Phenethylamines 2C-B, worth trying on its own?

[4DQSAR]

I've never tasted 2CB but am I correct in thinking it much like 2CI?

I have no idea how 2CB is being produced now but someone highlighted an interesting set of instrumental data which showed samples of 2CB which had positional isomers in it i.e. the -Br wasn't always at the 4 position. I don't know if the impurity is dangerous nor if it is psychoactive, but it was in there.

Now I come to look at the original synthesis as described in PiHKAL, it mentions that the bromination is exothermic which would be a barrier to scaling. So possibly cooks are using other modes of bromination? That is entirely a guess on my part but I have seen many examples of when something becomes much more popular and scaling introduced different syntheses, there were likewise impurities in the final product.

 

[iom]

Imo how heavily the compound desensitizes the G coupled protein receptors it signals through, tolerance won't form. That's how I currently understand tolerance formation with psychedelics at least. 25I-NBOMe can sometimes be 5-6 hours, but induces a 3-4 week tolerance, for example. Also allylescaline creates no tolerance in myself or my fiance (only administered it to one other person, once). Allylescaline is an 8-12 hour trip typically.

I think you are describing what is called receptor down-regulation. When down-regulated, receptors tend to actually physically move below the interfacial surface. Furthermore, receptors in a down-regulated state have a chance of being permanently destroyed, which leads to long-term desensitization. Technically, down-regulation leads to called tachyphylaxis but we here tend to call it "short-term tolerance" or something like that. Presumably this is why it is difficult to re-dose to boost a trip unless it's done very early on. An interesting feature of 5-HT2A is that most antagonists cause down-regulation just like agonists do. It's not clear whether any agonism is possible with down-regulation and tachyphylaxis. Another question is whether different agents can affect how long down-regulation persists, or if the timing is fixed---i.e. something like 3 days for 80% recovery or whatever.

Tolerance may be caused by many things though, and not just receptor down-regulation. Moreover, sometimes what appears to be drug tolerance is actually a more comprehensive shift in how the hormonal and signaling systems work. I.e., some tolerance manifests not just from desensitization of the particular receptor(s) but also by compensatory effects that arise throughout the various biological (sub-)systems that these drugs effect. These kinds of effects are likely to vary much more between different subjects because the drug use which induced it is taking these systems further from the state(s) that they evolved to handle.

Having said that, I want to point out that even if we consider only tachyphylaxis, any kind of model seeking to predict tolerance would necessarily factor in intensity (presumably correlating with the receptor occupancy fraction) and duration of effect. A successful model would have to be bit more complicated given that rapid-downregulation / tachyphylaxis llikely has a big impact on perceived intensity versus actual receptor occupancy fraction, but hopefully I've gotten my point across.

So I guess your contrary examples suggest that different compounds have widely different innate tendencies to induce both tachyphylaxis and longer-term tolerances. I tend to be quite skeptical of claims of any psychedelics not inducing tolerance at all. Maybe DMT is an exception? But some people do report tolerance with DMT if using repeatedly in a single day. That said, I think your examples actually suggest that tolerance is a much more complicated picture after all. Interactions at other receptors may be very important here, and it may be very difficult to untangle all the different possibilities between compounds. So does something like allylscaline really not cause down-regulation? Or is there something else going on that's counter-acting those consequences?

There's lots to think about here.

I've never tasted 2CB but am I correct in thinking it much like 2CI?

They are both 2C-series drugs, but otherwise I think they are quite different. Assuming you've had 2C-I before, I would say 2C-B is lighter, more forgiving, a lot less stimulating, and more empathogenic. I think it's maybe less visual at "typical" doses when compared to 2C-I, but I understand it can still provider strong visuals at high enough doses.

 

[xdrc]

I have no idea how 2CB is being produced now but someone highlighted an interesting set of instrumental data which showed samples of 2CB which had positional isomers in it i.e. the -Br wasn't always at the 4 position. I don't know if the impurity is dangerous nor if it is psychoactive, but it was in there.

I've seen 2-bromo-4,5-dimethoxyphenethylamine as an impurity in pills here and there now. But I don't think you mean that? This of course would not be due to unselective synthesis but rather what I suspect to be cut precursor (veratraldehyde, 3,4-dimethoxyphenethylamine).

 

[Kingoffrogs]

It is definitely worth trying on it's own for a mild psychedelic experience. For a more intense one, it is great with either weed, shrooms, or ketamine.

 

[Mr. Krinkle]

are you gonna put it in your ass?

 

[Mr. Krinkle]

slip it in


just the tip

 

[Skorpio]

I think you are describing what is called receptor down-regulation. When down-regulated, receptors tend to actually physically move below the interfacial surface. Furthermore, receptors in a down-regulated state have a chance of being permanently destroyed, which leads to long-term desensitization. Technically, down-regulation leads to called tachyphylaxis but we here tend to call it "short-term tolerance" or something like that. Presumably this is why it is difficult to re-dose to boost a trip unless it's done very early on. An interesting feature of 5-HT2A is that most antagonists cause down-regulation just like agonists do. It's not clear whether any agonism is possible with down-regulation and tachyphylaxis. Another question is whether different agents can affect how long down-regulation persists, or if the timing is fixed---i.e. something like 3 days for 80% recovery or whatever.

Tolerance may be caused by many things though, and not just receptor down-regulation. Moreover, sometimes what appears to be drug tolerance is actually a more comprehensive shift in how the hormonal and signaling systems work. I.e., some tolerance manifests not just from desensitization of the particular receptor(s) but also by compensatory effects that arise throughout the various biological (sub-)systems that these drugs effect. These kinds of effects are likely to vary much more between different subjects because the drug use which induced it is taking these systems further from the state(s) that they evolved to handle.

Having said that, I want to point out that even if we consider only tachyphylaxis, any kind of model seeking to predict tolerance would necessarily factor in intensity (presumably correlating with the receptor occupancy fraction) and duration of effect. A successful model would have to be bit more complicated given that rapid-downregulation / tachyphylaxis llikely has a big impact on perceived intensity versus actual receptor occupancy fraction, but hopefully I've gotten my point across.

So I guess your contrary examples suggest that different compounds have widely different innate tendencies to induce both tachyphylaxis and longer-term tolerances. I tend to be quite skeptical of claims of any psychedelics not inducing tolerance at all. Maybe DMT is an exception? But some people do report tolerance with DMT if using repeatedly in a single day. That said, I think your examples actually suggest that tolerance is a much more complicated picture after all. Interactions at other receptors may be very important here, and it may be very difficult to untangle all the different possibilities between compounds. So does something like allylscaline really not cause down-regulation? Or is there something else going on that's counter-acting those consequences?

Functional selectivity of G-protein coupled receptors (GPCR) is a concept that has become appreciated in the past decade or so. The original paradigm was that a GPCR agonist will always engage the G-protein (Gs, Gi, or Gq, depending on the specific receptor), and elicit the respective second messenger cascade. Activation of these receptors would lead to phosphorylation of the receptor, and binding by a scaffold protein called beta arrestin which (only) organizes proteins that internalize the receptor, causing tachyphylaxis.

Recently it has become apparent that beta arrestin scaffolds second messengers as well, contributing to the effects of many GPCR ligands. Different drugs will have a bias towards g-protein mechanisms, beta arrestin mechanisms, or be balanced.

The theory is that psychedelics which are more heavily arrestin biased are more likely to incur tolerance, and g-protein biased ones are less likely to do so.

Of course it’s probably not nearly that simple. Studies of mu opioid agonists (it just has the greatest body of work with regard to functional selectivity, partially due to it being an early one worked out and partially due to the quest for the philosopher’s stone a less addictive and safer opioid) have revealed that specific patterns of phosphorylation have a pretty large effect on arrestin recruitment, and deployment of the scaffolded enzymes. There are also a lot of subtypes of g-proteins, and it seems like different ligands can influence which ones are coupling to the receptor.

There could very well be other factors like an influence of binding affinity on tolerance as well.

 

[Skorpio]

Adding to my last post, this paper (open access) by Jason Wallach (honestly a rising star in drug research) characterizes psychedelics by beta arrestin and G protein activation levels (with its main point being that Gq signaling is what correlates with psychedelic activity).

If you look at figure 5 they map either Gq or beta arrestin response with mouse head twitches (the mouse version of tripping balls), and find that Gq signaling correlates very nicely with the head twitch and beta arrestin doesn’t. The 2C compounds screened fall in the middle of the pack for both Gq and beta arrestin activity with the NBxx compounds tend to have very potent beta arrestin and Gq signaling (with 25I-NBOMe being the strongest beta arrestin agonist screened). I would wonder about how these would scale when corrected for dose (ie mescaline is the weakest compound for both measures, but its dose is super high).

One of the reasons to believe that beta arrestin biased agonists will increase tolerance is that the beta arrestin signal pathway occurs simultaneously with beta arrestin mediated receptor internalization. This is the “classical” version of tolerance and it would make sense that these drugs produce it more strongly than weaker beta arrestin agonists.

@Esperighanto You have mentioned experience with differential tolerance gains on a number of psychedelics, do these values in figure 5 of the paper correlate with your experience? Seeing a paper work out all the local signaling modalities is nice, but we are not cells in a dish or mice, and the subjective experience of a human is really what we are looking to figure out.

 

[4DQSAR]

BTW I seem to recall someone mentioning that para halomethane derivatives of PEAs had even higher affinity than the halides. But do we see the problem here? Alkylation ahoy!

 

[Skorpio]

BTW I seem to recall someone mentioning that para halomethane derivatives of PEAs had even higher affinity than the halides. But do we see the problem here? Alkylation ahoy!

I wonder if there is a way to alkylate the receptor without inducing much beta arrestin signaling. It would make 2CP and Ganesha seem short acting.

 

[4DQSAR]

I wonder if there is a way to alkylate the receptor without inducing much beta arrestin signaling. It would make 2CP and Ganesha seem short acting.

I don't know. The few examples of irrevesible ligands I know of are sort of infamous for being internalised by β-arrestins. Oxymorphazone is supposed to induce internalization at pretty much the same rate as acute repeated dosing with crazy stuff such as lofentanil.

So there we have the names of two things I wouldn't go within a mile of.

 

[iom]

@Esperighanto You have mentioned experience with differential tolerance gains on a number of psychedelics, do these values in figure 5 of the paper correlate with your experience? Seeing a paper work out all the local signaling modalities is nice, but we are not cells in a dish or mice, and the subjective experience of a human is really what we are looking to figure out.

Thanks for the interesting post and interesting paper. I want to believe that beta-arrestin binding is that major mechanism for creating tachyphylaxis and/or tolerance. It is a very elegant explanation. I wonder if different beta-arrestins can bind and lead to different tolerance effects and if each of these may be ligand dependent?

I don't think Figure 5 there is going to be at all useful for assessing correlation between facilitation of beta-arrestin and human tolerance. I think the data needs to be normalized and analyzed in various ways. I already discussed that duration of action is likely to be a factor in general. Of course if the innate tolerance of the compound is very low because it does not allow many beta-arrestins to be recruited, then duration won't seem to matter because it's just multiplying an already very small number. The paper also says nothing about functional selective activation of different pathways within the Gq, which I understand is probably essential to model psychedelic versus non-psychedelic actions. I also would not compare effectivenesss percentages but rather look at relative effectiveness, and I'd bet that these don't scale at all linearly to one another with changes in dose. I don't think most people trip at a dose level that's close to full receptor occupancy, so we'd want to compare effects along different pathways at realistic doses.

Something I picked up while reading about these things is that all 5-HT2 receptors are associated with the Gq subunit and therefore may exhibit similar tolerance-building characteristics. Though of course, the biases towards Gq activation versus beta-arrestin recruitment maybe different for each receptor. This is important because 5-HT2B and maybe 5-HT2C also mediate a lot of psychedelic-related effects. A given drug could have different tolerance properties for each receptor sub-type. This means tolerance can be expected to not just be quantitative but also qualitative.

 

[Esperighanto]

@Esperighanto You have mentioned experience with differential tolerance gains on a number of psychedelics, do these values in figure 5 of the paper correlate with your experience? Seeing a paper work out all the local signaling modalities is nice, but we are not cells in a dish or mice, and the subjective experience of a human is really what we are looking to figure out.

I just gave it a read and it seems to align with my experiences. I think @iom is up to something though, as some drugs that produce high tolerance can be redosed if you're still tripping (like 25X-NBXXs), but others won't (like LSD or 4-substituted tryptamine).

 

[4DQSAR]

I just gave it a read and it seems to align with my experiences. I think @iom is up to something though, as some drugs that produce high tolerance can be redosed if you're still tripping (like 25X-NBXXs), but others won't (like LSD or 4-substituted tryptamine).

Is that universaly true?

I've always noted that 2CN gets a so-so review from Shulgin and likewise DON doesn't get a great review. But in that specific case I've always advocated for someone to resolve the enantiomers of DON as I do wonder if it's activity may be slightly different.

I say that but however many times I point out the (R) AMT or better still (R) 7-methyl AMT are entactogens, not psychedelics but resolving product isn't a popular step. I even pointed out that one could oxidize the amine back to the achiral ketone and reductively aminate again so no costly precusor is wasted. It seems like we haven't explored the seperate isomers very much.

 

[emkee_reinvented]

It’s one of the best drugs ever. Not very deep psychologically but visually stunning and very hedonistic

After 2C-T-2 and 2C-E, my experience. 2C-T-2 is not hedonistic imo.
Till 10 mg 2C-B is very handleable/ OK, was even sold as aphrodisiac.
Nexus [brandname] advised 5/ 10 mg. In sex-shops.

At 10 mg it gets a bit psychedelic, from 15 mg fits
"Describing a psychedelic trip with no magic [there is magic],
physical side effects like severe nausea [not for me], chaotic visuals [cartoonish] "
And body-load and feeling of typical trippin uneasiness [beyond 10 mg],

And yes its great at the tail end of MDMA, 10 mg enough ime.
See no point in mixing em the same time, especially first times.

 

[Allylbenzene]

I would wonder about how these would scale when corrected for dose (ie mescaline is the weakest compound for both measures, but its dose is super high).

I don't want to veer OT...but just wanted to bring up the possibility that mescaline is acting as a pro-drug for active metabolites. This is a likely factor of why such high doses are needed (lipophilicity aside). The proposed pathway from mescaline is via SSAO/MAO forming 3,4,5-trimethoxyphenylacetaldehyde which condenses with endogenous amines (eg dimethylamine or piperidine).
On that last bit:

The transformation process of L-lysine to 1-piperideine is though. It's a natural defense mechanizm of intestinal flora against pathogens, 1-piperideine is toxic to bacteria like salmonella or shigella. I think that the condensation reaction would rather begin with 1-piperideine than the piperidine, because of the double bond, and because it's a natural product of intestinal flora. The enzyme essential to this reaction is primary-amine oxidase, it's a copper containing enzyme like SSAO, it can also be inhibited by semicarbazide. Probably it's inhibited by the same or almost the same compounds which can inhibit SSAO. It's essential because of aldehyde being an intermediate.

• L-lysine -> cadaverine -> 5-aminopentanal -> 1-piperideine
• ^lysine decarboxylase -> primary-amine oxidase -> spontaneous conversion

There is also a corresponding reaction for 1-pyrrolidine

• L-ornithine (or L-arginine) -> putrescine -> 4-aminobutanal -> 1-pyrrolidine
• ^[Putrescine can be made by various pathways] -> putrescine oxidase -> spontaneous conversion

As for the intermediate 3,4,5-trimethoxyphenylacetaldehyde metabolite, it would get metabolised into the phenylacetic acid by aldehyde dehydrogenase (ALDH), aldehyde oxidase & possibly xanthine oxidase. Only once these enzymes are sufficiently inhibited can the aldehyde remain intact long enough to condense with endogenous amines. Here's a report on mescaline + prescription strength ALDH inhibitor.

 

[4DQSAR]

After 2C-T-2 and 2C-E, my experience. 2C-T-2 is not hedonistic imo.
Till 10 mg 2C-B is very handleable/ OK, was even sold as aphrodisiac.
Nexus [brandname] advised 5/ 10 mg. In sex-shops.

At 10 mg it gets a bit psychedelic, from 15 mg fits
"Describing a psychedelic trip with no magic [there is magic],
physical side effects like severe nausea [not for me], chaotic visuals [cartoonish] "
And body-load and feeling of typical trippin uneasiness [beyond 10 mg],

And yes its great at the tail end of MDMA, 10 mg enough ime.
See no point in mixing em the same time, especially first times.

I recall 2-CT-7 (Nexus) had just been banned in The Netherlands but knowing people meant I knew which 'Smart Shop' in Amsterdam was still selling it under the counter.

I was put off by the long duration had having had a TMA-2 experience that I didn't enjoy.

But friends of friends tested it and I remember them excitedly saying how they were both convinced it was sunny outside... at 2AM and although they loved it, even they said it went on a bit too long. Some people LOVE long duration compounds. I was told some TMA-2 ended in in Ibiza and how popular it was. I only learnt this after the fact as by then TMA-2 most certainly WAS legally controlled and believe it or not, I've never made an illegal comopunt much less risked smuggling such a thing.

 

[emkee_reinvented]

They sold it as 2.5-DiMethoxy 6 5 mg pill s, that was to vague, for me,
took 10 mg felt nada.
Binned the rest, 2C-T2 was the last sold open under its real name, downhill after.

Nexus was 2C-B they sold in sex-shops, smart-shops sold it as 2C-B.

 

[Skorpio]

I don't want to veer OT...but just wanted to bring up the possibility that mescaline is acting as a pro-drug for active metabolites. This is a likely factor of why such high doses are needed (lipophilicity aside). The proposed pathway from mescaline is via SSAO/MAO forming 3,4,5-trimethoxyphenylacetaldehyde which condenses with endogenous amines (eg dimethylamine or piperidine).
On that last bit:


As for the intermediate 3,4,5-trimethoxyphenylacetaldehyde metabolite, it would get metabolised into the phenylacetic acid by aldehyde dehydrogenase (ALDH), aldehyde oxidase & possibly xanthine oxidase. Only once these enzymes are sufficiently occupied (inhibited) can the aldehyde remain intact long enough to condense with endogenous amines. Here's a report using this approach combining mescaline with a prescription strength ALDH inhibitor (food-based inhibitors work too)

The N,N dimethyl homolog of mescaline seems to be inactive at comparable doses. Do you have any examples of tertiary amine phenethylamines maintaining 5HT2a agonism/psychedelic effects?

 

[Allylbenzene]

The N,N dimethyl homolog of mescaline seems to be inactive at comparable doses. Do you have any examples of tertiary amine phenethylamines maintaining 5HT2a agonism/psychedelic effects?

There are no examples as far as i'm aware. It's why I wrote the proposed pathway. It would be nice to properly characterise the metabolites that are formed under different enzyme environments (eg full ALDH inhibiton).

The potential for ALDH inhibition to potentiate/promote activity of different substances was being discussed prior to someone applying it to mescaline. I participated on the forum many years ago so followed the discussion as it evolved. ALDH inhibition was also found to significantly potentiate the effects of plain phenethylamine & tryptamine, likely involving their aldehyde metabolites. This implies some sort of amination occuring but I haven't found any research on this beyond formation of bio-active tetrahydroisoquinolines/beta carbolines via dopamine/phenethylamine/serotonin and acetaldehyde/dopaldehyde. (eg tetrahydropapaveroline, salsolinol, 1MeTIQ, tryptoline)

Acetaldehyde is a highly reactive compound that interacts with several endogenous neurochemicals in the brain to form a number of additional biologically active products (Cohen and Collins, 1970; Davis and Walsh, 1970; Walsh et al., 1970; Cohen, 1976). With regard to neurobiological and behavioral testing of the byproducts of ACD, the majority of attention has focused on two main classes of compounds which are formed through condensation of ACD with the catecholamines. The first class of compounds, the tetrahydroisoquinoline alkaloids (THIQs), are formed through both the direct and indirect condensation of ACD with the monoamines: dopamine, epinephrine, and norepinephrine (Cohen, 1976). The tetrahydro-beta-carbolines (TBCs) on the other hand, are formed through the reaction of ACD with the indoleamines: tryptophan and tryptamine (Buckholtz, 1980). The THIQs tetrahydropapaveroline (THP) and salsolinol (SAL) have received the most attention as to their role in alcohol use-disorders as both compounds can be detected in the brain following EtOH administration. The TBCs have received considerably less attention and contradictory data exists as to their contribution to the neurobiological effects of EtOH.

www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2013.00104/full

Mescaline metabolites & ALDH inhibition

The major and minor metabolic routes of mescaline are presented in (Fig. 5). In rabbit, mescaline metabolism occurs mainly in the liver by the action of an amine oxidase. While showing a significantly lower expression of amine oxidase, the lung also contributes for the clearance of mescaline, due to a larger blood flow, in comparison with the liver [75]. Mescaline undergoes detoxification mainly by oxidative deamination into an intermediate and unstable aldehyde, 3,4,5-trimethoxyphenylacetaldehyde, that is rapidly oxidized to the inactive TMPA or reduced to the inactive 3,4,5-trimethoxyphenylethanol [68, 71, 76, 77]. The fact that the peak of mescaline effects does not coincide with its peak concentration in brain, provided evidence on the contribution of its metabolites for hallucinogenic effects. In agreement, a study with rats treated with calcium carbimide (i.e., an aldehyde dehydrogenase inhibitor) showed that the metabolism into acid and alcohol follows the oxidation of mescaline to the aldehyde, whose concentration increased by metabolic inhibition, thus implicating this metabolite in the effects of the drug [43, 77]. The enzyme responsible for the deamination of mescaline to the aldehyde derivative is still a controversial issue among the scientific community. This reaction may be carried out by a monoamine oxidase (MAO) or a diamine oxidase (DAO). Studies with mice have shown that this route is inhibited by TPN, nicotinamide, iproniazid, semicarbazid, and other inhibitor compounds of mono or diamine oxidase [43, 78]. However, some authors discredit the role of these enzymes, as there are studies where their inhibition showed little relevance in the alteration of the metabolic profile, suggesting the existence of a mescaline oxidase [76, 79].

Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions - PMC

Mescaline (3,4,5-trimethoxyphenethylamine), mainly found in the Peyote cactus (Lophophora williamsii), is one of the oldest known hallucinogenic agents that influence human and animal behavior, but its psychoactive mechanisms remain poorly ...

pmc.ncbi.nlm.nih.gov

Another interesting study on mescaline activity & drugs in general

Novel, unifying mechanism for mescaline in the central nervous system: Electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships - PMC

A unifying mechanism for abused drugs has been proposed previously from the standpoint of electron transfer. Mescaline can be accommodated within the theoretical framework based on redox cycling by the catechol metabolite with its quinone ...

pmc.ncbi.nlm.nih.gov