6 replies to this topic

[John250]

I know I know this isn’t my first thread about this lol but I’m always on a never ending quest to find the best/easiest/most productive methods. I posted this on Reddit so I mine as well post it here lol

Everyone says amphetamine withdrawl is easy and to just suck it up for a few weeks. Well that’s simply not the case for a lot of people, especially those who have a career in a family they cannot risk losing and don’t have the time to be in bed with no cognitive function for up to 3 months.

I’m thinking the following could be the most extensive tolerance reducing and eventually going off method. Why not imply all extreme measures? Not including drugs like MAOi’s, SNDRi’s, Dopamine Agonists,etc.. that will
just cause their own withdrawal defeating the whole point of getting clean.

No medication is currently approved by the FDA for use in amphetamine dependence and only Psychotherapy is recommend which is absolute bullshit! The only randomized trials of amphetamine withdrawal agents have been of antidepressant drugs (amineptine and mirtazapine). Every other drug has more advanced withdrawl treatment and if you look at the mechanism behind amphetamine it shouldn’t be that hard and recovery should be much faster than opiates, benzodiazepines,etc.. Restore dopamine and norepinephrine and minimally restore Serotonin. Opiates negatively impacts he dopamine system worse than amps so similar therapy should be helpful.

If anyone has any advice to chime in feel free.

The goal is to hit it from all angles and just for this theory let’s say cost is no issue. And first off I do not believe amphetamines or and drug should apply the COLD TURKEY method. Just because the risk of a seizure is very low from amphetamine withdrawl does not mean there could not be major physical and mental side effects only to be ex’s exacerbated from not tapering.
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Drugs with low side effects/withdrawal(PAWS):

Most drugs to help with withdrawal attenuate the reinforcement positives of amphetamines which will just lead the user to abuse them more. Even though methamphetamine is GREATLY different than amphetamine whatever treatment works for Meth will definitely work for amphetamines. I also searched under cocaine as some methods could help but treatment may be different since cocaine is mainly involved with the reuptake inhibition vs a releasing agent from the synaptic cleft. However amphetamine is still technically a reuptake inhibitor as well.
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Topamax which seems interesting:

https://www.ncbi.nlm...ubmed/16448579/

“The experimental combination of topiramate and methamphetamine appeared to be safe and well tolerated, with few adverse events. Acute dosing with up to 200 mg topiramate appears to enhance, rather than attenuate, the positive subjective effects of methamphetamine. Perhaps this indicates a partial inhibition of methamphetamine's reinforcing effects.”

This is very interesting as you rarely find a drug to enhance rather than dull the positive effects.
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The only other drug that may help is Low Dose Naltrexone(LDN):

http://jpet.aspetjou...ntent/282/2/734

“Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role ofmu opioid receptors in these effects remains unclear.”
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Tyrosine Hydroxylase (TH)
This is very important and often overlooked.

Long term amphetamine use can deplete TH in the dorsal striatum taking up to 4 months to recover:

https://www.ncbi.nlm...pubmed/9694971/

https://www.scienced...006899384912216

https://www.ncbi.nlm...8750831/related

So how do we restore TH?

1.) Increase GDNF

https://www.ncbi.nlm...9694971/related

2.) Directly increase the reuptake of TH:

a.) Uridine Monophosphate with Omegas, Citicoline and B vitamins.

b.) Tributyrin

c.) N-Acetyl L-Tyrosine (NALT)
{although I did read a study that L-Tyrosine is better than NALT}

3.) Bromantane (Ladasten):
Perhaps the strongest yet somewhat safe drug to increase TH:
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Psychotherapy:
Dialectical behavior therapy (DBT)

Brain Stimulation Therapy:
(Why use just one? Can multiples interact?)

#1.) Transcranial Magnetic Stimulation (rTMS)
proven to help:
https://www.ncbi.nlm...les/PMC4206564/

And perhaps add:

*Vagus Nerve Therapy(VNS)

*Deep Brain Stimulation (DBS)

*Electrical Muscle Stimulation (EMS)

*Low-Level Light Therapy (LLLT)
(Perhaps Blue Light and Infrared Therapy?)

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Also this is important. It’s not well known as most focus on the dopamine system but GABA is greatly effected by amphetamine use. Although the absolute worst drug you could withdrawl from would be one that interferes with Gaba like benzodiazepines and Phenibut so natural methods to increase Gaba should be preferred.

https://www.ncbi.nlm...les/PMC4419710/

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Also there are lots of supplements to use to combat neurotoxicity but they have already been covered many times.

There are lots of other ways to increase/restore dopamine like BPC-157, 9-me-bc, Jiaogulan,etc.. but I wanted to mainly focus on restoring TH and using non traditional therapy to reverse tolerance and restore levels.
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Edited by John250, 24 February 2019 - 06:43 PM.

[MankindRising]

Have you looked into PDE4 inhibitors? They seem to improve both gating and prefrontal dopaminergic function.

 

The mediating role of phosphodiesterase type 4 in the dopaminergic modulation of motor impulsivity

https://www.scienced...166432818303541

"As a result, it would be interesting to test the effects of PDE4 inhibition in disorders affected by disrupted impulse control related to cortico-striatal-thalamic hypodopaminergia including attention deficit hyperactivity disorder (ADHD)."

Highlights

• CSRTT measures impulsivity via premature responding.

• Increasing and decreasing dopamine levels resulted in increased premature responding.

• Roflumilast increased premature responses in combination with d-amphetamine.

• Roflumilast decreased premature responding in a 6-OHDA model.

• PDE4 inhibitors could reverse motor impulsivity induced by hypodopaminergia.

 

Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex.

https://www.ncbi.nlm...pubmed/21833500

 

Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

https://www.ncbi.nlm...les/PMC2814340/

 

"The PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals that was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Rolipram induced a small increase in DARPP-32 Thr34 phosphorylation preferentially in striatopallidal neurons by activating adenosine A2A receptor signaling in striatum."

 

Not sure what to think about its effect on A2A receptors, afaik that would mean the oposite as caffeine does? Also A2A are obviously linked to D2 receptors.

Seems D1 and D2 receptors are more of a tradeoff, more cognition less joy? Idk I could be all wrong im not scientist.

 

All in all, PDE4i's seem excellent for work related focus n all that, but keep in mind Im not sure if PDE4i's would help with the depression sides and anhedonia that withdrawal of stims might be bring.

For what its worth Ill be trying Ibudilast (if I can get my hands on it) after Im done with resveratrol and wellbutrin.

 

ps. if anyone reads this that has a source for ibudilast please PM me it as im not sure if sourcing is allowed on here.

[MankindRising]

Oh yeah one last thing, you wouldnt have happened to try wellbutrin before?

[John250]

I actually haven’t tried any Pde4 inhibitors. I have some Ibudilast though. I have tried Wellbutrin and it actually dolls the positives of amphetamines because they compete for the same receptors.

But I did find interesting is there some good research on HDAC inhibitors being very effective. Only problem is they seem to come with a lot of side effects except for the natural inhibitor Tributyrin/sodium butyrate.

https://www.ncbi.nlm...ubmed/18848971/

https://www.ncbi.nlm...ubmed/17477979/

https://www.ncbi.nlm...les/PMC2992845/

[MankindRising]

I actually haven’t tried any Pde4 inhibitors. I have some Ibudilast though. I have tried Wellbutrin and it actually dolls the positives of amphetamines because they compete for the same receptors.

But I did find interesting is there some good research on HDAC inhibitors being very effective. Only problem is they seem to come with a lot of side effects except for the natural inhibitor Tributyrin/sodium butyrate.

https://www.ncbi.nlm...ubmed/18848971/

https://www.ncbi.nlm...ubmed/17477979/

https://www.ncbi.nlm...les/PMC2992845/

I will get my hands on roflimilast (if I can through my doc, who is openminded regarding trying new stuff for ADHD), the therapeutical dose seems as low as 100mcg and was devoid of any side effects. The good news it, it even worked in healthy humans (so without adhd) too, which makes me think it actually does something unlike the average snake oil supplement. See here:

 

 

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial

https://link.springe...0213-017-4770-y

 

"Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer’s disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating."

 

"No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study."

 

"The PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating."

[John250]

Interesting. I actually have a bottle of 20mg/ml Ibudilast from IRC.bio and check this out:

https://www.ncbi.nlm...les/PMC5617368/

Methamphetamine Beardsley and coworkers have done a series of studies examining the effects of non-selective PDE inhibitor ibudilast and its analogs on methamphetamine abuse. Similar to the aforementioned effects on cocaine-associated hyperlocomotion, they report that ibudilast and its analog AV1013 reduce the methamphetamine-induced increase in locomotor activity and sensitization without significantly affecting locomotor activity by itself (Snider et al., 2012).

{In addition, ibudilast and AV1013 are effective in attenuating methamphetamine self-administration and drug seeking behavior. Systemic administration of these compounds reduces methamphetamine self-administration on an FR1 schedule in the rat (Snider et al., 2013). Systemic ibudilast and AV1013 significantly reduces footshock- and prime-induced reinstatement of methamphetamine-seeking in the rat Interestingly, the reduction of drug seeking behavior by ibudilast and its analog may be associated with inflammatory processes.}


Methamphetamine activates glial cells and increases proinflammatory cytokine production in the brain, and glial cell activation and inflammatory responses have been linked to drug abuse-related behavior (Beardsley and Hauser, 2014). Ibudilast inhibits both PDE and glial proinflammatory activity, while AV1013 shares the anti-inflammatory activity of ibudilast but only negligibly inhibits PDE (Snider et al., 2012). These results suggest that modulation of glial inflammatory activity also contributes to the attenuation of methamphetamine-induced locomotor {sensitization}and relapse of drug seeking by ibudilast and AV1013, and targeting glial cells may provide a novel approach to pharmacotherapy for treating methamphetamine abuse.
Methamphetamine and cocaine are psychostimulants that share similar mechanisms of increasing extracellular dopamine levels in the brain (Anderson and Pierce, 2005), and many of the behavioral measures discussed above are dopamine-dependent. In vivo microdialysis shows that rolipram increases striatal cAMP levels but does not significantly alter methamphetamine-induced increase in striatal dopamine levels (Iyo et al., 1996), suggesting that rolipram-induced changes in behaviors are not due to direct modulation of striatal dopamine.

[MankindRising]

Yeah both PDE4 and PDE10 are interesting targets for dopamine related issues.

 

Tofisopam is another 'odd one' in a good way, apparantly an anxiolytic with zero sedative effects that has an effect on stratial dopamine modulation, both an anti-psychotic and also a potentiator of apomorphine, weird huh. Im trying to figure it out its something I am considered trying (roflumilast that is).

 

Heres another paper showing (atleast in animals) it can modulate behavior to a pretty large degree:

 

Phosphodiesterase 4 inhibitors enhance sexual pleasure-seeking activity in rodents

https://www.ncbi.nlm...les/PMC3065502/

 

My guess is that PDE4i's can modulate any form of sensation/thrill seeking/addictions, however what the outcome might be would depend on a lot of factors by the looks.

Edited by MankindRising, 28 February 2019 - 11:36 AM.