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[Ishmael Fleishman]

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Edited August 16 by Ishmael Fleishman

[Alchemica]

2 hours ago, Ishmael Fleishman said:

In the last year I have started getting migraines.

 

I was given rizatriptan (Maxalt, Maxalt-MLT) this helps with the acute symptoms. However I have just hesitantly started Sandomigran as a preventative. Since rizatriptan by itself effective I have to use four tabs a day everyday to keep the migraines away.

 

Now looking at the wiki page Sandomigran got me asking a few questions.

 

I am not a neuropharmacologist so forgive my silly questions.

 

Sandomigran is an antiserotonin medication which has been effective in in the treatment of serotonin syndrome or MDMA overdose.

 

From my limited understanding Mescaline is very similar to MDMA. Does this means that Sandomigran would inhibit the binding of Mescaline to the 5-HT_2A receptor?  Sandomigran half life is 23 hours.

 

Secondly could it be used to end a challenging mescaline experience being a antiserotonergic medication? Or to help come down from mescaline experience to help with sleep like some people use benzos.

 

Thirdly question is Sandomigran acts as an antidepressant, or for the treatment of anxiety or social phobia. The classical model says that depression is caused by a lack of serotonin - we know this to be largely incorrect. How can a Serotonin receptor antagonist in the classical model of depression treat depression if it reduces the binding of serotonin?

 

Things like ketanserin have been used as 5-HT2AR antagonists to block/attenuate the 'psychotomimetic' effects of psychedelics but interestingly, the combined effects of a 5-HT2AR antagonist and classical hallucinogens seems to retain some of the therapeutically beneficial effects ie antidepressant and some neural effects [1] so it's likely there would be attenuation of the hallucinogenic effects by sandomigran, particularly with a less potent agonist like mescaline (cyproheptadine which is related is OTC and probably would do the same). Similarly, olanzapine with decent affinity to 5-HT2ARs (along with D2Rs) seems to be used by some as an antipsychotic 'trip kill' [2] and is often conventional medicine's go to, to attenuate a bad trip/psychotic reactions. That said other schools of thought suggest the trip should not be aborted with such and instead benzodiazepines used as an anxiolytic to support a less anxiety-provoking reaction and social support be used more.

 

Mescaline is quite a 'shotgun' pharmacologically, with diverse binding profiles aside from 5-HT2 agonism ie adrenergic affinity etc. The stimulant effects from adrenergic etc activity might be somewhat attenuated by the antihistaminergic activity of sandomigran.

 

ie Mescaline has strong affinity [3] to 4.00 Alpha2C, 3.97 5ht2b, 3.61 5ht1a, 3.44 Imidazoline1, 3.16 5ht1e, 2.92 Alpha2A receptors much more so than 5-HT2ARs.'

 

Serotonin antagonists particularly 5-HT2 antagonists seem to be used in depression (think things like mirtazapine, which has that as a partial mechanism of action) as antagonism of the 5-HT2 receptor can have some pro-dopaminergic effects. Similarly, there are some PET studies linking depression and suicidality to overly high densities of 5-HT2 receptors, and it is thought one of the therapeutic effects of 5-HT2A agonists on depression (so too SSRIs) is to downregulate the excessively dense level of 5-HT2Rs, a similar outcome can be achieved through 5-HT2 antagonism.

 

The density (Bmax) of 5-HT2A receptors was significantly higher (by 39%) in depressed patients than in controls. Suicidal patients had significantly higher Bmax values than controls or non-suicidal patients. [4]

 

 

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Lastly does anyone have any experience with herbal based Treatments for Migraines?

 

Not personal experience but I've heard of people using feverfew which has some evidence base for use. You might want to consider such.

Edited September 3, 2023 by Alchemica

[Ishmael Fleishman]

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Edited August 16 by Ishmael Fleishman

[Alchemica]

35 minutes ago, Ishmael Fleishman said:

So are you saying that having to many 5-HT2A receptors can actually make you more depressed/suicidal? Is the quantity of 5-HT2A receptors determined by genetics or environment or both? I come from a family of depressed people however we all lived in a very bad environment - inter-generational political violence and racial suppression - aka apartheid.

 

 

I think I would easily have a Bmax value. Can you get easily tested for Bmax value?

 

Either overexpression of 5-HT2Rs with increased binding density or an altered regional expression of 5-HT2s seems to be common. There are polymorphisms of the 5-HT2A gene that can lead to changes in the density of those receptors but it more likely seems to be a complex interplay of genetics, environment and life-experiences that shape such an outcome [1]. There's likely epigenetic effects where adverse trauma could be transmitted transgenerationally, leading to an impact on, in part, the serotonin system.

 

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I think I would easily have a Bmax value. Can you get easily tested for Bmax value?

 

Not easily, it would likely only be if you're part of a special research study such would be possible

 

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However with such a short half-life Sandomigran. Should it not have any attenuation after a few days of Sandomigran abstinence?

 

Depending how potent an antagonist it is of the 5-HT2A receptor. Often as a "washout" a period of greater than 5 half-lives is used to estimate the practically total elimination of a drug and the cessation of it's pharmacological effects 

 

"Starting from a steady state, 5 half-lives will remove 97% or a drug; whereas 10 half-lives will remove 99.9% of a drug"

[Ishmael Fleishman]

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Edited August 16 by Ishmael Fleishman