Baclofen's anti-craving mechanism probably lies in: its modulation of dopamine and the mesolimbic reward system (of which the amygdala/emotional memory is a key part), inhibition of noradrenaline,5HT (serotonin),& glutamate, anxiolytic action at the GABAb receptor itself, plus effects on other neurotransmitters/chemicals like BDNF, substance P, and protein kinase C.
RedThread's link to the YouTube video on GABAa channels is super informative, and it's helpful to learn about the cellular mechanics and difference between ligand gated ion channel GABAa receptors (that benzos target) and G protein-coupled inwardly-rectifying potassium channel GABAb receptors (that baclofen targets) (alcohol hits both to some degree, but I think the gamma a-2l subset of GABAa receptor primarily). It's too bad there isn't a GABAb video.
A key point is that GABAa receptors react quickly for a very short duration (milliseconds) while GABAb receptors react slowly with a much longer duration (seconds-minutes). This relevant because it's the nature of the short action of the GABAa receptors (and the ever increasing amounts of the booze that we pour on to them) that probably drive alcohol addiction.
Reports on MWO (including my own) and review of the medical literature suggest that baclofen's effects present and resolve over the course of a few days (the "switch" is felt after a few days of reaching the relevant dose, and withdrawal from abupt cessation might take up to 72 hours to manifest) - this (to me) suggests that baclofen's effects (anti-craving effects) have a longer duration of action that exists outside the 2-4+ hour half life of baclofen doses (which we know is widely variable and reportedly 6 hours in chronic dosing).
I'm guessing that baclofen acts to steady/attenuate/normalize communication in neurological channels that have been changed/damaged/upregulated/downregulated by long term alcohol/substance abuse. The result is quelled craving and improved mood.
Some reading:
This paper (on Baclofen for cocaine craving) is a good place to start because it introduces some of the mechanisms I mention above and shows that (because it is also efficacious in treating cravings for other substances) baclofen is a medication that can be used to treat substance craving in general (and is not necessarily substitution therapy).
Neuropsychopharmacology - Baclofen as a Cocaine Anti-Craving Medication: A Preliminary Clinical Study
Here's a reference article from the above that's relevant (evidence that baclofen improves mood in abstinent alcoholics):
Baclofen administration for the treatment of affective disorders in alcoholic patients [Drug Alcohol Depend. 1993] - PubMed - NCBI
Ameisen states in his book that Baclofen works primarily as an anxiolytic/and a replacement for a deficiency of endogenous GHB. I don't believe this is true largely because GHB has lower affinity for (the inhibitory) GABAb receptor, obvious affinity to the GHB receptor (which is excitory through glutamate) and Baclofen has no affinity for the GHB receptor. Then again, GHB is used sucessfully as an anti-craving medication (for alcohol) in Italy among other places under the name, Alcover
Relevant to Baclofen, dopamine, and GHB:
Bi-directional effects of GABA: B: receptor agonists on the mesolimbic dopamine system : Article : Nature Neuroscience
Dopamine and Alcoholics:
Decreases in dopamine receptors but not in dopamine transporters in alcoholics [Alcohol Clin Exp Res. 1996] - PubMed - NCBI/a>
On whether or not baclofen is substitution therapy:
Suboxone is a direct substitute for other opioids. It is effective because it has a high affinity for it's target site (higher, I believe than other competing agents), and it has a ceiling dose after which it (or other competing agents) are not more effective. You get used to/build tolerance to a dose, no longer get "high" from it, can't effectively use more or alternate agents to achieve an additional "high." You don't experience craving, *if you get your dose everyday*, otherwise....withdrawal. Methadone is similar, although I believe you can still get additionally high with adjunct agents.
Benzodiazepines are cross tolerant with alcohol and can serve as a direct substitute. Tolerance can develop (usually develops) quickly and use can escalate. While, compared to alcohol, benzos are much easier on the body physiologically, cognitive/psychological impairment is a risk with long term use. Your mileage will vary with craving, tolerance, dependence and withdrawal.
Baclofen doesn't affect GABAa receptors (where alcohol largely acts) so it's not a direct substitute. Anecdotally, it makes drinking less or less than pleasurable. Tolerance (generally) doesn't develop, use doesn't escalate, and it has no pleasurable effects or abuse potential. Dosing is not anxiously anticipated (many reports here of forgotten doses). Though physical dependence is ostensible, tapering and discontinuation are readily manageable.
Interesting side-note here - Phenibut (which is nearly chemically identical to baclofen - minus a clorine atom) reportedly *does* carry tolerance/abuse potential (due to some GABAa affinity?).
Lastly, it's funny to me that the only people who suggest that baclofen is substitution therapy are those who aren't taking the medication themselves. Taking baclofen is not like getting a daily "fix," nor is it filling a hole that the absence of alcohol has left in our lives. It doesn't feel like either of those things - instead, baclofen prevents you from feeling that alcohol is a missing part of the equation in the first place.
-tk
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