How does baclofen work? Otter? Tk?

[terryk]

How does baclofen work? Otter? Tk?

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

[DonQuixote]

How does baclofen work? Otter? Tk?

Hello @all

Maybe O. Ameisens ?letter to the editor? in ?Journal of Psychopharmacology?, 2011, can be useful for you.

?Suppressing addiction using high-dose baclofen, rather than perpetuating it using substitution therapy?

You can find it here: https://dl.dropbox.com/u/59463672/Ameisen%20Letter%20to%20the%20Editor.pdf

DonQuixote

[Ne/Neva Eva]

How does baclofen work? Otter? Tk?

Cos--I hope that this week is much better than last. Is there anything you can identify as the reason for the lapse? Are you going to go up? Sorry for what you're going through.

Greg--so great that you're sober. All well here.

Tk. Thank you for taking the time. I know that it's all been said, and read! But great to have that summed up again.

DonQ--Thank you too! I had not seen that before. So nice to have you drop in and help to keep us informed.

Hope it's a good day/night for everybody!

[RedThread12]

How does baclofen work? Otter? Tk?

Yeah, terryk, I was pretty excited to watch that video, in particular, and a couple others. I really am going to see if I can contact him and ask for a similar explanation regarding Gabab, particularly in regard to addiction. Never know . . . he might say "yes!" And give us one more much needed tool. I'll post if I find out more.

[Otter]

How does baclofen work? Otter? Tk?

Here is how baclofen works:

All the various bits of your nervous system communicate with each other by electrical impulses travelling along nerve fibres. When the electricity reaches the end of the nerve cell it causes the release of tiny amounts of a highly specific chemical that passes across a small gap (the synapse) to the next nerve cell or, more usually, lots of cells. In order for the chemical to work, it must attach itself to a highly specific receptor that that particular cell will have so that the system works properly. When this chemical attaches to another nerve cell with the appropriate receptor it triggers another electrical impulse to pass the message on along it. And so on, until the final end-point is reached and something actually happens (e.g. making a muscle contract or a hormone to be released). These highly specific chemicals are called neurotransmitters (or neuromodulators), and there are lots of different ones for different functions in different parts of your brain / nervous system and elsewehere in your body. Importantly, nature has made a system where, within whatever the bodily process you are considering, one neurotransmitter might speed the process up, whilst another slows it down. This vital process allows for fine control or regulation.

Next, imagine your nervous system as a train set. The appropriate neurotransmitter, in the right amount, makes the train run smoothly in the direction you want; performing the precise physiological action required.

Scientists now routinely develop synthetic forms of these neurotransmitters (analogues) for therapeutic use. They are laboratory- created chemicals that are similar enough in structure to be able to attach onto the receptors that the naturally occurring neurotransmitter does. Some do what the transmitter does (agonists); some block or even reverse its actions (antagonists).

Consequently, these analogue drugs might have any or more of the following effects when administered to an individual:

Make the train go the way nature intended. It might help the taker considerably or not, depending on the dose and why it is being taken;

Make the train go in precisely the opposite direction. This again might help some diseases or make things worse;

Make the train stand still and not go at all. This might be beneficial if intentional and prescribed;

And some might make the train do really crazy things and mess the whole thing up. Many illicit drugs work in this fashion;

Lastly, the effects of some drugs make the train go in one direction at a low dose and do precisely the opposite at a higher dose.

Add in other brain altering drugs (e.g. alcohol) and the mix could be wholly unpredictable, and frequently is.

One such natural neurotransmitter is Gamma Aminobutyric Acid (GABA). Very simply, it is an inhibitory chemical. It makes the train run much slower. In general, it slows down many areas of your nervous system; regulating the degree of excitability of how the system works. If it wasn't there, or not working properly, the system would run out of control - in a sense, if would 'overheat'. There would be chaos. As such, GABA is intimately involved in regulating the tone of your muscles. Abnormalities of GABA's working result in your muscles becoming excessively toned, or spastic.

There is actually more than one type of GABA. There are at least two currently known - GABAa and GABAb. For our present purposes, we needn't concern ourselves too much with this. Baclofen is important in relation to GABAb.

Baclofen is the ONLY drug that, as yet, mimics GABAb.

For reasons discussed next, GABA also appears to be fundamentally important in the development of chronic alcoholism, and holds the key to why Baclofen is so effective in treating it.br />
Baclofen is a synthetic analogue agonist of GABA and enhances the effects of GABA. It makes the 'train' go in the direction nature intended. That is, to calm the system down. For individuals with problems with how their GABA works, it replaces or reinforces GABA, helping it to do the job nature intended.



Next, there is a very small area of the brain called the Amygdala(because it's shape resembles an almond), involved in a wide range of normal behavioural functions and psychiatric conditions. Until recently, it attracted very little interest from scientists, but recently has become the focus of a great deal of research. Why? It is because it is now extremely evident that the Amygdala is integral to how humans process their emotions (such as fear; sexual activity; pleasure; eating; aggression). It is essentially a bit of brain that thrives on excitement of whatever kind. It is often referred to as the pleasure centre. It also appears to have an important role in your development and retention of your emotional memories; and perception of your environment and perceived stresses applied to it.

In short, abnormalities of the Amygdala interfere with the individual's processing of the emotional significance of external stimuli; e.g. normal daily problems and activites get blown totally out of proportion and cause inappropriate stress. Further, and importantly, the Amygdala appears to be important in binge-drinking, and is damaged by repeated episodes of excessive drinking and alcohol withdrawal. Alcoholism is now known to interfere with the nerve pathways (including the Amygdala) that are responsible for the processing of your emotions.

Consequently, scientists now believe (although the details have yet to be worked out completely) that a malfunctioning or damaged Amygdala has a crucial role in the development of a wide range of psychological and psychiatric conditions. To date, these include:

? Alcoholism and other addictions, especially if they are caused by chronic anxiety

? Panic Attacks

? Bipolar Disorder

? Clinical Depression

? General Anxiety Disorder

? Obsessive Compulsive Disorder

? Post-Traumatic Stress Disorder

? Phobias

? Autism

? Schizophrenia



Recent studies have also shown that a naturally occurring brain peptide (CRF) has an additional effect when combined with alcohol. Both appear to influence activity within the Amygdala by increasing its transmission of GABA.



We now have to consider a little about how drugs exert their effects on our brains and bodies and how other administered drugs (medicines) might help treat addiction.

In 'positive reinforcement', the individual feels really great when they take the drug. This is clearly very important in why people initially take drugs or drink alcohol. For people like you and me, our positive reinforcement is that our anxiety was relieved when we drink. Medicines that reduce positive reinforcement to another drug might help block the euphoria that the individual feels after taking it, and help the individual stop taking it.

In 'negative reinforcement', the individual has to take the drug to get rid of the horrible feelings of NOT taking the drug. This is clearly important in why people find it difficult to come off drugs or stop drinking alcohol. Medicines that help reduce negative reinforcement might make the individual not feel the need to take the drug in order to stop the horrible feelings of coming off that particular drug.

It appears that different parts of the brain are involved in both of these elements.
>In order to test whether a new drug works in helping any addiction, scientists have to devise experiments that look at both positive and negative reinforcement. They often use laboratory rats. After all, rats know nothing of the 'psychology' or 'sociology' of why they do what they do. They just do it. Consequently, if they voluntarily take a drug when it is offered to them, they do it because it does something that they feel as beneficial. If they are then given medicines, scientists can look at how that medicine affects their behaviour with the other drug in question.

In laboratory rats, it has been shown that Baclofen seems to reduce the positive reinforcement of many drugs, including alcohol. Rats given Baclofen were less likely to drink and become 'alcoholic' when offered alcohol. Simply, they just didn't get anything from it.

Further, in rats made 'alcoholic', Baclofen makes it less likely that they will exhibit many of the horrible effects of coming off alcohol. They stop craving alcohol to get rid of these effects; taking less or no alcohol when offered it.


In conclusion, it is thought that Baclofen exerts its beneficial effects in patients taking it by doing what GABA should be doing when you take alcohol; diluting or eliminating the euphoric 'beneficial' effects of alcohol - eventually removing the craving for it. After all, it is not then providing you with any perceived ‘benefit’. It also alleviates many of the unpleasant effects of not taking alcohol.

Further, Baclofen also ‘calms your Amygdala down’, so helping to treat your chronic anxiety / panic attacks that caused you to drink in the first place.

This is all very rudimentary and the research still has a considerable way to go. However it is fair to say that, already, the whole focus on chronic alcoholism as a physical disease has shifted dramatically in recent years.




I wish I could take credit for that but it is the best description of what is going on that I have read.

[terryk]

How does baclofen work? Otter? Tk?

Otter;1457604 wrote:

There is actually more than one type of GABA. There are at least two currently known - GABAa and GABAb. For our present purposes, we needn't concern ourselves too much with this. Baclofen is important in relation to GABAb.

Baclofen is the ONLY drug that, as yet, mimics GABAb.

Otter, it looks like your explanation is based largely on Phil Thomas' B4a Handbook. Some of your information is inaccurate. Sorry to nitpick...

There is one type of GABA - GABA, the endogenous neurotransmitter..

There are GABA receptors, of which there are 2 main types (GABAa and GABAb) and several subtypes.

Baclofen is a GABAb agonist, which means that it acts like GABA does at GABAb receptors. It is surmised that it's unique chemical structure enables it to penetrate the Blood-Brain Barrier and exert a great effect than plain old GABA (which generally can't cross the BBB)

Phenibut is also a drug that mimics GABA at GABAb receptors

Lesogaberan is also a drug that mimics GABA at GABAb receptors

GHB (+GBL, 1,4 But, GHV ) is also a drug that mimics GABA at GABAb receptors

-tk

[Ne/Neva Eva]

How does baclofen work? Otter? Tk?

Thanks, Otter. I like the train metaphor.

I missed the video, RedT! But just watched it. Very cool. And oh the irony of the fact that he touches on baclofen and then moves right along...
Hope you can convince him to do one for us!
xo sister.

[Cassander]

How does baclofen work? Otter? Tk?

Ne/Neva Eva;1457688 wrote: Thanks, Otter.

Ditto to Otter, and tk, and everyone else who has contributed to this thread.

I have read what each of you has written, as well as everything I can find on the internet, about the effectiveness of baclofen in eliminating craving for alcohol, and continue to find it amazing that neither any government (other than perhaps the French government), nor the pharmaceutical industry, nor the rehab community, nor the medical profession, nor the mutual aid groups (AA) has moved aggressively to legitimize and routinize a treatment that could save thousands of lives and billions of dollars.

From a big picture point of view, if I am a doctor, and you come to me for treatment of alcoholism, and there is substantial evidence that an effective treatment exists, but I don't inform myself of the available treatment, or fail or refuse to administer it, or fail to at least refer you to someone knowledgeable of the most up to date and effective treatments, am I not negligent and liable for the consequences of my negligence? I don't know how doctors can hide behind "ignorance" (or the fact that the FDA has not specifically approved the drug for use in alcoholism) and not take notice of the effectiveness of baclofen treatment.

[Ne/Neva Eva]

How does baclofen work? Otter? Tk?

Cassander;1457763 wrote: continue to find it amazing that neither any government (other than perhaps the French government), nor the pharmaceutical industry, nor the rehab community, nor the medical profession, nor the mutual aid groups (AA) has moved aggressively to legitimize and routinize a treatment that could save thousands of lives and billions of dollars.

I KNOW! I've had the same reaction. It's absolutely outrageous. And it's got to change.

[Xadrian]

How does baclofen work? Otter? Tk?

Otter;1457604 wrote: Baclofen is the ONLY drug that, as yet, mimics GABAb.

In fact, there are a few more, like
methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate;

methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate;

2-(1-(2-(4-chlorophenyl)-5-methylpyrazolo(1,5-a)pyrimidin-7-yl)-2-piperidinyl)ethanol,

and some others with fancy names as CGP44532 and SKF97541.

but baclofen appears to be the only one with no severe side-effects (although some people here would argue that).

Moreover, baclofen is being used for decades and the patent is expired, making it relatively inexpensive to purchase.

[Otter]

How does baclofen work? Otter? Tk?

Cassander- yes, it would be negligent not to prescribe it, and negligent not to do the research to find that it is all over the internet as a treatment.

Xadrian- You mention "methyl" and "ethyl" derivatives. The other gaba b mimic is alcohol...ethanol. That is the point. Baclofen replaces ghb, rather than ethanol.

[Otter]

How does baclofen work? Otter? Tk?

Why not sue the booze companies as do smokers?

Court: Smokers Can Sue Tobacco Companies Over New Illnesses - California Healthline

Also, alcohol causes real physical damage even if one stops. Alcoholism Affects Men’s and Women’s Brains Differently | Psych Central News
Where on the packaging does it say this when you buy a bottle of vodka?

Isn't there a duty to warn that a product carries these risks to health?

This is why I set up the other sites, because I want something to come up on the internet when anyone googles about alcohol treatment so they cannot hide behind ignorance. Just imagine a doctor going to court and trying to testify that he couldn't find anything about pharmaceutical treatments for alcoholism.

Maybe we should contact some Lawyers4U contingency lawyers and see if they would take this on. Hmmm......

[terryk]

How does baclofen work? Otter? Tk?

Otter;1457604 wrote:

There is actually more than one type of GABA. There are at least two currently known - GABAa and GABAb. For our present purposes, we needn't concern ourselves too much with this. Baclofen is important in relation to GABAb.

Baclofen is the ONLY drug that, as yet, mimics GABAb.

Otter, the above statements are incorrect.

There is one type of GABA - GABA, the endogenous neurotransmitter. There are chemical analogues of GABA, and also chemicals that act at allosteric modulators (at GABA receptors).

There are GABA receptors, of which there are 2 main types (GABAa and GABAb) and several subtypes.

Baclofen is a GABAb agonist, which means that it acts like GABA does at GABAb receptors. It is surmised that it's unique chemical structure enables it to penetrate the Blood-Brain Barrier and exert a great effect than plain old GABA (which generally can't cross the BBB)

Phenibut is also a drug that acts like GABA at GABAb receptors

Lesogaberan is also a drug that acts GABA at GABAb receptors

GHB (+GBL, 1,4 But, GHV ) is also a drug that acts GABA at GABAb receptors

I've articulated my reasoning that I don't think baclofen works by replacing endogenous GHB. This article is a good read (GHB doesn't modulate dopamine neurons like baclofen does): Bi-directional effects of GABA: B: receptor agonists on the mesolimbic dopamine system : Article : Nature Neuroscience

I've noticed that you base (some of) your info on Phill Thomas' B4a handbook. It contains some of the same errors I've pointed out here.

-tk

[Otter]

How does baclofen work? Otter? Tk?

It may be a lot of drugs work on the Gaba b receptor, like arsenic, which stops them working for good.

[terryk]

How does baclofen work? Otter? Tk?

Otter;1457939 wrote: It may be a lot of drugs work on the Gaba b receptor, like arsenic, which stops them working for good.

Are you trying to poison me?

CGP7930: a positive allosteric modulator of the GABAB receptor [CNS Drug Rev. 2007] - PubMed - NCBI



Adams CL, Lawrence AJ. Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Australia.

Abstract CGP7930 (3-(3',5'-Di-tert-butyl-4'-hydroxy)phenyl-2,2-dimethylpropanol) is a positive allosteric modulator of the metabotropic GABAB receptor. CGP7930 has been found to modulate the GABAB receptor in the open, or high affinity, state increasing agonist affinity for the receptor and signal transduction efficacy following agonist stimulation. The GABAB heteromeric subunit B2, involved in signal transduction but not ligand binding, seems to be the site of action of CGP7930 and similar allosteric modulators. When administered alone in na?ve animals, CGP7930 acts as an anxiolytic in rodents without other overt behavioral effects and has also been demonstrated to reduce self-administration of nicotine, cocaine, or alcohol in rodents, suggesting that "fine tuning" of the GABAB receptor by positive allosteric modulators may be able to regulate abuse of these drugs. Baclofen, the GABAB agonist, is currently finding use in treating addiction and various other disorders, but this can result in off-target effects and tolerance. CGP7930 when co-administered with baclofen enhances its potency, which could in theory minimize deleterious effects. Further study of CGP7930 is required, but this compound, and others like it, holds potential in a clinical setting.


MID: 17894647 [PubMed - indexed for MEDLINE]

-tk