DHEA Supplementation and it's effects on Benzodiazepines

[mp44god]

Since DHEA is a negative allosteric modulator of GABA-A (basically polar opposite of benzo pharmacology) would this counteract the effects of the benzos? (Specifically 1 mg clonazepam)
I've been taking 25-50 mg of DHEA and 1 mg Clonazepam (which i have a tolerance to) and I'm not sure if its just placebo, but I feel like the anxiolytic effects are being mildly canceled out by the DHEA. Any thoughts, advice, knowledge on this subject appreciated.

 

[polymath]

DHEA should prevent the effect of GABA in a way that lessens anxiety and depression. Opioids cause euphoria in a similar way by removing the GABAergic block of dopamine release, but that's an indirect effect and not caused by direct binding to the GABA receptors. It was said somewhere that DHEA probably binds to the picrotoxin site of the GABA-A, which could explain why the effect is not anxiety-causing like with benzo inverse agonists.

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System - Neuropsychopharmacology

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate γ-aminobutyric-acid-type-A (GABAAR), N-methyl-D-aspartate (NMDAR), and Sigma-1 (σ1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether...

www.nature.com

DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli

Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been ...

www.ncbi.nlm.nih.gov

 

[mp44god]

DHEA should prevent the effect of GABA in a way that lessens anxiety and depression. Opioids cause euphoria in a similar way by removing the GABAergic block of dopamine release, but that's an indirect effect and not caused by direct binding to the GABA receptors. It was said somewhere that DHEA probably binds to the picrotoxin site of the GABA-A, which could explain why the effect is not anxiety-causing like with benzo inverse agonists.

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System - Neuropsychopharmacology

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate γ-aminobutyric-acid-type-A (GABAAR), N-methyl-D-aspartate (NMDAR), and Sigma-1 (σ1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether...

www.nature.com

DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli

Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been ...

www.ncbi.nlm.nih.gov

I don't really understand what you're talking about. What do you mean it "prevents GABA" in a way that lessen anxiety. My question is relating to DHEA negating the effects of benzos.

 

[polymath]

I don't really understand what you're talking about. What do you mean it "prevents GABA" in a way that lessen anxiety. My question is relating to DHEA negating the effects of benzos.

A benzodiazepine being a positive allosteric modulator means that it increases the effect of gamma-aminobutyric acid on the GABA-A receptor when both the benzo molecule and the GABA molecule are affecting the receptor at the same time. It doesn't have any effect by itself. DHEA doesn't stick to the same part of the receptor as benzodiazepines, so it doesn't displace something like diazepam from the receptors and its effect is not necessarily what you'd call "opposite" to sedatives.

 

[mp44god]

Thank you! Very informative reply.

 

[dopamimetic]

Yeah thanks, just thought this morning about DHEA as a possible aid against testosteron suppression and read the same statement on wikipedia this morning, that DHEA was a GABA allosteric negative modulator..

They also write that it acts as a NMDA allosteric positive modulator. Is this correct and will it reduce the effects of dissociatives (and increase tension and anxiety), do possibly both effects on GABA and NMDA lead to a net zero, or is it maybe again a misunderstanding/-Interpretation?

At least sarcosine as a weak partial NMDA agonist has been found to increase tension by susceptible individuals.

 

[polymath]

Maybe it would be possible to prevent opioid-induced hypogonadism with a peripheral mu receptor blocker. Risperidone is said to be an especially bad antipsychotic in terms of causing prolactin level increase, and this is because it crosses the BBB poorly and the pituitary gland is exposed to disproportionately high concentrations compared to the rest of the brain. The pituitary gland is at least partially outside the blood-brain barrier. This is not something to be tested at home, though. Even a peripheral naloxone-like compound could possibly precipitate some kind of a withdrawal state.

 

[dopamimetic]

Oh yeah now that you wrote that I remember speculating about the results of combining an opioid with a peripheral antagonist after reading that for nmda antagonists to stop morphine tolerance development it's enough to block the peripheral ones (did not specify whether centrally acting ones are of better efficacy and if it's just about the pain killing effects or the psychoactive ones too but they said blocking, not slowing tolerance).
And loperamide seems to help more with withdrawal than just stopping diarrhea.

Is such a peripheral antagonist known yet?

Naloxone is nasty shit indeed. Afaik it (naltrexone too) is an inverse agonist, and whyever the average opioid naive individual isn't supposed to feel anything from them, there is hyperalgesia in animals, these taking naltrexone for drinking report dysphoria and anxiety. I've had a truly hellish hour following accidental naloxone exposure without any opioid tolerance. No physical symptoms but felt like the single most sad and isolated soul in the universe. Must either have been an interaction with memantine, or just the how inversion of mu effects feels. Somehow both put a few findings in question - like compounds being labeled as opioid because their effects were reversed by naloxone - doesn't it?

Cause of this experience I never found the courage to give ULN, let alone LDN a try even when the point about ULN is that it should be too little for blocking opioids. And it's Rx only everywhere, expensive but primarily really that it's easier to get prescription for robust doses of morphine than a regular medicine for some off-label use unless the doc comes up with it by himself of course.

 

[polymath]

Is such a peripheral antagonist known yet?

Just make the opioid a quaternary ammonium compound like you would produce a peripheral anticholinergic.

Methylnaltrexone - Wikipedia

en.wikipedia.org

 

[Lil'LinaptkSix]

Sorry nothing to contribute other than I was lost in the middle of the fourth or fifth post and am dizzy now and exiting.
Thanks for the interesting read.
8(