A second topic came up in this episode - cardiac valve disease with use of 5HT2 receptor agonists . You also discussed this before, I believe in episode #17 with Andrew Chadeayne. The pharmaceutical pulled from the market was Fenfluramine, half of the combination Fen-PHEN (Fenfluramine-Phenteramine). Ryan mentioned the risk was up to 30%. the data is somewhat confusing on this one. The initial concern came from 24 case reports of valve damage after millions of prescriptions. Subsequent surveillance found several hundred cases. The incidence was low but relative risk was quite high - up to 20x that of people who did not take fenfluramine. There was one later study that showed as high as 23% of people on fenfluramine has some aortic regurgitation. This did not require long term usage. This could be of concern for daily microdosers of 5HT2B agonists. It took years before it became apparent with fenfluramine. I would worry that it would be very hard to detect as routine microdosing is not common and not in the open.
Nick, Excellent episode. After listening I had a question I was hoping you or Ryan could answer. As the 5HT2B receptor functions at least partly via with influx of calcium, do calcium channel blockers change efficacy of psychedelics? Calcium channel blockers are a very common medication for hypertension. It seems many do cross the blood brain barrier. A brief google search did yield papers on ca channel blockers and psychosis in mental health. I did not find any direct papers on psychedelics and calcium channel blockers. Thanks.
"I took some time to do some digging, and I don't think this has been directly examined in a meaningful way. There is some literature on this subject related to various neuropsychiatric disorders, but I don't think the mechanism is entirely clear. In my rudimentary understanding of channels, CCBs in particular dihydropyridines (DHPs) are designed to target L-type calcium channels. These are widely distributed in cardiovascular, smooth muscle, etc and can be found in the brain. However, when you are dealing with the brain things always get more complicated. According to this review that I found it seems that many of these CCBs have low(er) sensitivity to these drugs due to resting activation state (these drugs tend to favor inactive state of the channel) and alternative splicing (channels can be ridiculously complex, and will often form different arrangements of subunits). Here is an excerpt from the review.
'The low sensitivity of brain LTCCs for DHPs could be one explanation. It is most likely due to the short AP duration and negative resting membrane potential of most neurons. This disfavors inactivated channel states to which DHPs preferentially bind. Alternative splicing also affects DHP sensitivity. Cardiac splice variants of Cav1.2 are less sensitive to DHPs than their smooth muscle counterparts, which partially explains why arterial vasodilation occurs at much lower plasma concentrations than cardiodepressant effects. The low DHP sensitivity of neuronal Cav1.2 LTCCs may therefore also be due to alternative splicing. Cav1.3 LTCCs are slightly less sensitive to DHPs than Cav1.2 although their binding pockets can bind DHPs with similar affinities.'
There are N-type calcium channels (neuronal) found in the brain, there is one drug that has been approved called ziconotide which is used for pain relief (derived from a toxin isolated from the cone snail) -- my guess is that these would block neuronal firing, but I'm not sure if that would necessarily be a good thing (i.e. think neurotoxins potentially). And with this calcium blocker there are some nasty side-effects including paranoia, delusions, disorientation, and seizures. Maybe these would be more pertinent to test?
It is worth noting though, given the ubiquity of these drugs that there isn't any anecdotal evidence of them blocking or changing hallucinogenic effects in any way, but amlodipine, the most commonly used CCB does not cross the BBB so that could be another confounding variable.
I do think it would be interesting to test, at least pharmacologically, what would/might occur, but biologically in in vivo systems it is bound to be much more complicated.
I guess this is a long winded answer for, I don't think this has been looked into, it probably will have no effect, but would be worth trying given resources and time as well as a proper design experiment."
Thanks so much Ryan. I love the long winded reply. Very interesting. Yes, these systems are so complex it is hard to intuit what might occur. There is of course not much research into these areas due to legal concerns. I think an interaction between Ca blockers and psychedelics may go unnoticed for a long time even if it did occur. There would be no place to report this. It is more common older individuals are taking Ca blockers (other than amlopidine) and though not definitive, this population might be less inclined to be trying psychedelics. Thanks again.
A second topic came up in this episode - cardiac valve disease with use of 5HT2 receptor agonists . You also discussed this before, I believe in episode #17 with Andrew Chadeayne. The pharmaceutical pulled from the market was Fenfluramine, half of the combination Fen-PHEN (Fenfluramine-Phenteramine). Ryan mentioned the risk was up to 30%. the data is somewhat confusing on this one. The initial concern came from 24 case reports of valve damage after millions of prescriptions. Subsequent surveillance found several hundred cases. The incidence was low but relative risk was quite high - up to 20x that of people who did not take fenfluramine. There was one later study that showed as high as 23% of people on fenfluramine has some aortic regurgitation. This did not require long term usage. This could be of concern for daily microdosers of 5HT2B agonists. It took years before it became apparent with fenfluramine. I would worry that it would be very hard to detect as routine microdosing is not common and not in the open.
Yes, this is something on people's minds. Another episode where the concern over the connection between 5HT2B agonism & valvulopathy was discussed was M&M #46 with David Olson: https://mindandmatter.substack.com/p/podcast-46-david-olson-psychedelics#details
Nick, Excellent episode. After listening I had a question I was hoping you or Ryan could answer. As the 5HT2B receptor functions at least partly via with influx of calcium, do calcium channel blockers change efficacy of psychedelics? Calcium channel blockers are a very common medication for hypertension. It seems many do cross the blood brain barrier. A brief google search did yield papers on ca channel blockers and psychosis in mental health. I did not find any direct papers on psychedelics and calcium channel blockers. Thanks.
Here's a note from Ryan:
"I took some time to do some digging, and I don't think this has been directly examined in a meaningful way. There is some literature on this subject related to various neuropsychiatric disorders, but I don't think the mechanism is entirely clear. In my rudimentary understanding of channels, CCBs in particular dihydropyridines (DHPs) are designed to target L-type calcium channels. These are widely distributed in cardiovascular, smooth muscle, etc and can be found in the brain. However, when you are dealing with the brain things always get more complicated. According to this review that I found it seems that many of these CCBs have low(er) sensitivity to these drugs due to resting activation state (these drugs tend to favor inactive state of the channel) and alternative splicing (channels can be ridiculously complex, and will often form different arrangements of subunits). Here is an excerpt from the review.
'The low sensitivity of brain LTCCs for DHPs could be one explanation. It is most likely due to the short AP duration and negative resting membrane potential of most neurons. This disfavors inactivated channel states to which DHPs preferentially bind. Alternative splicing also affects DHP sensitivity. Cardiac splice variants of Cav1.2 are less sensitive to DHPs than their smooth muscle counterparts, which partially explains why arterial vasodilation occurs at much lower plasma concentrations than cardiodepressant effects. The low DHP sensitivity of neuronal Cav1.2 LTCCs may therefore also be due to alternative splicing. Cav1.3 LTCCs are slightly less sensitive to DHPs than Cav1.2 although their binding pockets can bind DHPs with similar affinities.'
There are N-type calcium channels (neuronal) found in the brain, there is one drug that has been approved called ziconotide which is used for pain relief (derived from a toxin isolated from the cone snail) -- my guess is that these would block neuronal firing, but I'm not sure if that would necessarily be a good thing (i.e. think neurotoxins potentially). And with this calcium blocker there are some nasty side-effects including paranoia, delusions, disorientation, and seizures. Maybe these would be more pertinent to test?
It is worth noting though, given the ubiquity of these drugs that there isn't any anecdotal evidence of them blocking or changing hallucinogenic effects in any way, but amlodipine, the most commonly used CCB does not cross the BBB so that could be another confounding variable.
I do think it would be interesting to test, at least pharmacologically, what would/might occur, but biologically in in vivo systems it is bound to be much more complicated.
I guess this is a long winded answer for, I don't think this has been looked into, it probably will have no effect, but would be worth trying given resources and time as well as a proper design experiment."
Thanks so much Ryan. I love the long winded reply. Very interesting. Yes, these systems are so complex it is hard to intuit what might occur. There is of course not much research into these areas due to legal concerns. I think an interaction between Ca blockers and psychedelics may go unnoticed for a long time even if it did occur. There would be no place to report this. It is more common older individuals are taking Ca blockers (other than amlopidine) and though not definitive, this population might be less inclined to be trying psychedelics. Thanks again.
Sorry - note above refers to episode #71 (not #17)