Agmatine is known for reducing tolerance and withdrawal for a range of drugs; might it reverse the loss of effect with Abilify?

[Hip]

I wonder if the supplement agmatine might reverse the loss of effect (poop out) that many ME/CFS patients experience with the antipsychotic drug Abilify (aripiprazole)?

It is common for ME/CFS patients to obtain major improvements from low-dose Abilify, only to find that some weeks or months later, Abilify stops working for them.

The supplement agmatine, an NMDA receptor antagonist, is known to reduce tolerance (loss of effect) and withdrawal symptoms for a range of drugs, including opioid drugs, GABAergic drugs like benzodiazepines and phenibut, and caffeine. Memantine is another NMDA receptor antagonist that reduces drug tolerance and withdrawal.

Here are some studies and anecdotes that indicate how agmatine, memantine and other NMDA antagonists can reduce drug tolerance and withdrawal:

• A mouse study demonstrated how agmatine reduced the symptoms of benzodiazepine withdrawal.
• Two people here found agmatine at doses of 500 to 1500 mg effective for mitigating benzodiazepine withdrawal.
• A study found memantine blocked benzodiazepine tolerance.
• According to a Reddit poster, there are reports of agmatine reducing tolerance to phenibut, an anti-anxiety supplement that agonises GABA-B receptors.
• A mouse study demonstrated that agmatine prevented tolerance to morphine.
• Some people report agmatine reduces tolerance to caffeine.
• A study states that memantine potentiates the subjective effects of alcohol, cocaine, and nicotine.
• Some people report agmatine eliminates nicotine cravings when trying to quit nicotine.
• Some people report agmatine potentiates the effects of cannabis.

It might be worth trying agmatine in cases of Abilify loss of effect, but whether it will work is open to question. I think it is a bit of a long shot. Abilify does not target opioid or GABA receptors, but rather hits the some dopamine receptors, some serotonin receptors, and some alpha adrenergic receptors, which makes Abilify different to the drugs agmatine works for.

 

[Springbok1988]

Agmatine makes me horribly, horribly depressed every time I take it. So does memantine. I’ve never figured out how common that is, though.

 

[Hip]

Agmatine makes me horribly, horribly depressed every time I take it. So does memantine. I’ve never figured out how common that is, though.

There seems to be some reports of increased depression when I searched Reddit.

I wonder what would happen if you tried high-dose transdermal magnesium, which is another NMDA receptor antagonist? Would that also lead to depression?

I sometimes apply saturated Epsom salts solution to my skin from head to toe, as an anti-anxiety treatment (as described in this post). Excess glutamate is associated with anxiety, and if you take high enough doses of magnesium, it blocks the NMDA receptors which glutamate normally activates. Oral magnesium does not work, because high doses result in bowel flushing. I find transdermal magnesium reduces anxiety level by about 5 ot 10%, so I have to use this in combination with other anti-anxiety treatments.



I've tried both agmatine and memantine in short-term tests for a few days, but don't notice much from them.

I recently came across some Reddit posts (here and here) about agmatine greatly helping anhedonia. So I am planning to try agmatine for a few weeks to see if it can improve my anhedonia.

 

[ryanc97]

Hello, new member here, mild for 1.5 months (still horrible crushing fatigue/brainfog) in the day though.

So I understand LDN helps abilify tolerance (for depression) in this study:

Filamin A is also found in dopaminergic D2 and D3 receptors,which led Bear and Kessler to propose that low (LDN) or ultra-low(ULDN) doses of naltrexone might reverse or prevent desensitization toD2/3 agonists (Bear and Kessler, 2014a, 2014b). This was tested inRestless Leg Syndrome (RLS), thought to result from a deficiency ofD2/3 compared to D1 agonism, and typically treated with D2/3agonists pramipexole or ropinirole. Periodic Limb Movements ofSleep measurements confirmed that ULDN allowed equivalent controlof limb movements at half the prior dose of D2/3 agonists. Althoughthe naltrexone dose was 0.15 μg, the effect was retained at 100 μg and1 mg (Bear and Kessler, 2014a, 2014b). Thus, naltrexone provedeffective for RLS, putatively by facilitating sensitization of D2/3agonists.

So naltrexone is said to help prevent desensitization to D2 agonist which is the mechanism LDA does its good work from.

I'm not sure about agmatine. I hope we can find a link. But for now what I read is that there are 3 possible combos to reduce the LDA tolerance:

1. LDN (as above) - This seems to have strongest evidence.
2. Amisulpride - This was more due to that empirical post which a redditor had LDA tolerance in 3W but combined it with this and lasted 8 months until tolerance was built. This is a D2 antagonist. By that logic it should stop abilify from working in the first place, but I'm not sure.
3. Agmatine - From your post.

 

[ryanc97]

So in a long shot, maybe dosing abilify with LDN and amisulpride and agmatine might prevent tolerance?

 

[Hip]

So in a long shot, maybe dosing abilify with LDN and amisulpride and agmatine might prevent tolerance?

Very interesting finding.

It is surprising that ultra-low naltrexone doses as low as 0.15 μg (which is 0.00015 mg) were found to be effective at preventing dopamine D2 and D3 receptor desensitisation by agonist drugs that act on these receptors. Such ultra-low doses are about 10,000 times smaller than low-dose naltrexone doses used by ME/CFS patients.

Although the receptor desensitisation effect still occurred at higher naltrexone doses of 1 mg and 0.1 mg.

In the study you quoted, they refer to this patent, which details these ultra-low naltrexone doses.



Aside from the possibility that ultra-low dose naltrexone might prevent Abilify loss of effect, I wonder if these ultra-low doses might have benefit for ME/CFS in general?

Most ME/CFS patients when they try naltrexone use doses around 4 mg before bed; I wonder what the effect would be with ultra-low doses?

 

[ryanc97]

Hey. Oh gosh I didn't see the dose is little. Well, to be honest it's hard to say. I can try it out, but I am ordering liquid naltrexone and abilify, naltrexone from Dickson's and abilify from GoldPharma. I'm not sure to the extent I can titrate out a tiny bit, but I plan to go at 0.1mg for both of them.

I am going to go on both at the same time, but abilify will be dosed infrequently, and I hope the naltrexone will improve me and also prevent abilify tolerance.

I am not sure about agmatine and amisulpride. Maybe worth a try to combine, but at least, in research, LDN + LDA should prevent tolerance (assuming D2/D3 receptor desensitization = tolerance).

I believe amisulpride has more empirical evidence, if you could remember the case studies of the redditor and the other guy and put it here, I would be really grateful.

 

[ryanc97]

For amisulpride, if it is a D2/D3 antagonist and abilify is an agonist, isn't that just negating out the effect by combining? How could that prevent tolerance in theory? Any ideas?

 

[bad1080]

ULDN (ultra low dose naltrexone) is used by people with substance use disorder to avoid withdrawal and potentiate or prolong an allotted dose of methadone. a lot of reports on r/ULDN

 

[Hip]

if you could remember the case studies of the redditor and the other guy and put it here, I would be really grateful.

I am not really sure what case studies you are referring to.

For amisulpride, if it is a D2/D3 antagonist and abilify is an agonist, isn't that just negating out the effect by combining? How could that prevent tolerance in theory? Any ideas?

Abilify is a partial agonist at dopamine D2 and D3 receptors, which means it can act as both an agonist and antagonist depending on the surrounding dopamine levels. It also has effects on dopamine autoreceptors.

Amisulpride is a dopamine D2 and D3 receptor antagonist. And amisulpride antagonises the dopamine autoreceptors.

By these various actions on receptors and autoreceptors, both Abilify and amisulpride act as dopamine system stabilisers.

A dopamine system stabiliser is a drug which acts as an agonist of the dopamine receptors at low dopamine concentrations, but acts as an antagonist at high dopamine concentrations. So such drugs boost the dopamine system when dopamine is low, but puts the breaks on the system when dopamine is high.


The first post in my amisulpride thread talks more about dopamine system stabilisation from amisulpride and Abilify.

 

[ryanc97]

Thanks for this. For case studies,

I mean I had read (I'm still new to this) a couple of posts here and on the CFS subreddit on people using amisulpride + abilify and noticing abilify tolerance did not build. I can't exactly remember where they are, I believe one was on a guy with depression and not CFS.

 

[ryanc97]

"Some researchers have speculated that glutamate levels are high in the brains of ME/CFS patients (and speculate this is the cause of the "wired" feeling in ME/CFS). If there is high glutamate, it would explain why the gain control on neurons is turned up to maximum. Copious amounts of glutamate are produced by microglia during brain inflammation, so if there is a chronic viral brain infection in ME/CFS, then that would explain the high glutamate.

So Abilify may be just compensating for an excessively high gain control setting on dopamine neurons. This drug will dampen any strong dopamine signals input to the neuron, so that the signal does not get over-amplified. But at the same time, it allows weaker dopamine signals to get through."

You mentioned this in your post.

But according to the itaconate/GABA shunt by Ron Davis, the shunting cells burn GABA/glutamate in the GABA shunt producing ammonia and the use of these neurotransmitters for fuel (and ammonia) is what drives the brainfog, so CFS patients should have low levels of GABA/glutamate by this logic?

Thank you for replying and being so knowledgeable, I hope we achieve something useful with this thread that us and everyone can use in terms of treatment.

For me, I believe the beneficial effects of naltrexone/abilify/amisulpride come from the anti-inflammatory/immune-modulation, whether that is a result the D2/D3 receptor pathways is what I am not sure about.