Alcohol, nicotine and caffeine are the most commonly consumed psychotropic drugs in the world. They are widely consumed by normal individuals, but their use is even more common in psychiatric patients, so patients with schizophrenia tend to abuse all three substances. The links between depression and alcohol are complex. These drugs can all be addictive, as understood in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Alcohol abuse is clearly harmful to the brain, causing acute and chronic mental disorders ranging from intoxication with impaired cognition to delirium tremens, halluosis and dementia. In contrast, the main health consequences of nicotine, especially cancer and cardiovascular disease, are outside the realm of psychiatry. However, nicotine addiction and motivation to smoke or quit are of concern to psychiatrists. Molecular genetics has identified polymorphisms in genes that interfere with alcohol pharmacokinetics (e.g., the enzymes aldehyde dehydrogenase and alcohol dehydrogenase).17 Recent research has shown the genetic association or association of alcoholism with genes that also play a role in other psychiatric disorders and response to drug treatment. Examples include the association of alcoholism with the y-amlnobutyric acid receptor GABAA 18 (GAB A is the main CNS inhibitory neurotransmitter); the association of severe suicide attempts and alcoholism with the tryptophan gene hydroxylase19 (the rate-limiting enzyme in the synthesis of serotonin [5-hydroxytryptamine, 5-HT]); the association of antisocial alcoholism with the autoreceptor-5-HT1B20 gene; and the association of severe and antisocial alcoholism with dopamine D2 and D4 receptor genes.21 Pain is a general term that today refers to both a physical and emotional experience (Price 2000). In addition to the activation of nAChR and a possible increased desire to consume alcohol-nicotine-coconut with dopamine, another contributing factor could be the analgesic (or antinociceptive) effect of such a combination. Nicotine itself appears to be effective as an analgesic and anti-inflammation in many situations (Decker et al., 2001; Yagoubian et al., 2011; Yoshikawa et al., 2006).

The analgesic capacity of nicotine was first demonstrated prior to the identification of nAChR (Davis et al., 1932), but activation of nAChR has long been proposed as a key component in mediating the analgesic effects of nicotine and other nicotine agonists (e.g., epibatidin, see below: Damaj et al., 1999; Khan et al., 1998; Simons et al., 2005; Vincler, 2005). Many brain nuclei express a variety of nAChR subtypes, and pain regulation zones are no exception (Millar & Gotti, 2009; Tracey and Mantyh, 2007). Nicotinic activation of nAchR, which contains α4, β2 and possibly α7 subunits, appears to be a key component of pain regulation (Damaj et al., 2000; Flores, 2000; Gao et al., 2010). To support this idea, mice with α4 and β2 mutations show no analgesic effect on nicotine delivery (Marubio et al. 1999). Treatment with α4- and β2-agonists shows similar, though not complete, analgesic effects as nicotine administration (Flores 2000; Gao et al., 2010), but administration of epibatidine and ABT-594, two α4β2 agonists, produces effects 200-fold stronger than morphine (Bannon et al., 1998; Spande et al., 1992). Although it has been suggested that the analgesic effect produced by nicotinic activation of nAChR receptors may be attributable to opioid release (Galeote et al., 2006), the majority of results suggest that it is independent of the opioid system when administered alone (Campbell et al., 2006; Cooley et al., 1990; Damaj et al., 1999; Khan et al., 1998; Rogers and Iwamoto, 1993; Tripathi et al., 1982). Low doses of nicotine have been observed in in vitro cell cultures (primary and immortal) to protect against or mitigate damage induced by inflammation induced by β-amyloid, inflammation induced by lipopolysaccharides (LPS), glutamate, alcohol, N-methyl-d-aspartate (NMDA), hypoxia and salsallinol (Copeland et al. 2005, 2007; Dajas-Bailador et al., 2002; Das and Tizabi, 2009; Guan et al., 2003; Hejmadi et al., 2003; Kihara et al., 1998; Liu and Zhao, 2004; Park et al., 2007; Ramlochansingh et al., 2011; Stevens et al., 2003; Tizabi et al., 2003, 2004). The effect of this protection is unclear, but appears to be mediated by activation of nicotinic receptors (see above: Dajas-Bailador et al. 2002; Das and Tizabi, 2009; Hejmadi et al., 2003; Picciotto and Zoli, 2008). Signal transduction mechanisms underlying neuroprotection may include direct or indirect calcium modulation mediated by nicotinic receptors and other anti-apoptotic mechanisms (Donnelly-Roberts et al., 1996; Kihara et al., 2001; Liu and Zhao, 2004; Ren et al., 2005; Stevens et al., 2003; discussed in Buckingham et al., 2009), but these potential pathways are still poorly understood.

In drug policy discussions, we usually talk about drugs in a binary framework: either you legalize them or you ban them. For example, every time I write about alcohol-related deaths, I get a lot of emails from readers asking me why I want prohibition back. Do I not know how bad it was? Alcohol has been used in the past to dampen central nervous system responses to pain before developing more sophisticated analgesics. Basic studies on pain tolerance have shown that even low doses of alcohol relieve physical pain (James et al.