5-ht2a antagonists and insomnia

[Foreigner]

I've had insomnia my entire life, and in my research I have come across entries about 5-ht2a polymorphisms being at least partially responsible for this. The reason why I am honing in on this receptor category is that my insomnia actually gets worse following the use of agonists like LSD, mushrooms, and even cannabis. Most people fall asleep if they smoke cannabis in the evening, but in my case it keeps me awake all night (regardless if it's indica or sativa). My research shows that cannabidiol is a partial agonist of 5-ht2a. Because 5-ht2a receptors nomalize fairly rapidly after being agonized, years of psychedelic use cannot really be blamed for my insomnia. There has to be an innate biological basis.

My father has insomnia patterns that match mine, whereas my sister and mother seem to fall asleep easily and wake up at normal times. The theory that there is a genetic polymorphic basis for insomnia seems to resonate. I'm sure there is more than just 5-ht2a involved but the fact that psychedelics aggravate my insomnia for several days after using them seems to point to it being a good starting point for investigation.

And yes, I've done all the soul searching about my insomnia already. I wouldn't be investigating neuro-pharmacology if there were already an easy answer.

What I'm wondering is if there are any known 5-ht2a antagonists out there that are useful sleep aids? My own google search has not yielded much. Seems like this class of sleep aid is still largely experimental. I would even be willing to sign up for studies relating to this.

EDIT: Something that sort of fits this profile might be trazadone. It's an anti-depressant and hypnotic that functions as a 5-ht2a antagonist.

 

[sekio]

Cannabis itself is actually a poor 5ht2a activator, though it does influence it indirectly. Also, most strains of cannabis typically consumed don't contain enough CBD to do anything significant, the ratio is 50 pts THC to 1 pt CBD or more...

LSD & other 5ht2a agonists causing wakefulness is well known.

There's a few 5ht2a antagonists used as sleep aids but none are very selective. A few antihistamines like hydroxyzine also knock down 5ht2a. The 5ht2c receptor is structurally quite related and is influenced by lots of sleep drugs like e.g. agomelatine.

 

[Toucan]

I don't see how you've fixated on this particular receptor, it sounds like you're being pretty hasty with self-diagnosis...
For a start,LSD & Mushrooms cause insomnia in most people, and cannabidiol isn't even active at 5-ht2a (although it is at 5-ht1a)

 

[Foreigner]

^ I'm still learning pharmacokinetics so go easy on me. Not so much about hasty self-diagnosis as it is researching and learning.

There's a few 5ht2a antagonists used as sleep aids but none are very selective. A few antihistamines like hydroxyzine also knock down 5ht2a. The 5ht2c receptor is structurally quite related and is influenced by lots of sleep drugs like e.g. agomelatine.

Thanks for this info... I will do more digging. Anticipate more questions

 

[Toucan]

I may actually have been a bit hasty saying CBD wasn't active at 5-ht2a, I see that wikipedia's 5-ht2a receptor page lists it as a partial agonist. However, the article cited for this concludes only that it may be active in vitro at 5-ht2a and whether as an agonist or antagonist is undetermined, and they seem to be leaning towards antagonist:

The results reported here argue that CBD is active as an agonist in vitro at 5-HT1a R and that CBD may also have in vitro actions at the rat 5-HT2aR. Should CBD prove to have antagonistic activity at 5-HT2A, it would support its role as a migraine prophylactic agent (19)

 

[AlphaMethylPhenyl]

OP is thinking of 5-HT1a (in regards to CBDs partial agonist activity).

Antipsychotics are routinely prescribed for insomnia.

 

[dingophone]

Antihistamines are a possible route to pursue as well. But yes, 5HT-2a agonism definitely seems to have a role in some insomnia. For me trazodone ended causing really nasty anxiety for some reason though. I've found diphenhydramine and eszopiclone to be there best for me, and amitryptiline is still prescribed in low low low doses for insomnia.

Melatonin agonists also are an interesting route to go, ramelteon is a really interesting drug...

 

[Black]

trazodone is pretty commonly prescribed for insomnia around here (especially for anxiety patients). it's main action is likely mediated through 5-ht2a and alpha1 antagonism.