The Secret Drug Tolerance Reversal Chemical Nobody Told You About

For those of you who haven’t a clue what Memantine is yet, please check out our first article: Memantine Basic Research Summary

Memantine has incredible potential for a huge variety of tolerance issues. It has the potential to reduce tolerance, or at the very least lessen the impact of rebound and withdrawal.

This is due to its incredible action as a moderate affinity, uncompetitive NMDA receptor antagonist with strong voltage-dependency and fast kinetics. 

This means that it acts as an NMDA antagonist, without affecting receptor function. NMDA part of the glutamate system is a crucial part of the brains nominal function.

As we have already discussed in other posts, NMDA antagonist has at least decent results in reversing drug tolerance, because, the receptor, when activated, facilitates ions, in particular, Ca2+ ions. A spike which is associated with neuronal changes to make further applications of the same drugs less effective.

You can see from this mechanism why it’s not immediately apparent for tolerance to develop, this is because receptor changes in neurones happen very slowly. This is because each receptor needs to be built from scratch, sort of like muscle recovery.

However this synaptic adaptation is the biggest reason why many drugs eventually become completely ineffective, and on the reverse make the person physically dependent on the drug to simply function.

Consequently, the irony is the spike in Ca2+ ions in excessive amounts is what creates conditions for neurotoxicity in the first place, which is why Memantine is also neuroprotective.

Memantine May Reverse Tolerance for Almost everything

Consequently because Memantine targets the NDMA receptor which is so responsible to some major reasons why drug tolerance develops (there are many). It has ample research to suggest that it has results on huge variety of chemicals.

Before we proceed its important to note that Memantine is not a magic pill for reducing drug tolerance, there have been many experimenters who thought Memantine would stop tolerance from developing, so they ended pairing it with Adderall (amphetamines), and thought the party would last forever. It didn’t. 

There is nothing in our current chemical knowledge that is capable of reversing tolerance whilst escalating euphoric dosages of chemicals. 

Tolerance works on many mechanisms, and when you take euphoric dosages of amphetamine, drug tolerance at the neuronal level isn’t the only reason the drug is becoming less effective over time.

Also, Memantine is different from other chemicals like Proglumide because it Proglumide acts as a potentiator, and is an analgesic itself and inhibits drug tolerance via a whole different pathway (The CCK network).

So Memantine (and other NDMA antagonists) has so far have evidence for reducing these drug tolerances: opioid, nicotine, ethanol, amphetamine and benzodiazepines only anecdotally.

And the great thing? Memantine has a stellar side effect profile compared to other psychotropics, almost next to none apart from the initial nicotinic antagonist effects which we will detail in another post.

[wl_navigator]

READ  Proglumide and Opioid Tolerance Reversal - A Summary

Memantine and Opiate Tolerance

The mechanisms underlying opioid tolerance are not fully understood but appear to be comprised of two types of plasticity or counter-adaptation, at the cellular level and through neuronal circuits.

This review focuses on the plasticity in neuronal circuits achieved through an enhancement of so-called anti-opioid glutamate/NMDA receptor synaptic activities. The anti-opioid action of glutamate-NMDA receptor systems underlying morphine analgesic tolerance.

Masui. 2009 Sep;58(9):1136-42.
Ueda H1, Matsushita Y.
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.

Above is just an overview to show that the NDMA drug tolerance hypothesis isn’t some made up idea.

Results showed that pretreatment with Dextromethorphan or midazolam decreased the degree of tolerance and withdrawal symptoms significantly

Pak J Biol Sci. 2008 Jul 1;11(13):1690-5.

Asl BH1, Hassanzadeh K, Khezri E, Mohammadi S.

Department of Pharmacology and Toxicology, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Dextromethorphan (DXM),like Memantine is a well known NDMA antagonists that work to potentiate and actually block opiate tolerance, like Ketamine it’s also illegal, and a recreational drug that has a fine line in-between. (Though a study from Iran? I checked the journal it looks legit)

NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats.

Adult male Sprague-Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine.Adult male Sprague-Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine.

Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine.

Psychopharmacology (Berl). 2008 Feb;196(3):497-509. Epub 2007 Nov 10.

Mendez IA1, Trujillo KA.

Department of Psychology, Texas A & M University, College Station, TX 77843, USA.

There are numerous other papers which connect NDMA Antagonists and Memantine to reducing or preventing opiate drug tolerance. Many of which can be found at the end of this post.

Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphine’s antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.

Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33.

Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors.

Wong CS1, Cherng CH, Luk HN, Ho ST, Tung CS.

Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

The results demonstrate that opiate tolerance is inhibited rapidly, and at low doses, by four different non-competitive NMDA receptor antagonists (MK-801, ketamine, dextrorphan and phencyclidine), suggesting that this inhibition results from blockade of NMDA receptors rather than from the ‘side-effect’ of a particular drug. The NMDA antagonists were found to inhibit the development but not the expression of opiate tolerance; i.e. they were able to prevent but not reverse tolerance. Finally, the results suggest that NMDA receptor antagonists do not interfere with associative tolerance; instead it appears that these drugs may specifically inhibit non-associative tolerance. It thus appears that NMDA receptors may have a fundamental role in the development of opiate tolerance, and that non-competitive NMDA receptor antagonists may be effective adjuncts to opiates in the treatment of chronic pain.

Brain Res. 1994 Jan 7;633(1-2):178-88.

Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists.

Trujillo KA1, Akil H.

Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720.

Overall it does seem most studies focus on preventing the development of drug tolerance rather than reversing it, though preventing tolerance over the long term can be also viewed as reversing drug tolerance, because it will keep medications effective in the long run.

I also suspect that the development of tolerance is due to far broader neuroplastic changes to brain structure over a long period of time,  preventing his plasticity is probably a good thing in most cases.

READ  Agmatine Sulphate - For Lower Opiate Tolerance - Research Summary

Some studies and anecdotal reports do seem to suggest Memantine can reverse certain tolerances. Perhaps this area warrants more study. It’s an interesting how anecdotal reports reveal completely new possibilities a well as problems that clinical research sometimes fail to note.

The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.

Neuropharmacology. 2008 Mar;54(3):588-96. doi: 10.1016/j.neuropharm.2007.11.013. Epub 2007 Nov 28.

Adam F1, Dufour E, Le Bars D.

Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75013 Paris, France

[wl_chord]

– Khemcorp

Disclaimer: All thoughts and advice expressed are the personal opinions and gatherings of the author and do not constitute medical advice. If you are seeking medical advice please consult a doctor.

References:

Masui. 2009 Sep;58(9):1136-42.
Ueda H1, Matsushita Y.
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.

Pak J Biol Sci. 2008 Jul 1;11(13):1690-5.

Asl BH1, Hassanzadeh K, Khezri E, Mohammadi S.

Department of Pharmacology and Toxicology, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Psychopharmacology (Berl). 2008 Feb;196(3):497-509. Epub 2007 Nov 10.Mendez IA1, Trujillo KA. Department of Psychology, Texas A & M University, College Station, TX 77843, USA.

Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33.

Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors.

Wong CS1, Cherng CH, Luk HN, Ho ST, Tung CS.

Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Brain Res. 1994 Jan 7;633(1-2):178-88.

Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists.

Trujillo KA1, Akil H.

Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720

Neuropharmacology. 2008 Mar;54(3):588-96. doi: 10.1016/j.neuropharm.2007.11.013. Epub 2007 Nov 28.

Adam F1, Dufour E, Le Bars D.

The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.

Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75013 Paris, France