5-HT2A agonists and antagonists

[polymath]

Well, on tuesday night I tried taking 5 g of ololiuhqui seeds, despite having taken 4 mg of risperidone earlier that day (did that just for the heck of it). Risperidone is a 5-HT2A antagonist and should block the action of psychedelics...

I didn't get any visuals, but I experienced a "body high", elevation of mood, enhanced music appreciation and also mydriasis and dry mouth, so apparently the risperidone did not completely block the effects of LSA.

I find this somewhat puzzling - risperidone has a high affinity for 2A receptors and 4mg is a rather large dose... Are the 5-HT2A receptors responsible for the physical effects of psychedelics (mydriasis, tachycardia), or are those effects caused by binding to adrenergic receptors? Is it possible that I have developed a tolerance to risperidone and that's why I was able to trip (increased receptor density, maybe)?

 

[serotonin2A]

The ergot alkaloids in morning glory seeds bind to most of the receptors for serotonin, dopamine, and norepinephrine.

 

[polymath]

I've read some trip reports where people have combined psychedelics and antipsychotics, and some say they can trip even on high doses of olanzapine/risperidone, while some others say taking a small dose of risperidone or quetiapine completely aborted a hallucinogen trip in 20 minutes.

The 5-HT2A agonists are a strange class of compounds, all of them bind to the same receptor but there are still qualitative differences in their effects (for example, DIPT causes mostly auditory hallucinations while psilocybin is much more visual). Is there any known explanation to these differences?

 

[serotonin2A]

DIPT is an extreme example. It will not be possible to explain why it acts so differently than other N-alkyltryptamines until the mechanism for it's auditory effects is determined. But it is entirely possible that some other receptor is involved. If 5-HT2A is involved, other possible explanations are 5-HT2A functional selectivity, non-homogenous distribution in the brain, or modification of the 5-HT2A response by other receptors.

DMT and 5-MeO-DMT are another example of psychedelics with different effects, with only the former being associated with strong visual effects. However, I have head of some people that do have some visual effects from 5-MeO-DMT. One reason for the difference between those two compounds may be that the latter drug is a much stronger 5-HT1A agonist, which might dampen excitatory effects in V1 and other regions of the visual and visual association cortices. In preclinical studies, 5-MeO-DMT also doesn't seem to concentrate in the posterior part of the brain, where occipital cortex is located.

It is important to note that these visual vs non-visual differences are not universal. There are people who don't have much of a visual response to hallucinogens. It may be that there are subtle genetic or physiological differences that influence the response to psychedelics.

It is also even more important to remember how much the effects of psychedelics are influenced by mental set. Owsley did an experiment where he took a batch of LSD and pressed it into different colored pills. People reported back to him that they had markedly different experiences depending on which color pill they took, even though they all contained exactly the same dose of LSD.

There certainly will be subtle differences between the effects of individual psychedelics, because they all have slightly different pharmacology and pharmacokinetics. But there is also so much variation that can occur in the response to the individual compounds that it makes it difficult to objectively determine whether some of the proposed subjective differences actually exist. Many people say they can tell the difference between the effects of LSD and psilocybin (ignoring the time course differences), but seldom has anyone actually done that in a valid way, by running a double blind comparison. If you know that you are taking mushrooms versus a dose of LSD, it is going to markedly influence your response. Also, the experience produced by psychedelics varies by dose, so you would have to take equivalent doses of LSD and psilocybin, but people taking them seldom know the exact dose. When controlled scientific studies were done to investigate this, with LSD and psilocybin, the volunteers (who were very experienced with LSD and psilocybin) couldn't tell which drug they had taken. There may be subtle differences between the two drugs, but the point is that they are much more similar than they are different.

 

[yaesutom]

I remember once I took too much DOC and tried to abort with quetiapine (50mg) and it did not work. It changed the trip in a weird way and made me extremely sedated but the trip was still strong.

I've found that mirtazapine (Remeron) totally cancels trips on 2C-T-4 and 7.. even a tiny piece of a pill aborts a +++ trip after about 45 minutes after eating the mirtazapine.