease in ACTH and cortisole levels. Han et al. (40) suggested that the balance between inhibitor and exitator neurotransmission is associated with alcohol and food craving and that acamprosate showed anti craving effect by modulating the balance between GABA and glutamate. Mann et al. (41) investigated 17 studies conducted with acamprosate in a meta-analyses and reported that acamprosate extended the alcohol free period and decreased craving in patients with recently completed detoxification treatment. Another recently published meta-analysis examined gender effects on acamprosate effectiveness and found that acamprosate decreased heavy drinking both in men and women and that treatment compliance is high (42).

Effects of several drugs other than drugs indicated for maintainance treatment of alcohol dependence on craving have been investigated. Antidepressants, antipsychotics and antiepileptics are promising in craving treatment (36). There are conflicting results on effects of antidepressants on craving. They have been found to be very effective on decreasing craving in animal studies but this can not be shown in clinical studies. Nevertheless, it has been suggested that these drugs may be effective in patients with alcohol dependence who have comorbid depression and obsessive type craving (36,43). 

Effects of typical and atypical antipsychotics have also been investigated. A typical antipsychotic, flupentixole, was reported to be effective on alcohol and cocaine craving, but these results could not be replicated (44). Results from atypical antipsychotics quetiapine and aripiprazole are more promising. Ray et al. (45), compared 400 mg quetiapine with placebo in patients with alcohol dependence and found that quetiapine was superior than placebo in decreasing craving. Martinotti et al. (46) compared partial dopamine agonist aripiprazole with naltrexone and found that aripiprazole was as effective as naltrexone in decreasing craving. Although particular studies with quetiapine and aripiprazole reported that these drugs are effective in decreasing craving, there are not enough studies to take treatment indications and results should be replicated in larger studies with bigger samples. 

Antiepileptic drugs are commonly used in alcohol dependence to decrease withdrawal symptoms and epileptic seizures during detoxification phase. Possible effects of carbamazepine, oxcarbazepine, valproate, topiramate and lamotrigine are investigated and the most promising appears to be topiramate. Topiramate opens GABA dependent chlore channels and antagonize glutamate by inhibiting AMPA and kainate receptors. Studies showed that topiramate decreases alcohol withdrawal symptoms, alcohol intake and craving. After obtaining positive results in replication studies, FDA approval process for maintainance period is going on (33,47). 

Other drugs claimed to decrease craving are baclofen, gamma-hydroxybutyric acid (GHB) and some other drugs effective on serotonine receptors (41). Baklofen, a GABA B receptor agonist, was found to be effective both in open and double blind placebo controlled studies to decrease alcohol intake, increase alcohol free period and prevent recurrence (48). Effects of ritanserine, buspirone and ondansetron, which are effective on serotonin receptors, on craving was examined, 5HT3 receptor antagonist ondansetron was found to be superior than placebo on decresing craving in early onset alcohol dependence while 5HT1A partial agonist buspirone and 5HT2 receptor antagonist ritanserine were not different from placebo (33,43,49). GHB, an endogenous neuromodulator, is claimed to decrease alcohol withdrawal symptoms and craving (50). On the other hand, research on cannabionid antagonists, corticotrophin releasing factor antagonists, neuropeptide Y and immunotherapies are continouing (51). 

In patients who do not respond to treatment, effect of transmagnetic stimulation treatment, an effective treatment in which neuronal cells are stimulated via magnetic fields, on craving has been investigated. In fortyfive patients with alcohol dependence in which high frequeny repetitive transmagnetic stimulation (rTMS) application to right dorsolateral prefrontal cortex (DLPFC) was compared with sham treatment in a single-blind design, craving scores improved significantly in patients receiving rTMS. This suggested that rTMS application along with drugs effective on craving might be effective on decreasing both craving and recurrence of alcohol dependence (52). 

Different aspects of craving have been investigated in the recent years on a molecular level. Slowly, data obtained from these studies are reflecting on treatment. Effects of current treatments on craving have been examined and together with known mechanisms, we begin to understand their effects on cell cytoplasm and nucleus. Together with developments in epigenetics, emergence of drugs directly effective on epigenetic mechanisms may be groundbreaking in craving in the next 10-20 years.

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