The effects of baclofen in the treatment of alcohol dependence have been thoroughly described by a physician suffering from AUD, Olivier Ameisen, who reported the cure of his alcohol dependence with a high dose of baclofen, first in an article published in 2005, then later in a book published in 2008 (
3,
14). He reported that, in his case, the dose of 270 mg/day produced a state of “complete indifference” toward alcohol. Indifference is not an operational concept in addictology. It is nevertheless a concept that should be taken into consideration.
The state of indifference is not transitory when the effective dose of baclofen is maintained: on the contrary, it is very long lasting, and people completely indifferent to alcohol can generally stop baclofen after one or a few years of treatment, and they most often do not relapse (as if all memories associated with alcohol had vanished). This differs from those who have been cured by using other methods, for whom abstinence most generally requires a lot of effort, and for whom craving for alcohol often returns when they resume some alcohol drinking or see alcohol cues. However, all AUD patients treated with baclofen do not reach such a state of complete indifference. My experience (more than a thousand patients treated with a high-dose of baclofen over the last 10 years) is that about one third of the patients reach this state of complete indifference; while another third experiences a clear decrease in craving, but not its complete suppression (these patients drink very significantly less, but still have moments of desire for alcohol); in the last third of patients baclofen treatment is ineffective despite often reaching very high doses.
Baclofen can also frequently promote anxiolysis; this could possibly be explained by an early occurring effect of baclofen on serotonin neurons and on the amygdala. Hyperactivity of serotonin raphe neurons or hyperactivity of the amygdala are mechanisms known to produce anxiety; baclofen acutely inhibits serotonin neurons and serotonin release (
27,
28) while short-term baclofen treatment inhibits amygdala reactivity to incentive cues (
29). Most importantly, it has recently been shown that alcohol addiction is associated with impaired GABA clearance in the amygdala, with an increase in GABA tone associated with higher anxiety-like behavior (
30).
Baclofen could possibly improve anxiety through a rapid normalizing effect on amygdala GABA tone. Clinical studies have shown that baclofen has anxiolytic effects in patients with AUD (
31) and
it has been hypothesized that the anticraving effects of baclofen could be related to an anxiolytic effect (5, 6, 32).
Studies investigating the effect of baclofen in animal models of addiction show that systemic administration of baclofen reduces the acquisition and maintenance of alcohol consumption (
52–
55), motivation to drink (
56), binge-like drinking (
57), relapse-like drinking (
58), severity of alcohol withdrawal signs (
53), cue-induced reinstatement of previously extinguished alcohol-seeking behavior (
59), and the reinforcing and motivational properties of alcohol (
60–
65) in different validated rodent models of AUD [for review, see (
2)]. That baclofen reduces alcohol consumption in animal models has been further strengthened by the demonstration that R(+)-baclofen, and not S(-)-baclofen selectively reduces self-administration of alcohol in rats (
66). Regarding the mechanism of action of baclofen in these models,
it is generally hypothesized that baclofen reduces alcohol consumption through an anti-dopaminergic effect. The hypothesis is based on two major points. The first is the fact that baclofen has clear anti-rewarding effects. These effects have been shown not only for alcohol consumption, but also for the consumption of cocaine (67), amphetamine (68), and even of non-drug reinforcers such as sucrose, saccharin, or regular food pellets, suggesting that baclofen produces a generalized suppression of reward-motivated behaviors (2).
It is therefore hypothesized that
chronic baclofen treatment produces a state of indifference through a normalization of brain network connectivity. Chronic baclofen produces many changes in the brain that could impact connectivity. We have previously mentioned that chronic baclofen produces plastic changes in regions of the reward system, including desensitization in G-protein-dependent systems and alterations in signaling of several kinase cascades (FAK, GSK3ß, DARPP-32) that are resistant to desensitization (
37). In addition, AUD is associated with marked brain neuro-immune alterations (
110); and studies have shown that baclofen has anti-inflammatory and neuroprotective effects on the brain
. Baclofen attenuates neuro-inflammation (111) and inflammatory signaling (112); inhibits the release of pro-inflammatory cytokines from microglia (113) and from astrocytes (114); and decreases oxidative stress (111); interestingly, baclofen is an allosteric modulator of CXCR4, a receptor for the chemokine CXCL12, which has been causally involved in several neurological disorders, including stroke, brain tumors, HIV encephalopathy and multiple sclerosis (
115). GABA-B-receptor activation alters also the activity of dopamine, serotonin, norepinephrine, GABA and glutamate, which are prominent neurotransmitters implicated in alcohol dependence and are involved in the modulation of brain networks. It is not known whether these effects of baclofen on neurotransmitter or neuroimmune factors can alter functional connectivity in AUD, but it has been shown that neuroimmune/neurotransmitter dysregulation in other psychiatric disorders, such as bipolar disorder, disrupt local brain network connectivity and have deleterious effects on the brain, and that these effects can be treated with appropriate pharmacological treatments (
116). Abnormal glutamate release and function have been found in the brains of AUD patients and glutamate and/or GABA neurotransmission may underlie resting-state functional deficits in drug addiction (
117). Therefore, the effects of baclofen on neuroimmune/neurotransmitter systems may participate in a normalization of functional connectivity in patients with AUD.
Baclofen also has important neuromodulatory effects in the amygdala, through its inhibitory action on neurotransmitters and complex effects on second-messenger signaling (
37).
It reduces the strength of excitatory (glutamate) and inhibitory (GABA) transmission in the amygdala by a presynaptic mechanism (131). Furthermore, as mentioned previously, alcohol addiction is associated with impaired GABA clearance and increased GABA tone in the amygdala, associated, in turn, with higher anxiety-like behavior (
30). GABA-B receptor stimulation, which inhibits GABA transmission, should therefore be useful in the treatment of alcohol dependence and associated anxiety (Table (Table11).
de Beaurepaire R. (2018). A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder.
Frontiers in psychiatry,
9, 506.
https://doi.org/10.3389/fpsyt.2018.00506
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