Peter R. Martin: Historical Vocabulary of Addiction, Vol. II

Melatonin

According to the Oxford English Dictionary (OED), the noun melatonin is a borrowing from ancient Greek μέλας (“black”) combined with an English element -tonin.  The structure of the word melatonin is related to that of the chemically related compound serotonin (“5-Hydroxytryptamine; a monoamine neurotransmitter, C10H12N2O, active in the production of vasoconstriction and anaphylactic shock, and in the regulation of cycles of body temperature and sleep”).  Specifically, sero (the combining form of the noun serum [“Watery animal fluid, normal or morbid; specifically blood-serum, the greenish yellow liquid which separates from the clot when blood coagulates.”]) is combined with ton (as found in the adjective tonic, meaning “pertaining to, consisting in, or producing tension”) and the suffix in (defined in OED: “Used to form the names of discrete substances extracted from living organisms or their products”). 

The definition of the noun melatonin in OED is: “A hormone, synthesized from serotonin by cells of the pineal gland and retina, which opposes the effect of MSH (melanocyte-stimulating hormone) and may play a role in regulating photoperiodic rhythms; N-acetyl-5-methoxytryptamine, CH3O·C8H5N·CH2·CH2·NH·CO·CH3.”

The American physician and dermatology researcher Aaron B. Lerner (1920–2007) and colleagues isolated a new substance with a similar chemical structure to the neurotransmitter compound serotonin while studying the skin pigment melanin.  The definition of melanin in OED is: “Any of various dark brown or black animal or plant pigments, (now) specfically those of high molecular weight derived from phenolic compounds (especially tyrosine) by the action of oxidase enzymes, and widely distributed in animal, plant, and fungal tissues (including human skin, hair, and eyes).  

In their hallmark article published in the Journal of the American Chemical Society, Lerner and colleagues combined/blended the names of the skin pigment they were investigating and the neurotransmitter compound that their newly-discovered compound resembled chemically (Lerner,  Case and Heinzelman 1959): “We wish to report isolation from beef pineal glands of the active factor that can lighten skin color and inhibit MSH.  It is suggested that this substance be called melatonin.”  The novel substance Lerner’s team isolated for the first time was subsequently found not only to chemically resemble serotonin but to be synthesized in the pineal gland from serotonin (Axelrod and Weissbach 1960).  Synthesis of melatonin in the pineal gland was via a sequential two-step reaction catalyzed by the enzymes aralkyamine N-acetyltransferase and acetylserotonin O-methyltransferase, a process integral to the physiological action of this hormone (Klein 2007). 

Since its isolation, investigations of the physiological actions of melatonin and the many functions of the hormone in the body have continued apace.  Within a decade, the eminent British neurochemist Henry McIlwain (1912–1992) would write in a review in Nature (McIlwain 1970): “Melatonin controls diurnal and seasonal adjustments of activity in many species.”  The hormone regulates circadian body rhythms and the sleep-wake cycle by a reliable diurnal secretory rhythm of melatonin into the bloodstream from the endocrine pineal gland in the midline of the brain (Wurtman, Axelrod and Phillips 1963b).  The entry of ambient light through the eyes turns off synthesis and release of melatonin from the pineal via a multisynaptic neural pathway from the retina to the suprachiasmatic nucleus of the anterior hypothalamus which is the master clock controlling circadian rhythms in mammals (Benarroch 2008).  This accounts for the very high concentrations of melaton observed in the blood during the night and almost none during daylight (Lynch, Wurtman, Moskowitz et al. 1975).  Melatonin has additionally been demonstrated to play a key role in regulating a wide range of physiological processes, including sleep, mood, immune function and reproduction (Pandi-Perumal, Srinivasan, Maestroni et al. 2006).

In the 1980s, researchers demonstrated that melatonin could be used to initiate physiologically normal sleep (Waldhauser, Saletu and Trinchard-Lugan 1990; Zhdanova, Wurtman, Lynch et al. 1995).  When melatonin was approved as a dietary supplement by the US Food and Drug Administration (FDA) in the mid-1990s, the hormone began to be widely used as a sleep aid.  Melatonin is now available over-the-counter and is also prescribed in higher doses by physicians for treating a variety of sleep disorders, including insomnia, jet lag and shift work sleep disorder. 

The melatonin receptor was cloned, characterized and demonstrated to be a G protein-coupled receptor (Reppert, Weaver and Ebisawa 1994).  The melatonin receptor is expressed in various tissues of the body and two recognized subtypes have been identified in humans: melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) (Pandi-Perumal, Trakht, Srinivasan et al. 2008).  Congeners of melatonin that activate these receptors have since been synthesized by the pharmaceutical industry (Uchikawa, Fukatsu, Tokunoh et al. 2002; Turek and Gillette 2004; Rivara, Mor, Bedini et al. 2008). 

Melatonin and currently available melatonin receptor agonists all bind to and activate both receptor types with numerous physiological actions.  Nevertheless, melatonin receptor agonists are primarily used for treatment of sleep disorders, even though they show some promise for treatment of neurologic and psychiatric disorders (Guardiola-Lemaitre, De Bodinat, Delagrange et al. 2014; Naskar, Prabhakar, Singh et al. 2015). 

There has been continued interest in a possible role for melatonin in pathogenesis of addiction.  This notion originated from the clinical observation that many patients with drug and alcohol use disorders have significant sleep disturbances (Brower and Perron 2010) and these are often associated with disruption in the normal rhythm and/or amplitude of melatonin secretion (Kay 1975; Martin, Loewenstein, Kaye et al. 1986b; Gillin, Smith, Irwin et al. 1994; Kühlwein, Hauger and Irwin 2003; Angarita, Emadi, Hodges et al. 2016; Meyrel, Rolland and Geoffroy 2019).  However, as the major physiological role of melatonin is regulating the sleep-wake cycle, disruptions in sleep associated with altered melatonin dynamics may either be a consequence of chronic alcohol/drug self-administration or a contributing factor in the development of these addictive disorders.  

Drug/alcohol use can disrupt normal sleep patterns, which can in turn lead to a decrease in melatonin production.  Certain drugs, such as cocaine, methamphetamine and ecstasy, can directly affect the production and release of melatonin from the pineal gland in the brain by altering either the activity of enzymes involved in the synthesis of melatonin or by directly activating the function of the pineal gland.  Similarly, some CNS depressant drugs can cause excessive daytime sleepiness, which can interfere with the normal production of melatonin at night.  Therefore, the mechanistic role of melatonin in addiction has been suggested but has not been fully established.

Diurnal variation in the tone of the brain reward pathway, implicated in addiction (Martin 2023), have been attributed to circadian rhythms in concentrations of the biogenic amine neurotransmitter dopamine (Blum, Oscar-Berman, Badgaiyan et al. 2014; Zhang and Volkow 2023).  However, the role of melatonin in modulating circadian rhythms and sleep (Cajochen, Kräuchi and Wirz-Justice 2003; Hasler, Smith, Cousins et al. 2012) is difficult to disentangle from independently demonstrated diurnal changes in concentrations of biogenic amines in the human brain (Carlsson, Svennerholm and Winblad 1980). 

For example, while diurnal variation in alcohol cravings have been reported (Hisler, Rothenberger, Clark et al. 2021), it is unclear whether this is a specific effect of melatonin on dopamine activity (Salinas, Mateo, Carlson et al. 2021) or simply circadian secretion of melatonin and biogenic amines based on photoperiod (Geller 1971; Vengeliene, Noori and Spanagel 2015) or sleep integrity (Hasler, Smith, Cousins et al. 2012; Koob and Colrain 2020).  Although some studies do suggest that melatonin supplementation may help to regulate dopamine levels (Naskar, Prabhakar, Singh et al. 2015), it is not clear whether this is the cause of why melatonin may influence cravings for drugs of abuse (Vengeliene, Noori and Spanagel 2015). 

If melatonin is potentially involved in pathogenesis of alcohol/drug use disorders, it may reasonably be considered as a component of their treatment.  A pilot clinical trial of melatonin supplementation in treatment-seeking individuals with alcohol use disorder did not demonstrate that the hormone significantly improved sleep quality, nor did it enhance the overall well-being of subjects (Gendy, Lagzdins, Schaman et al. 2020).  Nevertheless, because of the great importantance of sleep difficulties in alcohol use disorder (Brower 2001), the authors concluded that further research was needed. 

Other studies have been conducted examining the potential of melatonin in the treatment of nicotine, opioid and cocaine use disorders (Zhdanova and Piotrovskaya 2000; Das, Prithviraj and Mohanraj. 2022).  However, the few randomized clinical trials of melatonin for treatment of substance use disorders that are available in the literature have only shown mixed results (Das, Prithviraj and Mohanraj 2022).  This likely reflects that the doses and durations of melatonin treatment varies in each study and sample sizes and durations of the studies are insufficient to lead to conclusive findings.  Additionally, the existing studies have not specifically addressed the effects of melatonin on relapse rate or the potential role of melatonin in the management of substance use disorders or specific withdrawal symptoms per idem as distinct from the expected effects of the hormone on circadian rhythm and sleep.  Therefore, the sum of evidence is insufficient to recommend the use of melatonin in pharmacological treatment of alcohol/drug use disorders independent from potential benefits with respect to sleep quality.  

Activation of melatonin receptors by the agonist agomelatine may help reduce drug cravings in individuals with addiction (Fathi, Abulsoud, Saad 2021).  However, it is difficult to extrapolate the findings from this study in rats to humans, in which melatonin may be reducing alcohol craving indirectly by alleviating co-occurring and closely intertwined depressive symptoms in individuals suffering from alcohol use disorder (Guardiola-Lemaitre, De Bodinat, Delagrange et al. 2014). 

Under certain circumstances, however, antidepressant and other effects of melatonin are dissociable as suggested by the observation that mood changes tend to improve relatively quickly with abstinence (Brown, Inaba, Gillin et al. 1995), whereas normal sleep and diurnal melatonin rhythm may not normalize for months to years after discontinuation of drugs of abuse (Rundell, Williams and Lester 1977; Martin, Loewenstein, Kaye et al. 1986b; Kesner, Mateo, Abrahao et al. 2022).  More research is needed to better understand the relative contributions of changes in mood and in melatonin modulation of circadian rhythms/sleep to efficacy of addiction treatment using the hormone. 

Melatonin has numerous physiological actions in addition to those modulating circadian rhythms and sleep (termed chronobiotic effects).  Additional properties of melatonin that have been identified include neuroprotective effects presumably due to the anti-inflammatory and antioxidant actions of melatonin; antidepressant and hypnotic pharmacological actions; and a significant role in reproductive and sexual functioning (Pandi-Perumal, Srinivasan, Maestroni et al. 2006).  As these other effects of melatonin have been much less extensively studied than have the chronobiotic effects, their putative influence on alcohol/drug use disorders will only be briefly reviewed. 

The progression of alcohol/drug use disorders throughout a lifetime of exposure to these agents go hand in hand with neurotoxicity.  Specifically, accumulating brain injury from drugs of abuse may progressively modify the reward and inhibitory pathways of the brain and thereby further diminish the abilities of individuals suffering from addiction to overcome these out-of-control and self-destructive behaviors.  Brain injury sustained during alcohol/drug use may be attributed to either direct brain injury from exposure to these agents and/or as a result of the associated addictive lifestyle and complicating other medical and psychiatric disorders (Martin, Adinoff, Weingartner et al. 1986a). 

Melatonin has been reported to inhibit the neurotoxicity of stimulants such as methamphetamine through inhibition of oxidative stress and apoptosis of neurons as well as proinflammatory cytokine-induced effects on glial cells which are the supporting cells of neurons (Jumnongprakhon, Govitrapong, Tocharus et al. 2014; Wongprayoon and Govitrapong 2015).  Melatonin has also been reported to attenuate methamphetamine-induced neurogenesis in adult mouse hippocampus (Singhakumar, Boontem, Ekthuwapranee et al. 2015).   These protective effects of melatonin on stimulant-induced neurotoxicity may well moderate progression of stimulant use disorder but further longitudinal studies are required.

Similiarly, the neurotoxicity of alcohol consumption has been linked to thiamine deficiency associated with malnutrition in alcoholism which can result in brain injury by various mechanisms, including oxidative stress (Martin, Singleton and Hiller-Sturmhöfel 2003; Forsyth, Voigt, Burgess et al. 2015; Kurhaluk and Tkachenko 2020).  Accordingly, the antioxidant effects of melatonin may mitigate neurotoxicity associated with long-term addictive consumption of alcohol.  Reduction of brain injury may significantly alter the response to alcohol (Martin, Majchrowicz, Tamborska et al. 1985) and the clinical course of the disorder and thereby be of potential benefit in management of alcohol use disorder (Sönmez, Narin, Akkuş et al. 2012). 

One of the earliest physiologic effects of melatonin identified was its role in regulating ovarian function in the rat (Wurtman, Axelrod and Chu 1963a).  Supplementation with melatonin of patients with opioid use disorder on methadone maintenance has been reported to enhance sexual functioning and mental health compared to zolpidem and placebo demonstrating non-chronobiotic effects of the hormone on addiction in humans (Amini, Moeini and Etminani. 2022). 

Finally, melatonin may also play an important role in regulating the body’s stress responses (Martin 2021).  Decreased salivary melatonin concentrations have been observed in military personel suffering from posttraumatic stress disorder (PTSD), a frequent concomitant of addiction (Paul, Love, Jetly et al. 2019; María-Ríos and Morrow 2020).  Studies have shown that melatonin can help to reduce the physiological and behavioral responses to stress, which may in turn help to reduce the risk of relapse in individuals with addiction (Xu, Li, Sun et al. 2023).

In summary, there are many compelling potential interactions between melatonin and addiction.  While these are multifaceted due to the multitude of physiological actions of this hormone in the body that have been identified, none of the associations have attained a degree of confidence that would merit clinical adoption other than perhaps for effects on a variety of sleep disorders.

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July 13, 2023