Ketamine is approved to start and maintain anaesthesia or analgesia and known as an old drug of abuse showing currently a new wave in its spread [1-3]. Also, ketamine`s therapeutic quality is currently under strong observation, especially in terms of its value in the treatment of depression and suicidality [4-6]. A growing number of studies demonstrated a rapid and rigorous but transient anti-anhedonistic and antidepressant after-effect (ADE) occurring subsequent to subanesthetic parenteral ketamine doses (usually a single ketamine infusion of 0.5 mg/kg over 40 minutes) in 50-80% of the cases when applied the first time to patients with treatment resistant unipolar or bipolar major depression [4-6]. ADE emerged within the first hours after a single ketamine administration, peaked in the next 24 to 48 hours and dissipated within the following 3 to 7 days [4-6]. The onset and duration of ketamine`s ADE was highly inter-individual and increased with repeated or serial ketamine-infusions in those subjects, who did not respond on the infusions before [7] reminiscent of wellknown observations of early and delayed improvements using typical antidepressants. Adverse effects (mostly dissociation, dry mouth, tachycardia and elevated blood pressure) were mild, transient and dose dependent [4-6]. Recently, intramuscular, intranasal and oral routes of sub-anesthetic ketamine administration were demonstrated to be also followed by an ADE [4-9].

There are several speculations about sub-anesthetic ketamine`s ADE, including epigenetic mechanisms [6]. The most convincing hypothesis starts with an extracellular glutamate surge in corticolimbic brain regions due to disinhibited glutamatergic pyramidal neurons by an inhibition of tonic firing of GABAergic interneurons via inactivation of its NMDA-receptors by ketamine [10]. In this regard, increased glutamate activities were found in the medial prefrontal cortex of rats subsequent to the administration of sub-anesthetic but not anesthetic doses of ketamine [11]. Thereby, postsynaptic glutamatergic non-NMDA-receptors can be activated and sensitized, which should drive changes in cellular and synaptic plasticity assumed to be involved in ADE [12,13]. More specifically, an activation of mammalian target of rapamycin function (mTOR) should play a key role in remodeling synapses, thus mediating ADE [12-14]. Additionally, dopaminergic pyramidal neurons were assumed to be disinhibited or facilitated by ketamine [15] leading to dopamine surge in cortico-limbic areas [16,17], which was assumed to be responsible for stimulating and psychotomimetic effects of ketamine [15].

At this juncture, elevated glutamate concentrations were found recently i) in the blood of ethanol intoxicated patients, which declined during detoxification [18] and ii) in limbic brain regions of detoxifying alcoholics [19]. This is intriguing on the background that ethanol in physiological doses was demonstrated to antagonize NMDA-receptors non-competitively [20-22], just like ketamine. Of note, low doses of ethanol were found to be associated with antidepressant-like effects in Porsolt`s swim test on mice [23]. We can recall a few primary depressive ethanol-dependents [24], who reported in their early untreated history from `feeling better´, notably improved mood, more energy and better concentration (ADE?), after a few glasses of beer or wine, initially persisting over a few days before decaying. Assuming to better cope with their depression the frequency of ethanol-intake had been increased over time resulting in a tolerance towards their `feeling better´. In addition, aversive withdrawal symptoms had occurred that worsened their depression and promoted more frequent or continuous drinking (own unpublished observations).

Of note, chronic ethanol-dependents were described to have lower brain glutamate concentrations in sustained abstinence than normal controls [25,26], eventually pointing to long-term adaptation due to former repeated or prolonged glutamate-surge of regular drinking. Is this what can happen as a consequence of more frequent ketamine infusions, thus giving birth to an aberrant learning process, such as addiction [27]?

In mammalian animals, ketamine was found (i) to reduce ethanolseeking behavior and (ii) to substitute for ethanol in drug discrimination tasks [28,29]. In the late 1990ies, Krystal et al. had demonstrated that ketamine produced dose-related ethanol-like effects in detoxified alcoholics [30]. In healthy subjects, a usual sub-anesthetic intravenous ketamine dose was estimated to produce subjective effects similar to 5 standard drinks [31]; approximately three quarters a bottle of wine.

Addressing these substantial similarities between ketamine and ethanol, the question arises whether `sub-anesthetic´ ethanol is able to evoke ADE when applied modestly `with caution´ in low frequent pulses, i.e. no more than once to thrice a week, to depressives being not addicted to ethanol. Ethanol`s ADE might be less pronounced than ketamine`s ADE due to ethanol`s somewhat weaker antagonism of NMDA-receptors [20-22,32]. Subsequent to more frequent ethanol intake, ethanol`s ADE might be blurred by hangover and the development of tolerance and abstinence symptoms, which could partially result from ethanol`s stronger agonistic action on GABAA- receptors and up-regulation of NMDA-receptors [20-22,32]. There are some further intriguing clinical and biological characteristics, that ethanol shares with ketamine:

i) Increasing doses were associated with sedation, anesthesia, amnesia and more pain relief [6,31,32] - perhaps via increasing agonistic and activating actions on cortical, subcortical and brain-stem GABA-A-receptors and voltage-gated ion-channels [20,21,32-35].

ii) Modulation of cortico-limbic dopamine [17,21,35-38] and opioid pathways [31,32,39] potentially involved in rewarding [40,41] and affect regulation [42,43].

iii) Increased neurotrophin (BDNF, NGF) levels after acute administration [44,45] and decreased neurotrophin levels during prolonged intake [14,46].

iv) Inhibition of synaptic long-term potentiation (LTP) of rodent hippocampal neurons which persisted after washout of the respective drug, promoting the discussion about drug-induced metaplastic synaptic changes [47-49].

v) Activation of mTOR-signaling pathways [12,13,50,51].

vi) Synaptic adaptations, such as increasing number and size of dendritic spines in rodent hippocampal and prefrontal neurons [13,52,53].

vii) Repeated administration induced tolerance in euphoriant and stimulating actions [21,54] as well as in ADE [55-57], own unpublished observations].

viii) Repeated administration induced gene expression of specific NMDA receptor subunits in cortico-limbic brain regions [20,32,58-60].

ix) Down-regulation of cerebellum following repeated drug administration [59].

x) Chronic or regular intake was associated with the development of addiction and neurotoxic effects that could lead to brain atrophy [32,34,54,61].

xi) Bioavailability of oral ketamine is low (20%) [34] and that of ethanol decreased from about 85% in young people down to 40% in the elderly [62].

Among them, a good portion (ii-vi) is currently discussed to be specifically involved in both, the mechanisms of ADE (in case of ketamine) [6,12-14,45,52] and the development of addiction (in the case of ethanol) [21,44,47,50,51,53,58,59,63,64]. Other similarities (vii, viii) were more plainly associated with adverse effects, such as addiction and neurotoxicity [20,32,34,54,55-61]. Especially, an altered gene expression of specific NMDA-receptors (viii) due to repeated administrations of both agents might be crucial in attenuating ADE and augmenting the adverse effects of ketamine and ethanol. Most recently, further evidence was found that an overexpression of NMDAreceptor subunit epsilon-1 (NR2A) might promote vulnerability for major depression [65] perhaps contributing to a tolerance in ADE [55-57]. Frequent and regular ethanol ingestion was associated with an overexpression of NR1- and NR2B-subunit containing NMDAreceptors in cortico-limbic synapses, including the dorsomedial striatum, assumed to be involved in the development of addiction and abstinence syndrome [20,31,66]. However, both might be simply result from a weakened stress defense being characteristic for both, major depression and addiction [52,65]. In this context, chronic stress is associated with a loss of synaptic spines of rodent hippocampal and prefrontal neurons supposed to reflect an impaired synaptic plasticity there [52]. Intriguingly, a single and low dose of ketamine was demonstrated to increase spine density and reverse stress-induced deficits in synaptic function of prefrontal pyramidal neurons [52] hypothesized to contribute to ketamine`s ADE [52].

It is emphasized that chronic intermittent ethanol exposure to rats was also associated with an increase in dendritic spine density in prefrontal pyramidal neurons that occurred precisely within one week after ethanol cessation [63,64] and that seems to be similar to alterations in spine morphology found after a single, low dose of ketamine [13,52]. It`s a challenge to differentiate whether those dynamics in morphological plasticity of excitatory glutamatergic neurotransmission [52] are assigned to therapeutic, e.g. antidepressant actions [13] of the drugs, or simply to the development of substance dependence [53,63,64], unless being two clinical sides of the same coin generally reflecting the neurobiological trace of plasticity (cellular learning) in stress-regulation.

On the other hand, there are some ketamine-specific effects that differentiate from ethanol, such as short elimination half-live [21,32], minor potency in activating postsynaptic GABA-A-receptors [21,32,34,67] and augmentation of tau-phosphorylation in animal cortices [59] as well as producing genitourinary toxicology [34] and negligible physical withdrawal symptoms in humans [34,54,68,69]. Moreover, ketamine administration is associated with dose-dependent psychedelic, dissociative, hallucinogenic and psychotomimetic perceptions [4-6,54], which are not characteristic for ethanolintoxication.

Recently, dissociative symptoms were found to be positively related to ketamine`s ADE [70]. But one should bear in mind that depersonalization is clinically overlapping with dissociation and was found to be related to ethanol ingestion [71,72] and was hypothesized to be associated with increased brain glutamate [73] – just like ketamine [4-6,70]. Ambiguously, dissociative symptoms were found to be not unusual in substance abusers [74] and were assigned to co-morbidity of alcoholism [75]. However, both dissociation and glutamate activity were demonstrated to be not related to ketamine`s ADE in ten patients with major depression – unfortunately, the glutamate measurements were made in their occipital cortices and not in their cortico-limbic areas [76]. In healthy volunteers, sub-anesthetic ketamine was inconsistently associated with a glutamate surge in the prefrontal cortex [77-79], and in patients with major depression a glutamate sink was documented there, which normalized with clinical recovery [79]. In aggregate, further clarifying studies on the effects of both, ketamine and ethanol pulses on glutamate activities in cortico-limbic pathways of patients with mood disorders and its relation to ADE or `feeling better´ are warranted.

The explanation that ketamine exerts its ADE via antagonism of glutamate NMDA-receptor is called into question considering a lacking ADE of memantine being an uncompetitive antagonist of this receptor, too [80]. Nevertheless, there is new evidence that memantine has antimanic and mood stabilizing properties in the treatment of bipolar disorder [81]. Further support for the `glutamate-hypothesis´ of ADE comes from nitrous oxide - exerting also antagonizing actions on NMDA-receptors -, as this narcotic agent was also demonstrated to evoke a rapid and robust ADE in treatment resistant major depression subsequent to a sub-anesthetic dose [82], just like ketamine does [4-6].

The presented overview about the clinical and biological overlaps of ketamine and ethanol should draw the readers` attention in terms of the treatment of major depression to both, the possibility of a progressing transfer from ADE to addiction when using repeated ketamine pulses, and on the other hand, a hypothesized therapeutic `antidepressant window´ of low frequent and modest ethanol pulses in depressives, who are (still?) not addicted to ethanol.

More frequent and intense use of ethanol or ketamine would prepare the brain to tolerance and dependence upon in the same sophisticated neurobiological pathways considering aberrant cellular learning in cortico-limbic networks [83,84]. Recent epidemiological findings from a survey of a nationally representative sample of the population in the USA underlined the risky role of ethanol in affectregulation as it confirms that drinking to mitigate mood symptoms was associated with the development of ethanol dependence [85]. And without a doubt, at risk drinking of patients with major depression is reliably accompanied by a worsening of depression, social functioning, suicide risk and increasing health care utilization [86]. Nevertheless, the authors are not aware of any study that specifically assessed ethanol after-effects on mood and energy in individuals with affective disorders being or not being addicted to ethanol. Although the use of ethanol to relieve affective symptoms is common among patients with mood disorders [87] and despite the fact that ethanol has some mechanistic characteristics in common with antidepressants, such as enhancing monoaminergic neurotransmission [42], there is merely insufficient evidence of the self-medication hypothesis in mood disorders up to date [88-90]. To the contrary, there is increasing evidence attributing the nucleus accumbens with its projections to the prefrontal cortex to be a key circuit in both, regulating of antidepressant actions [91] and burgeoning as well as maintaining addiction [83,84].

The mood changes of acute mild ethanol intoxication (transient euphoria) and chronic alcohol intake (ongoing dysphoria) is commonly thought to be largely due to the mediation of central dopamine system, e.g. by indirectly increasing and decreasing the synaptic dopamine efflux in cortico-limbic dopamine circuits implicated in the learning of goal-directed and rewarding behaviors [21,37,38,40,41,92,93], respectively. However, one might speculate on the possibility of longer lasting favorable ethanol after-effects, just like ADE, due to sustained modifications in cortico-limbic glutamatargic synapses, notably being discussed to be also involved in the progression of adverse effects, such as addiction and neurotoxicity [20-22,53,58,59,61,83].

There are striking similarities between ketamine and ethanol, particularly in terms of modulating dopaminergic and glutamatergic pathways in cortico-limbic brain areas, evidently being involved in learning and affect regulation, thereby probably mediating ADE, as well as the development of addiction. Exceeding an individual threshold with ingesting a critical amount or using a critical frequency of administration of these drugs would turn its favorable, therapeutic effect (ADE) more likely to adverse effects (addiction, neurotoxicity).

U.B. received fees for lectures and the organization of training courses by the following pharmaceutical companies: Actelion, Boehringer- Ingelheim, Bristol-Myers Squibb, esparma, GlaxoSmithKline, Janssen- Cilag, Lilly, Lundbeck, Merz, and Servier. N.S. received fees for lectures, development of educational presentations and board memberships from Lundbeck, Jassen-Cilag, Reckitt-Benckiser and a grant from Roche.