Psychestim
Bluelighter
- Joined
- Feb 8, 2021
- Messages
- 447
Preface:
This section is about the structure-activity-relationship (SAR) of a small set of arylcyclohexylamines and focuses on pharmacology. If you find this boring, skip to the bioassay/experimental section. Most of the information is derived from Dr. Jason Wallach‘s dissertation titled
”Structure Activity Relationship (SAR) Studies of Arylcycloalkylamines as N-Methyl-D-Aspartate Receptor Antagonists“
Ki binding values for the NMDA receptor in rats determined by using [³H]-(+)-MK-801:
(+)-MK-801: 10 nM
3-MeO-PCP: 38.1 nM
4-MeO-PCP: 620 nM
3-MeO-PCPy: 22.3 nM
4-MeO-PCPy: 215.7 nM
3-MeO-PCE: 30.4 nM
3-MeO-PCPr: 17.9 nM
3,4-DiMeO-PCP: 1,727 nM
3,4-MD-PCP: 62.8 nM
3,4-MD-PCPy: 47 nM
3,4-MD-PCE: 35.5 nM
3,4-MD-PCPr: 24.9 nM
It’s well established that a methoxy group in the meta position is better tolerated than one in the para position on the arylcyclohexylamine pharmacophore. This is evident when comparing the Ki values of 3-MeO/4-MeO-PCP and 3-MeO/4-MeO-PCPy. Both 3-MeO-PCP and 4-MeO-PCP were previously available on the RC market, with the former being approximately 10 times more potent (human dose: 5–25 mg, p.o.) than the latter (human dose: 50–250 mg, p.o.).
Only one 3,4-dimethoxylated ACH was prepared by Dr. Wallach, but one can see that disubstitution leads to an even bigger decrease in affinity than the 4-MeO monosubstitution. Rigidification of the two MeO-groups to a benzodioxole however leads to a dramatic increase again. The pattern can be observed above comparing the Ki values of 3,4-MD-PCP (62.8 nM) to 3,4-DiMeO-PCP (1,727 nM).
Similarly, the binding affinity of 3,4-MD-PCPr was a bit lower compared to 3-MeO-PCPr. 4-MeO-PCPr and 3,4-DiMeO-PCPr were not evaluated.
Unfortunately there is no data set for 3,4-MD-PCiPr but it would be interesting to see if the PCiPr analogs follow similar patterns where the order of binding strength would go as follows: 3-MeO-PCiPr > 3,4-MD-PCiPr > 4-MeO-PCiPr > 3,4-DiMeO-PCiPr. Judging from first hand experience, the human potency of 3-MeO-PCiPr is greater compared to 3,4-MD-PCiPr but more about human potencies later.
Now briefly looking at other target interactions some of the compounds were tested for it seems that none of them are extraordinarily selective, which is common within the realm of small molecules.
Starting with 3,4-MD-PCP: introducing the methylenedioxy bridge drastically decreased its affinity to SERT because 3,4-DiMeO-PCP showed low nM affinity (47 nM), while 3,4-MD-PCP had Ki values >10,000 nM at SERT.
Other appreciable binding affinities (cut-off: >10,000 nM) were measured at:
5-HT3: 7,185 nM
NET: 5,127 nM
σ1: 1,305 nM
σ2: 393 nM
3,4-MD-PCPr was the most selective NMDA receptor antagonist shown in the dissertation, with over 40-fold selectivity over any other receptor tested. Out of the 3,4-MD-PCx evaluated, it also had the highest binding affinity at the NMDA receptor.
Other targets where it has appreciable affinities (cut-off: >10,000 nM):
DAT: 1,940 nM
KOR: 998 nM
σ1: 2,817 nM
σ2: 1,235 nM
Again, 3,4-MD-PCiPr was not evaluated.
Background information:
- sex: male
- age: 27
- weight: 73 kg
- prior disso experience: N2O, 3-Me-PCPy, 3-Me-PCiPr, 3-Cl-PCP, 3-HO-PCP, 3-MeO-PCP, 3-MeO-PCE, DMXE, MXPr, MXiPr, MXE, O-PCE, PCP, PCE, PCiPr, FXE, DCK, 2-FDCK, Ketamine, DXM, Memantine
- use pattern: I would classify myself as a habitual user of dissociatives who enjoyes this weird space from time to time but I‘m not keen on taking them regularily. Over the last six years I have tracked my drug use meticulously so I have a good overview of my dissociative consumption and while I‘ve had phases where I‘ve taken them more frequently the trend is generally going down. My last dissociative experiences were a bit lackluster and bland and I would attribute that mostly to personal circumstances and my mindset over the last year. My exploratory bug has generally gone down as well and my personal aspirations are shifting a bit. Whether this is a permanent thing or just a dip in the curve I don‘t know but it is worth mentioning because it influenced my drug experiences. This year I have had one experience with MXPr (one of my favorite dissos) which turned out to be boring and not worth getting into. The next experience was with 30mg 3,4-MD-PCP two weeks later which turned out in a similar fashion. I took a month and a half off dissociatives and then tried a large dose of ketamine (also one of my favorites) while watching TV, but again it was pretty bland and anhedonic. Similarily for my last experience with oral 3,4-MD-PCiPr at 20mg. I guess it‘s time to revisit dissociatives at a later date when I feel an urge to do them or when I‘m in a better spirit.
Summary of effects
3,4-MD-PCPr HCl (35mg, p.o.):
Starting with the first one I‘ve tried in the summer of 2024. I remember being in an Airbnb in Philadelphia having done other stimulating and hypomania inducing arylcyclohexylamines days before, among those were PCP, 3-Me-PCiPr, and 3-MeO-PCsBu. 3,4-MD-PCPr is noticeably less potent than the other MD-PCx I‘ve tried, I took 35mg by mouth on an empty stomach, and the effects were only light-moderate in intensity. If I had to guess a strong oral dose would be around 60-70mg for a person without tolerance. The duration was very long, but because my dose was not as high I am having a hard time giving an accurate prediction but when dosed high enough it’s probably >12h.
The comeup was really long, and first effects were felt around 50 minutes after ingestion. During the experience I was really hypomanic and stimulated which caught me a bit off guard. In fact I chose to start with the PCPr version because I was told it would be the least manic of the bunch. It might be possible that the hypomania and the effects in general were potentiated by the residual dissociatives in my bloodstream from the day(s) before. I was slightly anxious during the experience, with a general feeling of uneasiness and a feeling of dread, but I couldn’t pinpoint anything specific that would‘ve been responsible for it, granted my mindset during the time was not optimal.
Mentally it was quite electric and thought-provoking, I had manic internal monologues about a variety of nonsensical stuff. It wasn‘t particularily euphoric nor did it really feel warm compared to something like MXPr or MXiPr. I remember one instance from the experience where it was raining heavily outside and all of a sudden a few drops of water were coming down from my ceiling, I was confused and a little overwhelmed because I didn‘t know what to do so I talked to my Airbnb host on the phone while also conversing with my Airbnb mate trying to figure out how to solve the problem. English is not my first language either so it was challenging to navigate through this situation while on 3,4-MD-PCPr. Eventually we had to go outside in the rain and drain some water outlet and fix the hole in the ceiling so it was quite eventful. I think they didn‘t notice that I was impaired at the time but I definitely felt like a co-pilot during the whole situation.
Physically it was quite numbing and stimulating, but the impairment wasn‘t too bad at that dose. I walked and functioned quite normally, I would say but I‘m experienced at navigating dissociative states. I wouldn‘t have felt comfortable enough driving a car but a buddy of mine did on this exact dose and could do so without a problem (not encouraging this by any means). Appetite was suppressed and I didn‘t really eat anything that day.
3,4-MD-PCP HCl (30mg, p.o.):
Spoiler - This one is my favorite out of the bunch. The duration is more sensible than the one for 3,4-MD-PCPr, with the main effects lasting around 4-6 hours. The dosage was in the upper moderate range I would say. Maybe a bit much to take in public but it was not overwhelming by any means. I would say 30mg (p.o.) is a good dose to get a feel for it.
The hypomania this substance induces is similar to the one on 3-MeO-PCP where you are motivated to do something and you feel like you can achieve anything but I would say it‘s not as hedonistic or grandiose. When I took it at 30mg orally I was critical of myself but in a very affirmative, non-demeaning way and came up with a solid work-out and diet plan for me to reach my end goal. It was very motivating and to this day I‘m actually sticking to this plan (I modified it slightly but for the most part it stayed the same). The headspace was very clear, vivid, and lucid, not particularily euphoric but the clarity and hypomania felt revitalizing.
3,4-MD-PCiPr HCl (20mg, p.o.):
Two cups of coffee, 20mg telmisartan and some residual pregabalin were in my system before the consumption of this drug.
I tasted some of this stuff while transferring it over into a gel capsule and it had that familiar ACH taste that many members of its class share. Very hard to describe, not really pleasant but somehow very unique. No mouth numbing that I get from other compounds in the family.
First effects were noticeable after 45 minutes, and it started with blurry vision and lightheadedness. Total duration is similar to 3,4-MD-PCP and shorter than 3,4-MD-PCPr. The peak felt shorter and more intense compared to 3,4-MD-PCP though. Total duration maybe around 7-9 hours.
The headspace was neutral but there was a euphoric layer behind it all but I‘m not sure if it was a one-off or if I just generally felt good that day. Even though the effects weren‘t overwhelmingly strong the mental dissociation was outstanding. I had coordination problems and zoned out many times. It was certainly one of the more inebriating dissociatives I‘ve tried, not as lucid and fun as 3-MeO-PCiPr or PCP, especially for a stimulating rather than sedating one. A significant amount of time was spent thinking about the past and my old self and how I was as a person 10 years ago. My memories were vivid and clear, it felt nice indulging in nostalgia. I actually texted an old friend while on it because I thought about so many good old moments. A trip down memory lane would be a good description for the experience. Regardless of how nice these thoughts were though, I would still say the experience was fairly standard.
Physically it was stimulating but not in an uncomfortable manner, and I spent most of my time lying on the couch. It was not as numbing as other dissociatives but the dissociation was still very much apparent. Coordination was more difficult than on other stimulating dissos. I measured my BP/HR at T:02:00 and my systolic BP was a bit elevated but still within the range of high-normal, diastolic and HR were normal. One of the stronger aspects of the experience was the double vision and a feeling of disconnection or input lag between my vision and my brain processing the information.
The dose was decent but I think I would go for 25mg if I‘ll get my hands on it again. I took 1mg clonazepam on the comedown and fell asleep quickly.
Conclusion:
All in all I would say I like 3,4-MD-PCP best, followed by 3,4-MD-PCiPr, and then 3,4-MD-PCPr. The most potent one dosage wise is 3,4-MD-PCiPr followed by 3,4-MD-PCP, followed by 3,4-MD-PCPr. 3,4-MD-PCPr has the longest duration, 3,4-MD-PCiPr has the shortest peak and 3,4-MD-PCP felt the most well rounded. They all felt a bit more introspective, serious, and less recreational than other PCx analogs but certainly worth exploring. If you are looking for a fun way to spend your afternoon the 3-MeO compounds are superior, at least in the examples of 3-MeO-PCiPr and 3-MeO-PCP.
For the sake of completion I would like to try 3,4-MD-PCE, and also 3,4-MD-PCsBu. 3,4-MD-PCE has a low nM affinity at the NMDAr but also appreciable affinities at DAT (2,867 nM), SERT (637 nM) and σ2 (751 nM).
The ethylenedioxy analogs like 3,4-ED-PCP could be interesting as well because 3,4-ED-PCP showed similar Ki values at the NMDAr as 3,4-MD-PCP. Nevertheless, as we saw in the example of 3,4-MD-PCPr human potency can often not be extrapolated/predicted from animal binding data.
Psychestim
This section is about the structure-activity-relationship (SAR) of a small set of arylcyclohexylamines and focuses on pharmacology. If you find this boring, skip to the bioassay/experimental section. Most of the information is derived from Dr. Jason Wallach‘s dissertation titled
”Structure Activity Relationship (SAR) Studies of Arylcycloalkylamines as N-Methyl-D-Aspartate Receptor Antagonists“
Ki binding values for the NMDA receptor in rats determined by using [³H]-(+)-MK-801:
(+)-MK-801: 10 nM
3-MeO-PCP: 38.1 nM
4-MeO-PCP: 620 nM
3-MeO-PCPy: 22.3 nM
4-MeO-PCPy: 215.7 nM
3-MeO-PCE: 30.4 nM
3-MeO-PCPr: 17.9 nM
3,4-DiMeO-PCP: 1,727 nM
3,4-MD-PCP: 62.8 nM
3,4-MD-PCPy: 47 nM
3,4-MD-PCE: 35.5 nM
3,4-MD-PCPr: 24.9 nM
It’s well established that a methoxy group in the meta position is better tolerated than one in the para position on the arylcyclohexylamine pharmacophore. This is evident when comparing the Ki values of 3-MeO/4-MeO-PCP and 3-MeO/4-MeO-PCPy. Both 3-MeO-PCP and 4-MeO-PCP were previously available on the RC market, with the former being approximately 10 times more potent (human dose: 5–25 mg, p.o.) than the latter (human dose: 50–250 mg, p.o.).
Only one 3,4-dimethoxylated ACH was prepared by Dr. Wallach, but one can see that disubstitution leads to an even bigger decrease in affinity than the 4-MeO monosubstitution. Rigidification of the two MeO-groups to a benzodioxole however leads to a dramatic increase again. The pattern can be observed above comparing the Ki values of 3,4-MD-PCP (62.8 nM) to 3,4-DiMeO-PCP (1,727 nM).
Similarly, the binding affinity of 3,4-MD-PCPr was a bit lower compared to 3-MeO-PCPr. 4-MeO-PCPr and 3,4-DiMeO-PCPr were not evaluated.
Unfortunately there is no data set for 3,4-MD-PCiPr but it would be interesting to see if the PCiPr analogs follow similar patterns where the order of binding strength would go as follows: 3-MeO-PCiPr > 3,4-MD-PCiPr > 4-MeO-PCiPr > 3,4-DiMeO-PCiPr. Judging from first hand experience, the human potency of 3-MeO-PCiPr is greater compared to 3,4-MD-PCiPr but more about human potencies later.
Now briefly looking at other target interactions some of the compounds were tested for it seems that none of them are extraordinarily selective, which is common within the realm of small molecules.
Starting with 3,4-MD-PCP: introducing the methylenedioxy bridge drastically decreased its affinity to SERT because 3,4-DiMeO-PCP showed low nM affinity (47 nM), while 3,4-MD-PCP had Ki values >10,000 nM at SERT.
Other appreciable binding affinities (cut-off: >10,000 nM) were measured at:
5-HT3: 7,185 nM
NET: 5,127 nM
σ1: 1,305 nM
σ2: 393 nM
3,4-MD-PCPr was the most selective NMDA receptor antagonist shown in the dissertation, with over 40-fold selectivity over any other receptor tested. Out of the 3,4-MD-PCx evaluated, it also had the highest binding affinity at the NMDA receptor.
Other targets where it has appreciable affinities (cut-off: >10,000 nM):
DAT: 1,940 nM
KOR: 998 nM
σ1: 2,817 nM
σ2: 1,235 nM
Again, 3,4-MD-PCiPr was not evaluated.
Background information:
- sex: male
- age: 27
- weight: 73 kg
- prior disso experience: N2O, 3-Me-PCPy, 3-Me-PCiPr, 3-Cl-PCP, 3-HO-PCP, 3-MeO-PCP, 3-MeO-PCE, DMXE, MXPr, MXiPr, MXE, O-PCE, PCP, PCE, PCiPr, FXE, DCK, 2-FDCK, Ketamine, DXM, Memantine
- use pattern: I would classify myself as a habitual user of dissociatives who enjoyes this weird space from time to time but I‘m not keen on taking them regularily. Over the last six years I have tracked my drug use meticulously so I have a good overview of my dissociative consumption and while I‘ve had phases where I‘ve taken them more frequently the trend is generally going down. My last dissociative experiences were a bit lackluster and bland and I would attribute that mostly to personal circumstances and my mindset over the last year. My exploratory bug has generally gone down as well and my personal aspirations are shifting a bit. Whether this is a permanent thing or just a dip in the curve I don‘t know but it is worth mentioning because it influenced my drug experiences. This year I have had one experience with MXPr (one of my favorite dissos) which turned out to be boring and not worth getting into. The next experience was with 30mg 3,4-MD-PCP two weeks later which turned out in a similar fashion. I took a month and a half off dissociatives and then tried a large dose of ketamine (also one of my favorites) while watching TV, but again it was pretty bland and anhedonic. Similarily for my last experience with oral 3,4-MD-PCiPr at 20mg. I guess it‘s time to revisit dissociatives at a later date when I feel an urge to do them or when I‘m in a better spirit.
Summary of effects
3,4-MD-PCPr HCl (35mg, p.o.):
Starting with the first one I‘ve tried in the summer of 2024. I remember being in an Airbnb in Philadelphia having done other stimulating and hypomania inducing arylcyclohexylamines days before, among those were PCP, 3-Me-PCiPr, and 3-MeO-PCsBu. 3,4-MD-PCPr is noticeably less potent than the other MD-PCx I‘ve tried, I took 35mg by mouth on an empty stomach, and the effects were only light-moderate in intensity. If I had to guess a strong oral dose would be around 60-70mg for a person without tolerance. The duration was very long, but because my dose was not as high I am having a hard time giving an accurate prediction but when dosed high enough it’s probably >12h.
The comeup was really long, and first effects were felt around 50 minutes after ingestion. During the experience I was really hypomanic and stimulated which caught me a bit off guard. In fact I chose to start with the PCPr version because I was told it would be the least manic of the bunch. It might be possible that the hypomania and the effects in general were potentiated by the residual dissociatives in my bloodstream from the day(s) before. I was slightly anxious during the experience, with a general feeling of uneasiness and a feeling of dread, but I couldn’t pinpoint anything specific that would‘ve been responsible for it, granted my mindset during the time was not optimal.
Mentally it was quite electric and thought-provoking, I had manic internal monologues about a variety of nonsensical stuff. It wasn‘t particularily euphoric nor did it really feel warm compared to something like MXPr or MXiPr. I remember one instance from the experience where it was raining heavily outside and all of a sudden a few drops of water were coming down from my ceiling, I was confused and a little overwhelmed because I didn‘t know what to do so I talked to my Airbnb host on the phone while also conversing with my Airbnb mate trying to figure out how to solve the problem. English is not my first language either so it was challenging to navigate through this situation while on 3,4-MD-PCPr. Eventually we had to go outside in the rain and drain some water outlet and fix the hole in the ceiling so it was quite eventful. I think they didn‘t notice that I was impaired at the time but I definitely felt like a co-pilot during the whole situation.
Physically it was quite numbing and stimulating, but the impairment wasn‘t too bad at that dose. I walked and functioned quite normally, I would say but I‘m experienced at navigating dissociative states. I wouldn‘t have felt comfortable enough driving a car but a buddy of mine did on this exact dose and could do so without a problem (not encouraging this by any means). Appetite was suppressed and I didn‘t really eat anything that day.
3,4-MD-PCP HCl (30mg, p.o.):
Spoiler - This one is my favorite out of the bunch. The duration is more sensible than the one for 3,4-MD-PCPr, with the main effects lasting around 4-6 hours. The dosage was in the upper moderate range I would say. Maybe a bit much to take in public but it was not overwhelming by any means. I would say 30mg (p.o.) is a good dose to get a feel for it.
The hypomania this substance induces is similar to the one on 3-MeO-PCP where you are motivated to do something and you feel like you can achieve anything but I would say it‘s not as hedonistic or grandiose. When I took it at 30mg orally I was critical of myself but in a very affirmative, non-demeaning way and came up with a solid work-out and diet plan for me to reach my end goal. It was very motivating and to this day I‘m actually sticking to this plan (I modified it slightly but for the most part it stayed the same). The headspace was very clear, vivid, and lucid, not particularily euphoric but the clarity and hypomania felt revitalizing.
3,4-MD-PCiPr HCl (20mg, p.o.):
Two cups of coffee, 20mg telmisartan and some residual pregabalin were in my system before the consumption of this drug.
I tasted some of this stuff while transferring it over into a gel capsule and it had that familiar ACH taste that many members of its class share. Very hard to describe, not really pleasant but somehow very unique. No mouth numbing that I get from other compounds in the family.
First effects were noticeable after 45 minutes, and it started with blurry vision and lightheadedness. Total duration is similar to 3,4-MD-PCP and shorter than 3,4-MD-PCPr. The peak felt shorter and more intense compared to 3,4-MD-PCP though. Total duration maybe around 7-9 hours.
The headspace was neutral but there was a euphoric layer behind it all but I‘m not sure if it was a one-off or if I just generally felt good that day. Even though the effects weren‘t overwhelmingly strong the mental dissociation was outstanding. I had coordination problems and zoned out many times. It was certainly one of the more inebriating dissociatives I‘ve tried, not as lucid and fun as 3-MeO-PCiPr or PCP, especially for a stimulating rather than sedating one. A significant amount of time was spent thinking about the past and my old self and how I was as a person 10 years ago. My memories were vivid and clear, it felt nice indulging in nostalgia. I actually texted an old friend while on it because I thought about so many good old moments. A trip down memory lane would be a good description for the experience. Regardless of how nice these thoughts were though, I would still say the experience was fairly standard.
Physically it was stimulating but not in an uncomfortable manner, and I spent most of my time lying on the couch. It was not as numbing as other dissociatives but the dissociation was still very much apparent. Coordination was more difficult than on other stimulating dissos. I measured my BP/HR at T:02:00 and my systolic BP was a bit elevated but still within the range of high-normal, diastolic and HR were normal. One of the stronger aspects of the experience was the double vision and a feeling of disconnection or input lag between my vision and my brain processing the information.
The dose was decent but I think I would go for 25mg if I‘ll get my hands on it again. I took 1mg clonazepam on the comedown and fell asleep quickly.
Conclusion:
All in all I would say I like 3,4-MD-PCP best, followed by 3,4-MD-PCiPr, and then 3,4-MD-PCPr. The most potent one dosage wise is 3,4-MD-PCiPr followed by 3,4-MD-PCP, followed by 3,4-MD-PCPr. 3,4-MD-PCPr has the longest duration, 3,4-MD-PCiPr has the shortest peak and 3,4-MD-PCP felt the most well rounded. They all felt a bit more introspective, serious, and less recreational than other PCx analogs but certainly worth exploring. If you are looking for a fun way to spend your afternoon the 3-MeO compounds are superior, at least in the examples of 3-MeO-PCiPr and 3-MeO-PCP.
For the sake of completion I would like to try 3,4-MD-PCE, and also 3,4-MD-PCsBu. 3,4-MD-PCE has a low nM affinity at the NMDAr but also appreciable affinities at DAT (2,867 nM), SERT (637 nM) and σ2 (751 nM).
The ethylenedioxy analogs like 3,4-ED-PCP could be interesting as well because 3,4-ED-PCP showed similar Ki values at the NMDAr as 3,4-MD-PCP. Nevertheless, as we saw in the example of 3,4-MD-PCPr human potency can often not be extrapolated/predicted from animal binding data.
Psychestim
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