What are the effects of this in your opinion? I'm not well read in this aspect of psychadelic function.
In terms of therapeutic efficacy there have been correlative findings involving the subgenual cingulate and DMN - effects on these targets could be mediating the real efficacy of psychedelics for depression. But there is certainly room for multiple MAOs, and there could be simple 5-HT2A -> glutamate -> mTOR explanations, or just plain old BDNF. Maybe altered neural activity with enhanced neuroplasticity synergizes, and synaptic remodeling is enhanced during the experience. See also psilocybin's effects on neurogenesis.
I've always thought DRI's were better suited for DNM deactivation without inducing excessive reward seeking behavior. So, DRI's are preferential for my needs and are less depleting agents on the psyche. Only problem is that they tend to cause more psychotomimetic effects due to mechanisms which I don't fully understand as opposed to TAAR1 agonists and releasing agents like d-amp, TAAR1 agonists/partial agonists/PAM's are antipsychotic BTW.
DRIs cause more psychotomimetic effects than DRAs for you? Mind you many drugs are TAAR1 agonists but that won't come into play unless they are substrates for the respective transporters.
That's entirely possible; but, I tend to think LSD has greater efficacy at decreasing DNM power than psilocybin due to the aforementioned metabolites and D1&2 binding profile. It's also a more potent partial agonist at 5-HT2A receptors than psilocybin.
I'm not sure about the relative power of LSD vs. psilocybin in terms of decreasing the DMN coherence and subgenual cingulate metabolism but Nutt has shown that psilocybin has potent effects on the DMN/subgenual cingulate.
RE: Partial agonist at 5-HT2A - I wouldn't necessarily think about activation of 5-HT2A as 0%-100%. The intrinsic efficacy of a ligand at 5-HT2A may be low but it could still cause potent activation of a psychedelic cascade, so to compare a psychedelic ligand's activation of 5-HT2A to the (100%) full agonism that is defined by 5-HT may not be reliable in terms of predicting physiological effects.
Yea, there's still an overemphasis on dopamine present in the medical community and, well here as well. Dopamine is important for salience and motivation, which are intrinsically linked with the effects on DNM activity; but glutamate is as important in maintaining arousal and motivation in task-oriented goals. I mean, it's not only important to 'want' something; but, to also maintain interest in it after the duration of effects of some DRI or DRA.
There are a lot of glutamate/BDNF/mTOR theories going around for psychedelic efficacy as well, but the emphasis there is that its not just about the acute neural change that a drug elicits (
altered receptor levels are probably not that important as the neuroplastic changes that accompany the experience).
But RE: dopamine and working memory, its thought that D1 activation facilitates WM by enhancing NMDAr transmission. So yes indeed glutamate is important, but other neuromodulators are modulating all the other neurotransmitters (in this case it may be more helpful to think about the neurons themselves rather than the transmitters and receptors, especially seeing as eg dopamine receptors aren't just located on dopaminergic cells). And outside of just thinking about the neurons individually, we can think about the circuits intertwining and the brain as a whole.
Inverse agonism is a totally different beast and excludes the benefit of downregulation caused by persistent activation of a receptor. You also don't get the benefit from downstream effects mentioned in regards to LSD and glutamate function in the PFC. It's rather a bad way to induce changes in receptor levels, which I'm hoping LSD can do.
While its true that e.g. inverse agonism at 5-HT2C induces different effects than silent antagonism at 5-HT2C, I still maintain the altered levels of receptor expression are not where a benefit would really be derived from,
if there was benefit to repeated daily dosing. If you just want to downregulate 5-HT2A, then SSRIs should work as well.
Well, SSRI's don't actually "do" anything than increase serotonin levels. The lack of their efficiacy in treating depression can be attributed to more elevated receptor count in some depressed patients than less depressed patients, as vague as that sounds. Further, using more potent 5-HT transporter inhibitors doesn't necessarily do the job better. But, 5-HT1A receptors are probably of greater importance in treating neurotic depression here due to anxiety and lack of motivation.
You lose me at lack of efficacy in severely depressed patients (SSRIs work better for severe depression and aren't as good for treating mild/moderate MDD).
To a large deal SSRIs are probably inducing synaptic remodeling via BDNF et cetera. Sensitization of the post-synaptic 5-HT1A while desensitizing pre-synaptic autoreceptors may be to credit (and blockade of 5-HT1A autoreceptors can help decrease the response time to SSRIs but only really in the severely depressed). There are also direct agonist effects at 5-HT2B that are playing some role in SSRI's efficacy but I don't think the picture is quite clear.
Then what would you attribute it to then? I find it hard to believe that increasing sensitivity to dopamine activity via 5-HT2A agonism and decreasing anxiety due to 5-HT1A partial agonism isn't the cause for LSD' therapeutic potential in treating depression along with probably a myriad of other effects on norepinephrine.
Psychedelic effects probably have more to do with 5-HT2A/mGlu2 heterodimers than 5-HT2A/D2 heterodimers, but while there may be various theories, my important point is to look beyond the topic of receptor homeostasis. Some correlative studies are examining effects on the subgenual cingulate.
