antlion

Wednesday, May 15, 2024

2023 in Review

 Stagnation time. It’s been a long time since I’ve complained this much in a year in review.

[This was written many months ago, in March of 2024. I am only deciding to share it right now]


*CW: Addiction, self harm, suicide*


*this post is not a cry for help. Its a frank assessment of my circumstances in the vein of the same posts I made every other year. There is nothing anyone can do for me. I haven’t been doing well, but it’s my own battle. Advice and suggestions are not welcome. But also as I currently am posting this I am completely sober and in wonderful circumstances, looking back at a dark time from the outside*


It probably stands out that in the course of 2023, I have not contributed a single trip report. Not for lack of trying anything new, though novel experiences have also declined drastically. 


It’s not like I was doing less drugs- in fact, I was doing more than I ever had before in my life. I am thrashing around in a field of psychological polydrug addiction, a daily affair striking from multiple sides that began to spiral into absolute preeminence this year. Daily use is of course a given. The worst culprit is dissociatives- I am badly addicted to dissociatives. My tolerance to them has skyrocketed. In fact this is the reason why there are so few new reports or novel experiences- Every night I am urgently chasing that familiar comfortable reliable relieving dissociative high, using drugs that I know will do what I want, leaving little room for novelty and experimentation; in a sense, the experimentation was always to find things that I could revisit with regularity, and perhaps I have achieved that. There is little motivation to do more. 


The only times I abstain from dissociatives is when I have my spouse physically hide them from me, and even then, I could sneak doses in from other sources sometimes; sometimes something would be forgotten in a drawer; at my worse I would even squirrel away a dose or two to be taken when I was alone; the collection is growing so large that hiding them is becoming more and more challenging. 



When I am abstaining from them I am filling in the gaps with everything else possible, an onslaught of depressants, mostly various pharmaceuticals (I don’t combine any of these don’t worry)- Mostly pregabalin and carisoprodol and 1,4-BDO, a whole bestiary of various pharma benzos; and less frequently such delights as codeine, Hydromorphone, gabapentin, cocaine. Prominently absent is the dominant drugs of my younger days- the psychedelics; but more on that later. And of course, cannabis, nonstop, though it does little for me anymore and mostly serves as a idle comfort habit, an appetite stimulant, and a potentiator of dissociatives. The only days I have been sober in the last year have been when I am traveling with family. 


The nature of how drugs affect me has changed entirely too. These substances are nearly unrecognizable to how I experienced them years ago, all of them a well worn path colored both by steady neurological wear and tear and repetitive psychological conditioning and familiarity. First and foremost, I rarely ever take psychedelics anymore. In the last year I used psychedelics a grand total of 7 times (For several years they were more or less a weekly habit). I recently posted a thread on Twitter about this, but the taxing bodyload has simply become too great for the experience to feel worth it anymore. I have always struggled with psychedelic bodyload (mainly in the form of severe GI distress as all-consuming pain and nausea and purging; muscle aches and tremors and tension and chills), but it has absolutely gotten progressively worse as I have gotten older. There was a point for a long time where it still felt worth it, where the pros outweighed the cons, but I feel like I have now passed that threshold, that the experiences have little to offer me beyond intense physical suffering. This has not gotten better, I have tried so many different methods and medications to ameliorate it, I have tried changing my diet etc; I promise whatever suggestion is offered I have already tried. I think this is just my body aging out of being able to do this, my nerves worn thin through almost a decade of concentrated and frequent use of various psychedelics rcs. The bundles of neurons bearing 5-HT2A receptors on my guts carved out, strung up to dry. Psychedelics defined a decade of my life but their time seems to be passing. I doubt I will visit them beyond my annual bicycle day experience. I don’t feel like there are any lessons to be gained from them at this point that justify the suffering. The visuals I once delighted in have turned dull and subtle and vague, no matter the substance. Perhaps there is still something to be learned from very powerful experiences but I am doubtful my body would make it out intact.


Benzos are rarely anything enjoyable these days, which is frankly truly a blessing. Their own suite of negative side effects keeps me on my best behavior, it keeps me from dosing frequently, and this has probably saved me from a lifetime of battling the worst physical addiction known to man. What was once a fun and casual experience has turned to a multi day trial punctuated by a few hours of euphoria immediately upon dosing. Repeated phases of frequent use and breaks has developed a debilitating kindling where I am left hungover for a day or even days after fairly normal recreational doses of once fun and familiar compounds I could use causally. For those days I am so fatigued I can’t make it through a day without sleeping multiple times. I am in a state of irrational deep depression, my mood is pinned to the sea floor, every input is cast and tainted with an inescapable dreariness that defies reason or cognition. And I am left in a state of amnesia for days after, even stronger than the amnesia during the fun peak of the experience - this proves to be extremely inconvenient for a job that requires my constant attention and knowledge, for meaningful social interactions or simply for trying to live joyous or pleasant experiences; the color of life fades to nothing. As much as I miss the warm fuzzy nights barred out playing videogames or the hedonistic rage of a pure present euphoria not bound to the strictures of memory or the anxieties of the future, it is objectively for the best that this cannot continue. I will cherish the non-memories forever. 


Dissociatives have come to the defining forefront of my life, and those experiences too have become dulled and reshaped through constant unrelenting use. My poisons of desire are mainly FXE, DMXE, ketamine, 3-MeO-PCP, 3-MeO-PCE, 3-MeO-PCiPr, 2F-DCK, 3,4-MD-PCiPr, and a whole plethora of others with lesser frequency. I do these just about every night. 


Once upon a time I got my kicks just doing a single dose of a single compound but that is too dull for me now. Each session sees a mixing and matching of drugs with several redoses of certain ones; typically playing on their varying durations; a base layer of something or a combination of things longer lasting and functional is applied, then layered with punctuated saturated moments of higher doses or small bumps of the shorter acting ones. Like drinking a beer and taking a shot. My tolerance has shot up and I find myself in a troubling place where it is hard to have a “hole” experience. I am troubled by knowing that this is likely forever, as dissociative tolerance never really fades. That these experiences I love so much will only grow duller and less fulfilling, yet I am still compelled to pursue them every day, a little bit of the magic chipping away each time. I don’t know how this will end. This magic is frankly, what I mostly lived for. Perhaps I will eventually be so bored and understimulated that I just stop trying. I hate this tolerance, I hate that I no longer feel like I can accurately report doses of novel substances to others, I hate that I’ve dulled the instrument I used to collect so much data in the past. But there’s no going back is there; I did this to myself. Persistent use of dissociatives, my preference mostly being towards stimulating ones, has exacerbated the sleep issues I already had, as has the frequent use and rekindling of benzos. It is very challenging for me to sleep anymore without some cocktail of drugs, and my addiction to dissociatives has a symbiosis with Zolpidem as my absolute fail safe sedative. I am prescribed hydroxyzine and trazodone for sleep, the trazodone I am fully dependent on, only abstaining when I plan to use psychedelics. Sleep is usually also aided by melatonin, doxylamine, and carisoprodol.


I have begun to notice that the following cumulative negative effects have become observably worse: 

-short term memory loss; issues with word recall 

-odd gaps in registration of long term memories 

-persistent nausea 

-frequent urination 

-bladder aches

-fatigue 

-persistent anxiety and insomnia 


Some of this may be connected to contracting COVID-19 twice within the last year. 


There’s a lot I could whine about.

My mental health has correspondingly been abysmal, worst it’s been in years, everything consumed by that bleak sort of nihilism - not the liberating kind but the kind that smothers the color from the daylight. Suicidal ideation and bouts of self harm have reared their ugly heads as delusional BPD episodes grow more frequent and intense. Blackouts and bouts of drug induced psychosis and catatonic panic; “incidents” as termed between me and my spouse have become dispiritingly regular occurrences. Each week is a whiplash of wild mood swings, languid depression and bouts of frenzied mania, one day after another. It's hard to really know what to feel. Does this make the drug use worse? Or is the drug use fueling this instability? It’s a chicken/egg sorta thing.


A lot of misfortune befell this year, certainly a factor in everything. I lost a dear friend to a drug overdose, they were a lifelong fighter, the most free and liberated person I have ever met and one of the toughest, one who inspired so much hope in me, for whom I held so much respect. Their loss felt like a true loss for the whole world. Rest In Peace Koda. As mentioned before I contracted COVID-19 twice, after avoiding it for 3 years. I don’t know what effect this has had on my overall state of being, it’s so difficult to determine. I was whipped by an irrationally heartbreaking rejection, from the same person twice! I ran into deeply stressful financial and legal hiccups. My country has committed itself fully to the genocide of the Palestinians of Gaza, and all I can do is watch helplessly. This course of events has by proxy strained my relationship with one of my closest friends. All of the memories from this year are dulled and blurry. I’ve found myself more often at odds with my spouse, I’ve found my temper shorter, myself less and less patient, and I’m terrified I am going to do or say something I will regret and won’t be able to recover from. 


There’s been good things too- Beautiful times spent with dear friends, sometimes fueled by drugs, sometimes not. Times in nature, under the glorious sun among the trees and insects. I took a few wonderful trips with my spouse or my friends and saw such beautiful things and had such beautiful experiences. Seizing every chance to be outside in the summer heat in the everlasting pursuit of insect life. I met new lovers and rekindled old ones. I got really into painting warhammer 40k and dub music and they have both served as a comfortable grounding meditative routine. I began seeing a therapist, for better or worse. Many of these things feel, relative to the bad, trivial, but I am grateful for what respite I have gotten. 


My time at a certain well known pharmacology lab has come to an end with the expiration of my contract. I’ve ended on good terms and will hopefully continue to collaborate with this lab in some capacity. I am deeply grateful for the time I spent there, for the people I met and the experiences I had. My colleagues were some of the most brilliant people I have ever met and it was an honor to work alongside them, to actually be included and respected among such giants. Their contributions have been and will be immense! Shoutout especially to the undergrads whom I mentored- I might not know much but I’m glad I could impart what experience and knowledge I had! You will be giants in this field. Despite the fun times, the joking and socializing, the feeling of being a part of something revolutionary in a burgeoning field, just how damn cool it was to get paid to make drugs, I think I am ready to end this chapter of my life and move on to other things. Through experience, I learned that chemistry just isn’t for me. I miss being outside, I miss the sun beating down my skin, the rain soaking through my clothes, I miss fighting through underbrush and stomping through mud and driving on dirt roads. I miss working with animals and being immersed in biodiversity, in being able to stop to look at a cool bug or a snake or a turtle while on the clock. I miss being forced to watch the sunrise on a misty morning, of the smell of sap heated by the summer sun, of coming home dirty and sweaty and torn up by thorns and insect bites, not smelling of sulfur and ether and rotten cheese, feeling like I am truly a part of this beautiful natural world as it has always existed. I miss spending my time inside sifting through and organizing vast libraries of specimens, of encountering Earth’s wondrous diversity firsthand in physical form. I would like to go back into Entomology or maybe marine invertebrate Zoology. But most of all, I miss feeling competent.


My work in chemistry was saturated with imposter syndrome- but it truly genuinely felt valid, not a delusion in the least. I don’t fundamentally understand chemistry. I am forced to confront this when extremely basic gaps in my knowledge come to a head. Just humiliating beginner level stuff that I can’t seem to wrap my head around. I don't understand stereochemsitry. If you named common reactions I couldn't tell you which reagents would be used and what the desired outcome would be. For fucks sake, I couldn't even really tell you what an sn1, sn2, and elimination reaction really are, what their utility is or how you would achieve them. That's not imposter syndrome, that is genuinely and objectively not understanding the fundamentals of the field. My lack of foundation was more noticeable every day, it was unsustainable and would have reached some sort of breaking point had my contract not expired.


I still did accomplish a lot. I am proud of what I accomplished. I synthesized ~90 completely novel compounds. By the end of my term I was completely independent, devising my own methods and optimizations and troubleshooting my own problems. Despite my massive shortcomings in the field, I made it work for the time I was doing it, I produced an end result, my compounds were ultra pure, USP grade for analysis. A dear old friend was able to do various binding and affinity assays - the feeling of collecting data on compounds that I made for the first time ever is incomparable.


Some compounds were submitted for patents- the majority of my work (I have complicated feelings about this but I have to be pragmatic about how this work can happen). They will likely be slated for publication some day too. Until anything is published I sadly cannot go into much detail about them, though there’s a lot I would like to say! The last series was a project completely my own- I decided what compounds I would make, I determined their structures based on what I knew about SAR, I went ahead and synthesized them, most of them made for the first time ever. This series consists of arylcyclohexylamines, made through a novel route that was devised and optimized by my colleagues and I. I am very excited to talk about these more, which I hope to do in the near future- likely in late summer pending some other work. This will hopefully be a publication with me as one of the primary authors. 


Nevertheless, I am hoping that my time ending there will help improve my life in ways that I cannot disclose. All I will say is that certain aspects of the job served to the detriment of my sobriety. Being away from drugs in my day to day life will hopefully help me to recover somewhat. 


Recovery :’) imagine. If I’m being honest, I don’t want to recover. At all. I enjoy doing drugs, I still enjoy doing drugs, when I’m not on them I think about them all the time. Despite being detrimental to my mental and physical health, despite all of the “incidents”, despite how much it is interfering with me living a worthwhile productive life, despite how it is eroding my relationships, despite it being completely unsustainable and setting myself up for a disastrous future- I still love them. One could call that addiction. I still have, every now and then, experiences that are wonderful and beautiful and profound, ones that rekindle the fire of my life. Ones that genuinely feel beneficial and productive to my life. Or even ones that just provide a steady and familiar comfort, or that seem to keep the deepest depths of despair at bay to some degree, for some time. My use has always been excessive but there was a time I considered it moderate before I fell into using every day- something like using dissociatives once or twice a week, which I know seems, once again, ludicrously excessive to most. But I maintained this frequency for several years without much issue. My desire is to go back to something like that, where they are a feature of my life, a treat reserved for sparing occasions, not a habit that overshadows and colors everything. But I know too that this is intensely idealistic - that I have already tasted the sweetness of using every day and now I can never go back- at first I began finding excuses to use every night even though I didn’t plan to before- “oh I’m feeling a little sad; oh work was stressful; oh I’m seeing x person; oh I’m engaging with x media” and I imagine it would be near impossible to work myself out of that mindset. Or even if I do find moderation, it would be exceedingly difficult to avoid going down that path and falling into a daily habit again. Now that I know how it can be, now that I know what I can get away with, I fear there is no going back. The only options are continue the way it is or total abstinence. Both seem bleak.


I think I would rather die than give this up. The world seems like a place I am simply maladapted for. It's hard to imagine getting older again, it's hard to exist with any kind of long term in mind. In my mind I am just enjoying what moments I have left. Everyone else is dying. 


I have become avoidant of all of my friends, I only want time alone, I only want time alone to do drugs. I rarely see anyone, I offer little to anyone, to the people that offer so much to me, I rarely have the energy to see anyone. I don't know why anyone cares to maintain a relationship with me that I am not able to maintain myself. Maybe if they forget about me less people will be hurt should anything happen. I don't want to be around anyone much anymore.


No one can break my will to do what I want. I will just lie more, I will learn how to be even more quiet. What is to be done with this? At least I get what I want. 


The drugs are what I think about. They are what I care about. Much else falls to the wayside. But I tell myself that it makes delectable what is left. I will not allow myself to be treated. I refuse it, I will fight it, I will complain but god help me will I be motivated to do anything about it. 


"Freedom is beautiful and terrible its nothing soft and sweet... It's watching people die because they got back in it, and knowing that I don't have any say in it."


This next year will bring about a several months sabbatical from my normal life where I will be traveling through Southeast Asia and Oceania. I will likely not have access to any drugs during this time, and no real exposure to them. A part of me is hoping, perhaps in vain, that this is going to be my miracle cure, that time away will allow for my brain to reset, for the cravings to fade, but only time will tell if that is how things will play out. I could very well return home and immediately just go back to square one. Or perhaps the change of perspective will break that habit, shake that desire- maybe I will stop altogether, or maybe I will shift back into that pie-in-the-sky fantasy of using in moderation. I recognize that like much of the rest of my life, i entrust these results to twists of fate, inscrutable games of neural function, rather than any amount of effort on my part. I don’t want to change. I just want things to change around me.


Anyways, I did write a little bit about drugs;


I personally corroborated reports that what was being sold as FXE (3-F-2’-oxo-PCE) was really 2F-3’-oxo-PCE.


I summarized the result of a colleagues doctoral dissertation analyzing structure activity relationships of diarylethylamines.


I did an AMA on Reddit while very manic on pregabalin and 3-MeO-PCiPr while sick with COVID. I don’t think it went very well or represented me well, because I answered everything in a state of arrogant mania. I wish I could redo it with a clearer head. 


Ok that’s it really. 


Now then, I suppose I can try to offer my usual ranking of drugs that I have tried this year, even in the absence of any reports. There are some things I cannot really speak on for the time being. But I will attempt to discuss those that I can.


1. 3-MeO-PCiPr - This is my bread and butter. I love this compound so much. It’s like a smoother gentler 3-MeO-PCE, perfect for casual use, perfect for exploring the world, but still insightful at higher doses. Deeply pleasant and euphoric.

Dose: 20-30 mg IN

Duration: ~6-8 hours total 

2. 3,4-MD-PCiPr- Another stimulating dissociative, this one has a powerful psychedelic edge, it is deeply euphoric, excellent for socializing and dancing when taken in the right context. It is only ranked lower because it is not as forgiving as 3-MeO-PCiPr and can be prone to runaway paranoia.                                                        Dose: 20-30 mg IN                                                 Duration: ~8 hours total 


3. Oxazepam- hands down the most euphoricand recreational benzo I’ve taken yet. Just a pleasant soft imaginative euphoria, the kind I’ve been chasing in benzos for forever.


4. Midazolam- a fun floppy impairing benzo. Great to get wasted on. But so damn expensive. 

5. 4-HO-MsBT- A fairly standard tryptamine psychedelic with a short duration. I didn’t find it as euphoric or insightful as 4-HO-DsBT, but it’s still worthwhile. I wish I could experience it without being taxed by the bodyload. 


6. Morphine- A classic opioid. Not much to say, it’s the universal standard and it feels like it. 


7. GBL- I like GHB/1,4-BDO, this is fun too but god damn does it taste awful. Hard to get down.


8. 3F-DCK- Honestly I need to explore a higher dose but what I gathered was that it was a fairly dull standard heavy dissociative, like an even less exciting ketamine, not too potent either. But worst of all, the burn from snorting it is blistering. 


9. Bromomescaline- A bright stimulating psychedelic that ultimately was mostly just physical discomfort for me.


10. Nitrazepam- A short sleepy benzo. Not too fun but pretty useful.


11. 3-MeO-PCPy - Like how b-phenethylamine is described in neuromancer. Just a blinding almost painful explosion of stimulation. Doesn’t feel that dissociating even. 


12. Prolintane- Just an anxious uncomfortable stim. Bleh. 





 

Monday, March 18, 2024

Almost all "FXE" (as in 3F-2'-Oxo-PCE) is not actually FXE, and "canket" is the same thing as what we have all been calling "FXE". Confirmed via NMR.

(This is a verbatim copy of this post that originally made on reddit)


So for maximum clarity, in this post, FXE refers to 3F-2'-Oxo-PCE, CanKet refers to 2F-2'-Oxo-PCE. I am going to say "FXE" when I refer to the batches of drugs that have erroneously referred to as FXE.

The tl;dr is this:
Save for a single sample I tested this previous summer, 3F-2'-Oxo-PCE has not been widely sold online, and almost all of what we have been calling "FXE" for the last 2 years is actually 2F-2'-Oxo-PCE. But real FXE, 3F-2'Oxo-PCE does indeed exist- though in a very limited scope under the confusion of this nomenclatural confusion.
2F-2'-Oxo-PCE is what was identified in Australia and labeled as "CanKet"/2F-NENDCK/2F-NENK in reality, it was just regular old "FXE" that had entered their drug supply, the Canberra lab was just the first one to actually correctly identify it, as they used NMR, which is not used by most drug testing services. Without a standard, 3F-2'-Oxo-PCE and 2F-2'-Oxo-PCE will appear identical via GCMS, and all of us took the word of the lab that originally synthesized and continues to synthesize "FXE" and assumed the 3-Fluoro substituted compound was what was being tested.

What follows is an explanation of how I determined this and the evidence.
So I recently happened upon this post:
Which brought to my attention something I had missed on drugsdata.org- If you look at any of their tested samples of "FXE", they are now identified as "2F-2'-Oxo-PCE", which is also the drug that has been labeled as "CanKet" in Australia.
They all include this statement:
All samples analyzed by the DrugsData lab prior to early 2023 that were reported as containing Fluorexetamine have been reexamined in comparison to this new standard. They have all been retroactively revised; they all contain 2-Fluoro-2-oxo PCE, including this sample. To date, no samples tested by DrugsData have contained 3-Fluoro-2-oxo PCE.
This update was appended in late April 2023- no idea why it didn't make more waves then, I am sure some people caught on but clearly there is little awareness about this!
Anyways, I found this claim to be extraordinary, I had to find this out for myself. How could this happen? How could such a widespread drug have been mischaracterized for almost 2 entire years now?
The issue lies in analytical methods- the primary means of identifying drugs is GCMS, which gives you the distinct molecular weight of a compound. The only problem is, 3F-2'-Oxo-PCE and 2F-2'-Oxo-PCE are compositionally identical, and would have the same molecular weight. What IS distinctive is their retention time when running GCMS- this is the point in time when the compound is detected, and while this doesn't predictably quantifiably correspond to a specific property of each compound, it can at least help us differentiate between two compounds of identical mass. Unfortunately, this is only an effective means of differentiation if there is a known standard to compare it to. What likely happened is that almost all of the "FXE" in the world was coming from a single source, which was taken at its word that this was the compound being produced. Maybe this was a typo, or maybe they misidentified what they themselves were making. I am not going to speculate as to what caused this misunderstanding, it is not something that really happens by accident though, the reagents required to make one compound vs. the other are entirely different. But anyways, the samples from this source that was supposedly trustworthy were used as a standard, under the assumption that they were the 3-substituted FXE, creating a self-replicating chain of misinformation. This highlights the importance of using independently manufactured standards! Preferably from a reputable source like Cayman.
So without a standard on hand, how do you differentiate between these 2 compounds? Enter nuclear magnetic resonance, or NMR. Owing to the cost, NMR is not available to or used by most drug testing services, which is why this has escaped notice for so long. The Canberra testing service, CanTEST, was able to perform NMR testing at the University in which they are based, which is why they were the first to correctly identify this compound. I will not pretend to understand how it works, but I do know how to interpret the results to some degree. NMR is the best tool for determining the structure of an unknown molecule, not just its composition. The graph that is returned corresponds to interactions between the different components of the molecule, and from there the actual structure and placement of the different atoms can precisely be determined. To get an idea of how a 2-Fluoro substitution would appear, I ran a sample of 2F-DCK (confirmed via GCMS w/ retention time) as a reference.
The sample was obtained in May 2023, and originally came from a lab in China. The nmr was run as 1H NMR (400 MHz, DMSO-d6). I was returned 2 graphs. I have zoomed in on the area corresponding to the subtituted phenyl ring.

The placement of a substitution on a phenyl ring will give back different patterns of peaks. A 2-position substitution is distinguished by having 4 separate sets of peaks corresponding to the different unique hydrogens on the ring. These 4 peaks will then manifest as two sets of two distinct patterns: 2 doublets of doublets and 2 triplets of doublets (which will be further split apart by Fluorine in this example). We don't need to go into what that means, all that matters is, that same pattern is seen in this region of the graph for 2F-DCK and "FXE"- and this tells us that the "FXE" has a substitution on its 2 position, not its 3 position.

So that sealed it, I had a sample of a compound that was sold as FXE, but was confirmed to actually be CanKet, or 2F-2'-Oxo-PCE. I could now use this sample as a reference for other analytical methods that would be a lot faster and simpler, namely GCMS.
Now i have a quick reference for whether a sample is 2F-2'-Oxo-PCE!
This is what the GCMS for 2F-2'-Oxo-PCE looks like. So now we have a characteristic retention time (~12.79 min) and diagnostic mass peaks for the major fragments (~178.16 and 207.21). But perhaps this was just a sampling issue- maybe its only recent batches of "FXE" that have been misrepresented! Well I had also tested the very first batch of "FXE" to hit the market- the one that was contaminated with the stimulant A-D2PV. Lo and behold, the same retention time, the same mass (not visible in the picture I forgot to highlight the peak sorry). Almost all "FXE" has been coming from China, as did these two batches. I can say with confidence that any "FXE" being sold out of China, unless otherwise specified, is 2F-2'-Oxo-PCE.

So has real FXE ever existed? The answer is: Yes! I tested a sample for a friend back in July of this year- Curiously, this has the same major fragments as the mass (178, 207), but it has a different retention time: 13.39! I don't have this sample on hand anymore to confirm this via nmr, but if the mass is exactly the same, it can be presumed that this random sample was indeed a batch of genuine FXE that somebody out there had made separate from the current flow of "FXE". Interestingly enough the friend had reported this batch was much more potent than other batches of FXE and had very different effects. Ironically, I think at the time I concluded that this was an errant sample of CanKet!
FXE is too embedded into our collective conscience to correct the name to something like 2-FXE. Perhaps when batches of the genuine material appear, they must annoyingly be referred to as 3-FXE. That is for the community to decide. This is a stark and appalling example of misinformation spreading from taking a vendor at their word.

Wednesday, December 13, 2023

Reddit AMA verification!

  Hello! This is verification that it is indeed me conducting an AMA on reddit on 12/13/2023


tentatively linked here, pending moderator approval: https://www.reddit.com/r/IAmA/comments/18hqohb/iama_amateurprofessional_researcher_of/




Monday, April 17, 2023

Structure-Activity Relations and Synthesis of over 70 new Diarylethylamines (Diphenidine type Dissociatives)

So many new drugs to explore!
I should note that the publication of this paper for the most part renders my old post on Diarylethylamines and the corresponding flowchart more or less obsolete. The answers I sought out in my hypothesizing in that article have largely been answered by this publication, and I am too lazy to completely revise the whole article and the chart. All the information anyone could gain from that article is more or less contained in this dissertation and even just this summmary.

Hot off the presses is the PhD dissertation of my friend and colleague Michael Dybek (you can find the full document here)- a comprehensive analysis of the 1,2-Diarylethylamines, the class of dissociative drug to which belong drugs like Diphenidine, Ephenidine, and MXP. Other compounds within this fascinating class are known to be opioids (MT-45, AD-1211, Diphenpipenol), antidepressants (Lanicemine), and stimulants (A-D2PV). This class of drugs is actually derived from the Phenethylamine structure- but there is another aromatic ring in the alpha position, and the amine is substituted to be at least a secondary or tertiary ring structure. This paper delves into an vast range of variations on that basic scaffold, analyzing how substitutions on the two rings or variations on the amine affect the activity on the NMDA receptor (In other words, dissociative activity). A total of 80 compounds, 67 of which do not yet exist in literature, are analyzed in this regard. 34 of the compounds are also analyzed for their off-target affinity at other receptors, like K-opioid, M-opioid, Sigma, and Muscarinic, and for monoamine transporters, which can modulate antidepressant or stimulant effects.

Structure of various Diarylethylamines





For the chemistry people (you can skip this bit if you’re not a chemistry person), the synthesis and analysis of every compound is extensively detailed. All of these compounds are synthesized from an incredibly simple and elegant and usually high-yielding one pot reaction- It is ridiculously accessible, save for some of the more exotic substitutions they can all be made in one step from common, inexpensive reagents- this is data that I think could revolutionize development and study of this class of compound! It is a synthesis so simple even I can do it! All are produced through a combined modified Mannich-Barbier reaction, in which the benzyl group comes from the corresponding benzyl bromide which reacts with Zinc dust. Trifluoroacetic acid helps optimize for a higher yield by etching the Zinc. This reaction was performed in THF at room temperature. After allowing the organometallic halide nucleophile to form, the amine and the α-position substitution (as an aldehyde) are added, yielding the final product which can be extracted via an acid-base workup. All of this is performed at room temperature, and most of the compounds easily crystallize (though I have to caution against using alcohols as a recrystallization solvent, as it forms a seemingly unbreakable solvate with EtOH). This simple process can offer a high yield and makes it incredibly easy to make substituted analogues. Some extra work may need to be done for certain analogues to produce certain expensive or unstable intermediates that aren’t commercially viable or to protect/deprotect to form target substitutions.
While this class of compound has a very high affinity for the NMDA receptor, with lead compound Diphenidine having an even greater affinity than even PCP, they are curiously impotent in vivo, with active doses of Diphenidine in the range of 60-140 mg in my experience. So far there hasn’t been a definitive explanation for this disparity. Also stymying their popularity is the fact that they can instill a seeming week long cross tolerance with other dissociatives- perfect for the occasional user but unfortunately not preferable for the heavy users who drive the markets. The only compounds that had a higher affinity than Diphenidine were the 2-Chloro and 2-Methyl analogue (with the 3-MeO and the 2F analogue coming pretty close too!), so it is to be expected that every other compound in this study would dose in the range of >100 mg. They are also primarily active orally, and are incredibly painful to dose intranasally. Most disso fanatics I know love snorting things, so this also takes out some of the thrill. Some experimented with vaporizing diphenidine, which apparently induced extreme compulsive redosing, with some users describing it as “dissociative crack”- though there are unconfirmed claims of toxic byproducts being produced by pyrolysis of these compounds, so I would caution against that ROA until that is studied further. Despite all these detractive qualities, I find these to be fascinating and worthwhile compounds that I encourage people to explore and hypothesize and generally be curious about! There are probably incredible, beautiful discoveries out there that have been clearly mapped out for us, just waiting to be documented!
It is a monumental work that clearly maps out development of this class of drug within the scope of dissociative activity and I encourage curious researchers to delve deep into it! It is also 604 pages long, so for people who want to know the juicy Structure Activity Relations, here is the meat of it:
First, a little nomenclature- numbered substitutions are for the α-position aromatic ring, double prime” numbers are substitutions on the benzyl ring, the amine is designated as a 6-member Piperidine (as in Diphenidine) by P, a 5 member pyrrolidine by Py, and any secondary alkyl amines by the basic alkane abbreviations (methyl, ethyl etc.). α-position denotes anything attached to the carbon that is connected to the nitrogen, the β-position denotes the next carbon over, between the α-carbon and the benzyl ring.
Generalized structure of a Diarylethylamine, showing positional nomenclature



As Diphenidine is considered the base structure and lead compound of this class, it will serve as a standard and point of reference for the other Diarylethylamines. A good number to remember is 18.2 ± 2.2 nM, this is the Ki value for Diphenidine, the number that represents its affinity for the NMDA receptor. A lower number means a higher affinity, which usually (but not always) corresponds to a higher potency.
So lets get cracking- what variations exist that are worth exploring?
First, here's the master list, with affinity for the NMDA receptor noted:





First we look at substitutions on the α-position phenyl ring. Affinity is highest at the 2 position and lowest at the 4 position. In some cases, such as a Methyl or Fluorine substitution, the loss of affinity was fairly linear, in others, such as the Chlorine or Trifluromethyl, there was a very steep loss at the 4-position to render the compound inactive.
Thus, for α-phenyl substitutions, it is clear that affinity is in rank order of 2>3>4.
There is a notable exception however- with a methoxy group, the rank order is 3>2>4, reminiscent of arylcyclohexylamines. No idea why this is the one exception. Would be curious to see if thiomethyl or ethoxy have the same trend.
Then we look at the different substitutions-
For halogens affinity rank order at the 2 position was Cl>F>Br>I. This pattern probably holds for the other positions. A CF3 substitution had an even lower affinity than Iodine.
Looking at the benzyl ring, substitutions in general had a lower affinity than substitutions at the α-phenyl ring. The rank order for substitutions at that position appears to be 3”>2”>>4”, (which also follows the SAR pattern for arylcyclohexylamines) with substitutions on the 4”-position being completely inactive. The only substitution that really appeared to yield anything in an active range on this ring was a fluorine and 3”-Me.
We can then look at the Amine- Diphenidine, with the piperidine, had the highest affinity. Pyrrolidine, and a variety of secondary alkyl substitutions were also assayed, giving us the rank order of:
P (18.2 ± 2.2) >E( Ephenidine)(66.4 ± 3.7)>iP (Isopropylphenidine)( 98.1 ± 6.3)>Pr(124.5 ± 8.9)>Allyl(161.5 ± 14.4 )>Py(280.0 ± 18.0)>cP(333.0 ± 19.8)>tB(254.2 ± 2.8)>>DPMe( 813.0 ± 7.2 ). Interestingly, the 2-Cl substitution for all of these yielded a higher affinity except for the Pr and tB amine.
Replacing the phenyl ring with a Thiophene also yielded appreciable affinity- with the 3-Thiophene being higher (48.8 ± 4.3), but with both having an affinity between Diphenidine and Ephenidine (2 thiophene was 65.1 ± 12.2). The 2-Furan saw an affinity just a bit lower than Isopropylphenidine (119.4 ± 2.1). Heterocycles, namely 2-Benzothiophene, 2,3-MD, and 3,4-MD were also assayed, with the benzothiophene being inactive, and the 2,3-MD (51.7 ± 8.4) having a higher affinity than 3,4-MD (131.2 ± 12.0, both within an appreciable range! And while these substituents had lower NMDA affinity, they displayed higher affinity for different monoamine transporters (more on that later), meaning they could see higher stimulant or even entactogenic effects relative to Diphenidine.
Disubstitutions had a lower affinity than most other substitutions.

Graphical representation of structure activity relations for NMDA affinity for ring substitutions



34 compounds were also analyzed for peripheral receptor effects. While the main focus of this post is NMDA antagonism, one of the peripheral effects I’d like to look into is at the monoamine transporters. These control the flow of the neurotransmitters Dopamine, Serotonin, and Norepinephrine. Affinity for these transporters leads to reuptake inhibition, which increases the concentration of the corresponding neurotransmitter, as seen in many pharmaceuticals like SSRI’s, NDRI’s, SDRI’s etc. Cocaine is a reuptake inhibitor for all 3 transporters! (Other stimulant drugs can modulate rote monoamine neurotransmitter flow; they are called releasers. Examples of this are NDRA’s, like amphetamine, or releasers for all 3, like MDMA. We are looking at reuptake inhibition though)
All of this is to say, the monoamine transporters are like 3 levers that can be adjusting synergistically to achieve a variety of effects.
Some patterns emerge, like DAT affinity being modulated by a rank order of 3>2”>3”>4>4”>2. So interestingly, while the 2 position strongly increased NMDA affinity, it pretty much eliminated affinity for the dopamine transporter (oddly enough with the exception of 2-Cl-DPP. Most of the compounds were not active at SERT, and those that were only had moderate affinity, with the highest being 4”-F-DPPy. All of this translates into some yet unknown complicated interworking of synergistic effects that would produce a unique subjective experience for each compound!

Graphical representation of structure activity relations for monoamine transporter affinity for ring substitutions

I know this has been a very long and dense summary (to be fair it is a vast amount of data), but I hope it can be of use to those interested enough to delve into this massive contribution to our understanding of dissociatives and dissociative structure-activity relations.
Happy explorations, fellow researchers!