An Assessment of Numerous Benzodiazepines and Benzodiazepine-like compounds

People feel a lot of ways about benzodiazepines. I personally find great utility and benefit in them, though it is remiss to discuss them without acknowledging their recreational and addictive potential. Indeed they are useful, but also quite fun, and also quite destructive.  

While some of these compounds do not technically fit the standard benzodiazepine structure, and could be referred to as thienodiazepines and the like. Their near identical mechanism of action however, will have me just lumping them as benzodiazepines and for shorthand I will be referring to them as such.

A note on my experiences- My mainstay for several years was etizolam, using it a few times a week fairly sustainably for a few years. During this time I also indulged in a variety of pharmaceutical benzodiazepines purchased on the street or from friends. I introduced flualprazolam into my rotation and found in it a utilitarian hypnotic. My curiosity was piqued and I sought out what range of experiences the rest of this family has to offer- With such an explosive variety of compounds currently on the market I had to wonder- what made each of these unique? The benzodiazepine experience is afer all fairly standard and substances can at times be indistinguishable but I wanted to see for myself.

My primary directive in using benzodiazepines was usually a gentle end to a night of using other drugs, such as psychedelics, stimulants, or dissociatives, it would snuff out any residual stimulation and put me to sleep. They were also quite fun in their own right and I would spare myself some time alone with them in a purely recreational space. I would always take them at night, to enjoy a few hours before bed. I slipped into a period of dependence, but was fortunately able to quickly taper off without incurring the nightmarish depths of what benzo discontinuation can afflict. I got lucky, I stayed off for a month or so, then gave up and came back. So long as I am a polydrug user, benzos are just too useful. I track my use in an excel sheet to monitor my usage and budget days per week. It's a fine line to walk on a slippery slope. 
In my current state, and under the course of many experiments, my average use is 2-3 times a week, varying compounds, varying doses. I have built up a mild tolerance. I find I can abstain for a time without experiencing kindling. It's still difficult for me to sleep unaided.

For my judgment of each compound, I look to a number of metrics to characterize them- duration, potency, and the different proportions to which they express the varying effects of benzodiazepines. To give context and a point of reference for how the benzodiazepine experience manifests for me, the qualities I analyze are:

Amnesic: The degree to which the substance inhibits memory. It is rare that I get a full blackout, but hazy memory is definitely a consistent effect that can often linger for several days. This is usually how I can tell with certainty that the drug is having an effect.

Hypnotic: The sedating potential of the substance, both during the experience and in the following days.

Muscle relaxant: How much the substance affects muscle tension, physical sense of relaxation, and ultimately loss of motor control at higher doses.

Functional: How functional the substance is, particularly linked to its sedative, amnesic, and muscle relaxant properties, which act in constellation to affect overall functionality. Such properties can manifest in strong ways that may inhibit movement, linear thought, induce confusion, and reduce the ability to communicate coherently.

Euphoric/creative: This is why I love benzodiazepines. Some have an inherent euphoria, but what shines for me is their enormous creative potential. The effect I most seek from benzodiazepines is they offer a childlike imaginative immersion into any task at hand. Whether it be videogames, house chores, or tasks at work, my imagination would color these menial experiences with a creative veneer. Think to Calvin and Hobbes, where Calvin projects the worlds of his imagination onto the mundanities of his daily life. Benzos make me feel like Calvin.

How benzos make me feel

Anxiolytic: The degree to which the drug reduces baseline or acute anxiety, the general sense of "calm" and well-being.

Disinhibiting: The degree to which the drug will lower inhibitions- whether that be socially or through inducing risk-taking behaviors and impulsive decisions.

Interaction with other drugs: The ability of the drug to reduce or cancel out stimulant effects of other drugs, abort terrifying hallucinogenic experiences, and the ability to induce sleep in the presence of stimulants. Also worth consideration is a possible synergistic or positive relation it may have with other substances, particularly dependent on dose.

The dose and response will be in reference to what I consider discreet tiers of intensity that benzos can offer.

Therapeutic dose: Yields the subtlest anxiolysis, a fleeting mist of amnesia, maybe a fleck of euphoria. Absolutely functional and outwardly sober.

Recreational dose: A compounding of effects that would compromise functionality, with burgeoning euphoria. I am certain that I am under the influence of this drug. I can for the most part disguise my high from others.

Intoxicating dose: I can't maintain a coherent string of thought or conversation, I trail off and slur my words and have difficulty moving around, the amnesia strikes much of the experience from memory. I am visibly intoxicated to others.  It should be noted that some compounds seem to simply pass from recreational dose to hypnotic dose and bypass the intoxicated experience.

Hypnotic dose: A dose which ultimately just smothers out all other effects and puts me to an uncontrollable sleep no matter what task I'm engaged in. While sleep does come more easily with any dose of benzodiazepines, I consider a hypnotic dose to be one that forces me to sleep against my will. Many a time I've woken up somewhere that isn't my bed. This is typically a signifier of a very high dose- I can't seem to reach this point with certain compounds, and with others I simply haven't tried yet. 

So with those criteria in mind, here is a brief description of every benzodiazepine and benzodiazepine-like compound that I have ever consumed. Some were consumed just once when they crossed my path via friends or strangers. Others were consumed habitually. I factor this into my characterizations of each. My descriptions will be as detailed as I can make them.

IMPORTANT NOTE: The dosages I list are purely a reference for me- due to my tolerance they will be slightly higher than what would be effective for a benzo-naive person. I do this to show the range of doses that will achieve certain effects. DO NOT use this as a dosage recommendation guide- turn to psychonaut wiki for that. That information is shared just to provide context for my experiences. 

Substances listed in Alphabetical order. 

Alprazolam (Xanax)

 Alprazolam is a very standard and neutral benzodiazepine that delivers all of the expected effects, short acting, with a timid presence that definitely grows heavier with increasing doses. The short activity makes it primed for binging. It would drive euphoria and imagination, it was sufficiently hypnotic, the binging potential is the only danger of blackouts. There's a reason it's so widely prescribed, and there's a reason people consume exorbitant amounts of Alprazolam. It really is fun to spend a day just tossing them back and certainly getting heavily incapacitated but still being conscious to enjoy it. It wouldn't force me asleep, but made sleep fast and easy. It had a fleeting presence in my life, I would grab some whenever it crossed my path but that was rare, usually via a friend with  prescription or street dealers (which has become incredibly dangerous in the age of Fentanyl). Oddly enough I still have never had an Alprazolam "bar", all the pills I've encountered have been other forms.

My typical oral dosage (with tolerance) would be: 

Therapeutic: .5-1 mg. 

Recreational: 1-3 mg

Intoxicated: 3+ mg

Hypnotic: n/a (never could get it to work)

Duration would be typically be 4-6 hours, with little effects the next day. 

Bromazolam

When researching novel benzodiazepines, Bromazolam showed a lot of promise in online discussion. Users reported strong recreational effects- euphoria, a nice sedation, and a sense of gentle hazy warmth. This is one of the most amnesic compounds I have consumed. Even short term memory was compromised which made holding a conversation difficult. It is sufficiently sedating, and it has a pleasant warmth to it that is absent from other benzodiazepines. It is good for spending a night relaxing on something soft. What I did not like however, was the intensity of the amnesic effects- especially in that they persisted for multiple days even after the other effects had receded. This would lead to me inadvertently and unexpectedly losing days which I would've liked to remember. I saw little mention of this in online discussion, but upon bringing it up, a handful of people reported a similar experience. This is a nice and useful and gentle benzo, sublimely relaxing, warm and sociable, but losing the next 2 days of my life with little other effects during that time is a dealbreaker for me.

My typical oral dosage (with tolerance) would be: 

Therapeutic: not attempted

Recreational: 4-6 mg

Intoxicated: 6+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 6-8 hours, with amnesic effects continuing into the next 1-2 days. 

Clonazepam (Klonopin)

Clonnazepam is a fun benzodiazepine. It has a rushing euphoria, and an impeccable creative drive. It is long lasting- but most of all it lets me feel really really high without being fully compromised. It's an intense and bright and imaginative high, where I feel motivated and content, near blissful. A lower dose was perfect for social situations. A higher dose was a wonderful way to spend a night playing videogames or making a menial task more fun. This was my first exposure to longer lasting benzos, and was my first hard lesson in memory fog lasting well into the next day. It also was the first one I had consumed recreationally.

My typical oral dosage (with tolerance) would be: 

Therapeutic: .5-1 mg  

Recreational: 1-2.5 mg

Intoxicated: 2.5+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 8-20 hours depending on dose

Clonazolam

Clonazolam has a bit of a reputation. Any foray into an online research chemical community will yield people who believe this drug has some sort of infernal provenance, that it is a curse upon mankind. Plenty of these tales come firsthand from users, who share their experiences as a cautionary measure. Yet, it is one of the most common item seen in the stock of online vendors, it is clearly immensely popular and there is clearly very high demand for it. For the uninitiated, Clonazolam's reputation is owed to many things. It has an extraordinary potency, with active doses well in the sub-mg range. It tends to be very amnesic. It has a relatively long duration, similar to Clonazepam. The potency and amnesic tendencies can be a recipe for disaster. Clonazolam also has a reputation as a last stop for heavy benzodiazepine addicts, as the potency and duration ultimately offer the most financially sustainable way to maintain a severe habit. Personally however, I find Clonazolam to be fairly unpleasant. For me, it is extremely sedating. The times I have tried it I have inadvertently slept through my alarms and missed various obligations. Until it has left my body, I am in a groggy amnesiac fog where I feel like I could doze off if I blink too long (save for the first few hours, which can be pretty functional, if a bit hazy and unremarkable). I am rendered useless for a day or two and don't gain much from it. It was never particularly euphoric or imaginative for me, perhaps owing to its smothering sedation. It is definitely good if you want to skip a day of your life or two. I somehow never managed to fully black out on it, thankfully. I cannot imagine using this every single day, but I'm sure a tolerance smooths its edges out a bit. It seems like a drug that is meant to serve the needs of those who need to maintain a heavy habit and nobody else. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: not attempted  

Recreational: .5-1 mg

Intoxicated: 1+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 10-20 hours depending on dose

Diazepam (Valium)

Diazepam is well known as a golden standard for benzodiazepines, one of the first to appear on the market way back in the 60's. I had been seeking it out for years, just to try it for reference, and just by sheer fortune, an abundance of it appeared before me. Diazepam is a very middle of the road benzodiazepine- I use the term neutral a lot to describe benzos and it really expresses that it delivers the advertised experience without anything extraneous to remark on. It neatly checks all the boxes- anxiolytic, euphoric, a tad sedating, amnesic in higher doses. Its a lucid and functional benzo, which is probably the property to which it owes its commercial success. Something I have noted about this compound is that it is hardly sedating at all- to the point that it is actually completely ineffective at silencing the tail end of stimulants and putting me to sleep. I have gone up to 30 mg and ended up laying in bed staring at the ceiling until dawn broke, I was certainly hazy but it ultimately lacked the power to snuff out the other drugs coursing through my system. It is a subtle benzo that works in the background. Something I noticed is that the onset is very rapid, which is probably useful in addressing acute episodes of anxiety. While it is common knowledge that Diazepam is long lasting, the effects seemed to leave me fairly rapidly, and I rarely would get amnesia lasting into the next day. Maybe I just metabolize it differently.

My typical oral dosage (with tolerance) would be: 

Therapeutic: 5-20 mg

Recreational: 20-40 mg

Intoxicated: 40+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 8-12 hours depending on dose

Diclazepam

If one is seeking coherent information on Diclazepam here, they are in the wrong place. I really cannot wrap my head around this drug. Its activity is questionable and I personally have never felt remarkable effects from it, even when taking what is considered a "heavy" dose. This seems to be a point of contention- sifting through internet discussions on Diclazepam one will find two camps- those who claim that it is a subtle drug without any noticeable effects, that simply functions to keep a user with a dependence well and that there is no "high" or intoxication to speak of. The other side will claim that it is indeed very psychoactive and can be quite intoxicating, and that those who claim it is subtle have been using bunk batches of the compound. I am of the former camp, though I have also only worked with one batch. I have not had the opportunity to get it tested. When I brought this up for discussion, it quickly turned contentious with people on either side of the debate passionately defending their positions. For now, I can't say I can definitely comment on this drug. I have taken doses up to 8 mg and the only noticeable effects I had were excess salivation and loss of libido- which was still very interesting to note, those are not things I normally experience from benzodiazepines. When I ingest it, there is definitely something having an effect on my body, but it's hard to discern much else. Having only tried this one batch it's hard for me to say anything definitive on this contentious compound. Perhaps this information will become more clear in the future.

My typical oral dosage (with tolerance) would be: 

Therapeutic: n/a

Recreational: n/a

Intoxicated: n/a

Hypnotic: n/a

Duration for me is maybe a couple hours. Hard to say when the effects are barely discernible.

Etizolam

Etizolam is by far my favorite benzodiazepine (technically a thienodiazepine but oh well). This is by a significant margin the one I have the most experience with, the one I use most regularly and probably the most enjoyable yet utilitarian of the whole lot. Etizolam is sublimely euphoric and imaginative. So many cozy nights were spent wiling away the hours playing videogames while fuzzed out on Etizolam. It always felt exciting and colorful, yet relaxing and gentle at the same time. It isn't too sedating unless I push doses higher, at which point it becomes intensely intoxicating and confusing, eventually passing into a disoriented sleep. Residual amnesia would often last into the next day. It is bubbly and sociable and allows for free-flowing conversation. It can be useful for so many different situations. While it used to be my standard trip killer/sleep aid, my use of Flualprazolam no longer allows it to serve this purpose. For now it is simply something that is a great pleasure on its own. This is the standard to which I compare every other benzodiazepine.

My typical oral dosage (with tolerance) would be: 

Therapeutic: .5-1.5 mg

Recreational: 1.5-6  mg

Intoxicated: 6+ mg

Hypnotic: n/a (never reached this point)

Duration would typically be 6-12 hours depending on dose

Flualprazolam

Flualprazolam is my other most-used benzodiazepine, and another one with notable utility. The utility in this case is sedation. I have never encountered another benzodiazepine that offers such an instant and workable sedation without dragging on for days. There is no hypnotic that will knock me out like Flualprazolam, period. No matter what else is coursing through my system, this drug will slip its hand over my face, conquer all, and put my ass to sleep. A long, restful, and very deep sleep, dependent on dosage. Higher doses are the kind of sleep where I will effortlessly drift through my alarms. I have learned that it will sneak up on me no matter what I'm doing- I've woken up with my laptop still open or in places that aren't my bed on several occasions, when I take a dose of this I must accept that the night has come to an end. Lower doses can be recreational, in which it is a hazy drowsy kind of high without much push behind it. This is particularly enhanced when combined with a low dose of a basic stimulant like caffeine. Otherwise, this serves the purpose of putting me to sleep in any situation, especially after taking other drugs. It was unfortunately my overuse of this that led to me developing a slight dependence to benzodiazepines, and my use of it is probably the reason I have great difficulty sleeping unaided nowadays. It is a great power that must be used responsibly. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: <.5 mg

Recreational: 1-1.5 mg

Intoxicated: ~1.5 mg

Hypnotic: 1.5+ mg

Duration would typically be 6-12 hours depending on dose

Flubromazepam

Flubromazepam is one of those rare benzos that can be reliably measured on a standard mg scale. Flubromazepam is also distinct for me in its absurd duration, a memory fog that can drag on for 3 days or more. Like many long lasting substances, there is a very long, slow comeup, it can be up to 3 hours before peak effects are felt. I have only taken it a few times, usually during depressive episodes, where I seek to just skip through time. It is not something to be taken lightly and its a blessing that it is fairly impotent- otherwise it would be an extremely dangerous substance to handle. The actual experience is blank and neutral, listlessly drifting through time. There isn't much to remark on, no imaginative rush, no heavy sedation, not even a full-on blackout, just a lingering haze. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: not attempted

Recreational: 8-14  mg

Intoxicated: 14+ mg

Hypnotic: n/a (never reached this point)

Duration would typically be 24-72 hours depending on dose

Flubromazolam

Similar in name to Flubromazepam and somewhat similar in effect. Another long haul benzo. This however, has the distinction of being extremely potent and extremely hypnotic. This is not a substance to be trifled with. For reference I only took it once- I really cannot see any utility driving me to take this again. It is also quite long lasting, droning on for multiple days. Unlike Flubromazepam, those days were spent near-non-functional, the drowsiness overcame everything to leave me listless and useless. Similar to Clonazolam, but even longer lasting. I do not see much purpose in this drug, unless one has a heavy benzo tolerance and severe insomnia and needs something long, potent, and sedating.

My only trial was a dose of 400 μg. It was functional, within what would be considered the "recreational" range for other substances, save for the heavy sedation. It lasted for about 60 hours.

Flunitrazolam

Another ultra-potent compound, another heavy sedative, another one I only tried once that I don't feel eager to revisit. Unlike other ultra-potents, this compound is extremely short lasting. There wasn't much of a 'high' to speak of, just a sudden sleepiness as though I had taken doxylamine or melatonin. There is no residual grogginess into the next day- in fact it was quite the opposite- it quickly and assertively induced sleep but it was a short and restless sleep that had me waking up early the next day not feeling groggy but not feeling well-rested either. The next day however, I felt stimulated, on edge, as though the short and acute experience had suddenly induced a rebound stimulation. My muscles were tense and twitchy, my teeth clenched, I was fidgeting and anxious all day. While I can see a short-acting and super-potent hypnotic as being useful, I am hesitant to revisit a compound that seems to have induced mild withdrawal effects the next day.

My only trial was with a 200 μg dose, which yielded almost no effects beyond a slight amnesia. About an hour and a half later an additional 250 μg was added, which induced a rapid and powerful drowsiness. There was no "high" to speak of between baseline and sleep. While I went to sleep it appears to have left my system before I woke up-  I would place the total duration probably somewhere between 2-4 hours.

 

Lorazepam (Ativan)

I have limited experience with this compound, only trying it a few times when offered by friends. I wouldn't say I can fully characterize it, as the doses I took were either so low they were hardly noticeable, or so high that I was fully intoxicated. It is generally regarded as a short-acting and mild benzo, and it was certainly mild when I wasn't taking a handful of them. When I was fully intoxicated though, it was a confusing rush, dizzying and aloof. I had fun, I felt silly, I can't fully remember what happened but I remember bordering on delirious. I kept thinking people were in my living room that weren't actually there, that imginary friends were unexpectedly visiting. It seems it induced more short-term than long-term amnesic effects, as according to others, I apparently had difficulty maintaining continuity in tasks. I would love to experiment with this one more in a more controlled manner- it's not to be dismissed, it is certainly something interesting.

My typical oral dosage (with tolerance) would be: 

Therapeutic: 1 mg

Recreational: n/a

Intoxicated: 6+ mg

Hypnotic: not attempted

Duration would typically be 4-6 hours.

Meclonazepam

Meclonazepam is lovely. I only say this because it is near-identical to clonazepam, just a bit less potent. I doubt I could distinguish between the two of them in a blind test. The same euphoric, creative rush, the same duration, the same degree of sedation and amnesia. Clonazepam is something I hold close to my heart, a friend of Clonazepam is a friend of mine and I've found it in Meclonazepam. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: .5-1 mg  

Recreational: 5-10 mg

Intoxicated: 10+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 8-20 hours depending on dose

Norflurazepam

Norflurazepam is another compound that is cited as being perfect for a taper, in the vein of Diazepam and Diclazepam. This is owing to its low potency, allowing for doses to be precisely adjusted, and its purported long half life. For me, the experience did not drag on for days as I expected. Perhaps for those with dependence, this would be a subtle tail that would keep them well for long enough to maintain a stable taper. I found that most of the acute effects departed in a reasonable amount of time. In terms of the experience this drug offers, it is fairly standard for a benzodiazepine, similar to Diazepam. It is a bit more sedating and intoxicating at higher doses than Diazepam can be, and I would say it has greater recreational potential in that regard. A perfectly somewhat above-average compound. Not too hazy or amnesic, can put me to sleep and overwhelm other substances without interfering with my day to day life. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: 5-10 mg  

Recreational: 15-20 mg

Intoxicated: 30+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 10-16 hours depending on dose

Pyrazolam

In the large suite of novel unmarketed benzodiazepines I have tried as of late, Pyrazolam has proven to be the most desirable and useful of the batch. It is a highly functional benzodiazepine that falls into a goldilocks "just right" zone in terms of sedation, able to snuff out other experiences and put me to sleep but absent of overwhelming hypnotic effects. It is perhaps one of the least amnesic benzos I have consumed- I doubt I could black out on this no matter how hard I try. While it is distinctly slightly hazy, even into the next day, it seem the amnesic effects simply cap off and do not increase past a midrange dose. At higher doses it is certainly fun and recreational, at lower doses it is quietly anxiolytic and would be perfect for needing to do things in public with less anxiety. It is not quite as recreational or intense as Etizolam but it fits neatly into my rotation and serves a specific utility that I find quite valuable. 

My typical oral dosage (with tolerance) would be: 

Therapeutic: 2-4 mg  

Recreational: 4-6 mg

Intoxicated: 8+ mg

Hypnotic: n/a (never reached this point)

Duration would be typically be 8-12 hours depending on dose

I am certain I will encounter other Benzodiazepines in the future, and this will be updated as I try them. I have not encountered any "Z-drugs" yet, but due to similarity of action they too will be included in this post should I cross their path. There are still plenty of benzos that I would love to try, just to bolster my points of reference and develop a wider vocabulary in this class of drug. 

Some of the compounds on my wishlist are: Deschloroetizolam, Metizolam, Midazolam, Temazepam, Oxazepam, Triazolam, Nitrozlam, Nitrazepam, Flunitrazepam, Bromazepam, Lormetazepam, Nifoxipam, Phenazepam, 3-Hydroxyphenazepam, Metaclazepam, Ethyl loflazepate, Clobazam, Delorazepam, Medazepam, and Nordazepam. Someday! 

2020 in Review

Whelp here it is, yet another year of doing drugs has come and gone. It goes without saying that it was a unique year but I'll still say it anyways- Unprecedented wildfires sweeping through many different parts of the globe, an unprecedented storm season, unprecedented uprisings against authoritarianism and police worldwide (particularly in my home country, which had seen relative stagnation on that front for some time), one of the most contested and polarizing elections in my country in living memory, and of course the one that casts a long shadow over the rest, the global coronavirus pandemic.

The consequences of the pandemic have been felt on every level by almost every person on earth at this point. For drug users, it has been a watershed year- loss of employment, lockdowns and restrictions have led to many people turning to substance in the abundant time alone in their homes, some exploratory, many sinking into addiction and despair.  While it is still too early for the data to be fully analyzed, what has been observed so far paints a picture of sharply increasing drug use in every form. The coronavirus pandemic has almost certainly compounded the already devastating opioid abuse epidemic seen primarily in the U.S., and use of stimulants and cannabis has also been on the rise. 

The Global Drug Survey is sure to yield some very interesting results this year, go and fill it out if you haven't already! The deadline is January 30th.

Interesting new frontiers have been opening up too- acceptance of certain hallucinogens for treating mental illness has gained exponential acceptance, with an explosion of studies, trials, and new laws facilitating this belatedly burgeoning frontier in psychiatry that had been strangled by prohibition for decades. Psilocybin mushrooms have seen significant strides in the medical and legal arena, as has ketamine. A global movement against police brutality and racial injustice has made many aware of how criminal justice systems cruelly leverage drug prohibition to target minorities (especially in the U.S.) 

On a personal level, I have done more drugs than I ever have before in my life. Both in quantity and frequency of use and in the number of novel substances consumed. The simple attribution here is long periods of time spent indoors, alone, which happens to be my favorite setting in which to consume drugs. A number of novel compounds entered the market this year too, especially within my favorite class of drugs, the dissociatives. I also at last did away with my personal stigma against non-hallucinogenic drugs- for much of my psychonautic career I dismissed whole words of substances for being "shallow", or out of fear of certain effects. I finally accepted that a comprehensive understanding of psychoactive substances and altering my mind involves truly exploring the full suite of ways in which I can alter my mind. For the most part, I have particularly found myself exploring variety within stimulants and benzodiazepines. I reoriented my intentions with drug use during the summer, distilling them into a single essay to guide myself going into the future. I do not intend to stop using drugs in the forseeable future, they are an inextricable part of my lifestyle. I intend to use them more intentionally and in ways that specifically benefit me and others, but I feel like I say that every year and fail to measure up. It's hard. Not to say that I'm not trying, but the path of least resistance is the reason why drugs are so popular in the first place.

 I have to acknowledge the privilege I've had to be able to explore this- that I can sustain multiple habits while still having a roof over my head and eating enough. I am blessed that I had enough of a safety net from when I was employed to keep me afloat when I wasn't- I know that it is so much more precarious for so many. Confidence and self assuredness in navigating online markets facilitated an unprecedented rate of purchasing, along with a series of windfalls of mobile liquidatable BTC that I couldn't really use elsewhere. I also owe many novel experiences to the generosity of friends and vendors who have lent me samples of things to guinea pig with my body and mind, an for that I am infinitely grateful. I must admit though, that I have spent an untoward amount of money on drugs this year, resources that would absolutely serve humanity better if requisitioned elsewhere. This I cannot reconcile. 

I have to acknowledge that using drugs like I have in 2020 is in no way sustainable, in terms of my own health, the health of my relationships, the health of my financial stability, the health of meaningfully moving forward with my life. I have certainly stagnated in a way and I would like to just chalk it up to circumstance but perhaps its something deeper. I would like to go into this year using more intentionally and primarily seeking novel experiences, but we shall see how it plays out and what this year will bring.

On stimulants- I approach these mostly from a functional perspective. I am seeking substances that will keep me awake, enhance focus and motivation, and overall improve cognitive function and energy levels. Particularly as of the last few months I've found myself listless, fatigued, unmotivated, distractible, and struggling to do even basic chores and tasks, much less approach larger projects and longer term goals. I have been experimenting with a variety of rc stimulants to try and alleviate this- and they do indeed help! They make me feel normal and functional, and I am questioning whether I have undiagnosed ADHD and whether taking a daily prescribed dose would serve my life for the better. As of now I just take a low-medium dose of my choice compound as needed, on days when I plan to be productive. I don't particularly enjoy the stimulant high, and I find that many of them give me a whole suite of unpleasant side effects, especially as I push doses higher. I never get a compulsion to redose nor do I typically suffer strong comedown effects beyond drowsiness and fatigue. The more "recreational" stimulants, particularly the cathinones, have proven to be largely unpleasant for me. The one that I have found most helpful in my life is IPPH (or Isopropylphenidate). 4F-MPH, 3-FPM, and 2-FMA (I tried this for the first time just after new years but shh) have also provided a modicum of relief.

I developed a complicated relationship with benzodiazepines this year- I have been maintaining a habit of using benzos 1-3 times weekly for the last few years.  From the fall of 2019 onwards however, use steadily increased, and I found myself using them at higher doses and with greater frequency. Most dangerous was the addition of flualprazolam to my arsenal- flualprazolam is powerfully hypnotic, it will put me to sleep in an instant and cut through any other drugs to give me deep, long lasting, extremely restful sleep. It became my perfect post-psychedelic/disso/stim knockout drug. It soon became difficult to sleep without it- I would often combine it with recreational doses of etizolam (which was my sleep aid before) to finish the night off, which eventually culminated in having even etizolam not sedate me anymore. While for most of my life, I could instantaneously abstain from benzos for any period of time without issue, I soon found myself suffering the dreaded withdrawal effects on days I abstained. Eventually I was completely unable to sleep unaided- any sleep that came along was brief and restless. My usual peripheral hypnotics, DPH and melatonin, were no longer doing the trick. During the day my heart was pounding, my thoughts racing, my muscles were twitching, and I felt extremely tense and on edge. I mercifully only experienced very very mild discontinuation symptoms- I have read plenty of horror stories of just how bad benzo withdrawal can be. I did a quick taper and quit, thankfully.

For a bit- it was about a month later that I was back on the horse- I was consciously keeping track of my use now however, and was back to just 1-2 times a week. I intentionally discontinued use for weeks to ensure I was doing okay. I seem to have avoided amassing kindling effects, and I pay careful attention to my doses and increases in tolerance (part of why things began to get out of hand before is that I was really just eying out doses of powder or eying drops of an unmeasured solution). I don't want to give up benzos forever- they have utility that few things can replace. I still have trouble sleeping, I still take something most nights to sleep, typically DPH or Doxylamine. Due to the utility of benzos I found myself curious about the variety that existed and set out to explore as many as I could. In sampling a wide variety, the only really valuable one I picked up for my toolkit was pyrazolam. I really circled back to Etizolam as my staple. I will write a post summarizing my experience with a wide breadth of benzos in the near future. For now I am carefully monitoring my use. I'd like to think I have it under control, but every addict likes to tell themself lies. And I know how quickly and easily it can slip out the illusion of control I have now. I am grateful for my partner for checking me and my use.

Psychedelics and dissociatives maintained a constant presence as always. Dissociatives in particular were a poison of choice that I used heavily throughout the year. The fact that 4 new compounds appeared on the market in 2020 only made exploration of dissociatives all the more exciting. DMXE, 3-Cl-PCP and MXiPR have proven to be absolute gems.

I also have introduced .Δ8-THC and kratom into my regular rotation. They're neat. I spend most of my free time playing Chivalry: Medieval Warfare. I got rejected from graduate school. I'm mostly lazy and unmotivated. I took up watching a movie a day for a time period, mostly through the Criterion Channel, and I've taken up cooking and playing with spices a lot recently. The time I spent alone in quarantine with 0 responsibilities other than being alive, when everyone else was at least trying a little bit to distance themselves and there was a general sense of postponing obligations, was probably some of the most comfortable times of my life. But it as at the expense of shielding myself from the unfolding and skyrocketing tragedy striking down so much life and livelihood around me. Maybe I'm just destined to be a NEET fueled by drugs and welfare.

This year I've also developed a lot of wonderful connections in the community and made many new friends, from vendors, to scientists, to fellow hobbyists old and new. They have helped me explore the world of substances firsthand, improve my writing and research skills, brainstorm new ideas, and learn so much more. I won't give a shoutout to anyone specific because of the nature of this blog, but if we've met through the internet drug community and maintained contact, just know I value our friendship! :) 

In the abundance of free time at my (mostly) unemployed disposal, I have dedicated myself to various projects involving the study of drugs via literature reviews. I have undertaken two large overarching projects- 

The first is my series Obscure and Unknown (catalogued in this reddit post)- this was a revival of an idea I hatched in 2017 but never followed through on, in which I would dig through medical literature or forgotten forum posts or written literature and write about interesting and little-known substances. My main focus has been on hallucinogens. I have had a lot of fun working on this, I hope the articles are accessible and interesting and enjoyable to read, definitely check it out if that interests you! (it's on the side bar too). I spent a great deal of time teaching myself some of the basics in pharmacology and structural organic chemistry to help understand these papers better and interpret the information I could find. Which leads into my next project:

My other massive undertaking began over the summer when I began to think beyond the obscure drugs and began to consider introducing new drugs to the world. I began to dive into SAR, "Structure Activity Relations"- as the name implies, it's the analysis of how the structure and composition of a molecule affects the way that molecule is received by the body (and mind). After much research and correspondence, I broke down the base structures of 3 different classes of dissociative, the arylcyclohexylamines, the Diarylethylamines, and the Dioxolanes. For each of these families of compound I made a flowchart as a visual aid to demonstrate the ways in which one could systematically design or modify a molecule in hopes of preserving dissociative activity. A lot of it is admittedly pure conjecture that awaits real world in vitro (or perhaps in vivo) experimentation and analysis to confirm these hypotheses. But perhaps these could serve as guide posts or a loose framework on which to base legitimate research. Ultimately they are fairly long, tedious, and wordy and most of the meat and potatoes of each essay is likely only of interest to the few individuals who may be seeking to develop new substances. But I hope it will serve those people well. I aim to write similar essays for the myriad of miscellaneous dissociatives out there, phenethylamine psychedelics, tryptamine psychedelics, and lysergamides, beyond the seminal work already done by giants like Alexander Shulgin.

Now then- I go on to a familiar part of my year in review essays. I list and rank and briefly summarize every new drug I've tried this year. There are more this year than ever before, so buckle up for a long ride! Without further ado (substances with corresponding reports are linked):

1. DMXE: DMXE is a miraculous substance. An absolute gem. No its not exactly like MXE. I wrote a whole essay about how we should move on now. It is something entirely of its own, something that may not fill the MXE shaped hole in your heart, but will form a new wonderful hole in your heart that will ache when it inevitably disappears. Stock up while you can! It's a delightful versatile dissociative that has enjoyable qualities at any dose- lower doses are fun and stimulating and a bit manic, higher doses yield a deep and colorful hole. I am so excited to spend more time exploring this compound for all its worth. My only gripes are the high dose and short duration, though neither of those should be an issue for fans of ketamine.

2. 3-Cl-PCP: This was one of two brand new halogenated dissociatives that came out this year- halogenation had largely only existed in the realm of in vitro studies until 2020 when 3-F-PCP and 3-Cl-PCP came onto the market. You will see that other compound 3-F-PCP much further down this list. It's amazing what a world of difference is made when you add a slightly bulkier halogen. 3-Cl-PCP is a wonderful substance, though it doses much higher than most dissociatives, it is perhaps one of the most unique ones I've tried so far. It is remarkably anxiolytic and "soft", just an experience of absolute dissociated comfort that manages to be simultaneously gentle and intense, with a good touch of visuals too. It's seriously underrated and talked about little, I can't recommend it highly enough especially for those psychonauts seeking novelty and breadth of experience. 

3. 1cP-LSD: For the longest time I regrettably slept on lysergamides other than good ol' LSD- my limited experience with a few of them saw little novelty in them and little variation between experiences.This year I began to key into them a little more- initially getting some new ones as addons to larger orders I was making. 1cP-LSD proved to be one of the most unique and interesting of the ones I've tried so far- remarkably lucid but incredibly visual. While there's good amounts of evidence that 1-substituted lysergamides just metabolize into LSD, some of them have proven to be inexplicably unique in their effects, like this one. It's like the 2C-B of lysergamides if I may make the comparison. The first time I took this I spent the whole trip watching livestreams of day 3 of the uprisings in Minneapolis. 

4. MXiPr: Another purported MXE replacement. This one also has proven to be a unique drug unto itself. When it comes to dissociatives, I am a deep diver, I go for the hole as often as I can. I prefer more intense experiences. The hole of MXiPr is unlike any other. It is energetic, exploratory, and vividly colorful. Its a journey on the back of my eyelids, with structure and sequence. It's so exciting, so fascinating, so enjoyable. The only reason this isn't higher on the list is that it lacks in versatility- I've found lower doses are fairly boring and unremarkable, much like lower doses of MXPr. DMXE shines at pretty much any dose which is why it's #1. MXiPr is also absolutely something valuable and worth investigating however.

5. IPPH: Of all the stimulants I've tried, none have really met my needs quite as well as IPPH. I don't enjoy the high of stimulants much, I do not seek recreational value, for the most part I am looking for something that will just allow me to function at a baseline level of motivation and focus that I seem naturally deficient in. IPPH checks all those boxes neatly- minimal side effects, and just the right amount of push and confidence to get things done without bubbling over in any regard- not too much stimulation, not too much euphoria, just exactly the right amount, within a fairly wide margin of doses. All around worthwhile.

6. 3-Me-PCP: This is another novel dissociatives that really bears comparison to more famliar compounds- it is much like regular PCP or 3-MeO-PCP, similarly lucid and stimulating and manic. It has a remarkably shorter duration than either and a bit more of a euphoric rush and physical dissociation, almost like alcohol or GHB. It is fairly shallow and not too useful for introspection- the short duration and relative lucidity make this a perfect party drug, but owing to current events I have been unable to test it within that context.

7. Pyrazolam: When I first began using this I began to question the common descriptor for it that was served on the internet- the best functional benzo. After repeated use however it became clear that while higher doses carried a pleasant high, it was ultimately less amnesic and inebriating than other benzos. Sufficiently hypnotic too. I think it has a nice euphoria and can let you get through life without causing too many problems- ultimately a very utilitarian drug, making it my favorite new benzo I tried this year.

8. Δ8-THC: I'm not well versed in the variety of cannibanoids so I can't compare this to anything other than regular cannabis. It's a lighter gentler high, definitely odd in its contradicting gentle intensity if you push it, but I've found I really have to dig in deep to feel something equivalent to a higher dose of cannabis. I find it to be lacking on its own, but it pairs excellently with regular cannabis to take some of the edge off (Oh yeah, as a consequence of my benzo use most likely, cannabis is no longer something relaxing, its more of an edgy stimulant at this point, and I still smoke it every day. Whatever)

9. Meclonazepam: This is near indistinguishable from clonazepam, a bit shorter in duration I guess, and less potent. I like clonazepam a lot, so naturally I like this a lot too. Not much else to say on it. Euphoric and fun with a lot of creativity, just as clonazepam is.

10. 4F-MPH: Okay I lied a little, sometimes stims offer a fun high. 4F-MPH has a lot of fine lines you have to carefully walk to make the most of it. Lower doses are the same sort of functional as IPPH, but a bit more tense and edgy, without as much wind behind the sails in the right places. High-mid doses are where it really shines, where it carries what I would call an "aggressive motivation" with a strong euphoric push. It makes you do things and feel good about it, it's a great drug for doing chores and menial tasks. It's a hell of a sweet spot with dose though- overstep it by just a little and a whole mess of side effects come crashing down, mostly tweakiness and tension and nausea. It's made me throw up before. To be used responsibly. It seems that sweet spot varies however, and I can't hit it consistently with the same doses. I have to generally gently feel it out and titrate up with tiny bumps until I hit the mark.

11. 3-FPM: The first stimulant I began studying in earnest, I adhered to it for quite some time because it was all I had. It's nice, its mild, there isn't too much there unless you really plunge deep into it. Effects are subtle at low doses, effects are marked at high doses without too many side effects. I did notice an odd tingling in my toes after using it for two consecutive days however. It's a nice neutral stimulation, not much rush and a gentle sprinkling of euphoria in the right settings. Mostly just very useful for staying awake or going to work a menial retail job.  

12. 1F-LSD: It feels unfair to gas this up, it will probably never be available to other people. It was nice though, a gentle psychedelic trip where I felt at the helm the whole time, just a bit visual. Made for a nice day out. Was gifted this as a test batch, but owing to purported instability and more viable alternatives, it probably won't be coming to market. Not that there's anything wrong with it, the market guides all I guess.

13. 1B-LSD: Also quite gentle and enojayable. A simple pleasure that makes for a nice day out. Kinda boring in the usual setting. Not as visual as 1F-LSD, or rather the visuals are more of a color-shifting than a patterning nature- still present but not as pleasing to me personally. All in all a worthwhile compound, but not too deep.

14.  5-MeO-DPT: I admittedly had extremely low expectations for this one. 5-MeO compounds can be gnarly on the body. So can DPT. I expected to spend a day throwing up and begging for mercy. What followed was an oddly non-visual but intense and emotionally raw experience that nearly brought me to tears with its pleasantry and beauty. It's an odd and unique compound that definitely isn't for everyone, but I was pleasantly surprised by it. 

15. 4-HO-MALT: A gentle psychedelic- remarkably free of any body load. That's really all the credit I can give it, it was pretty standard otherwise. Maybe I'm being a jaded stickler for expecting more of my drugs, for what its worth it is definitely trippy tryptamine that will give desired effects, especially to someone drug naive. To be fair I only tried it a few times as I didn't have much at my disposal. Perhaps I would like it more if I acquainted myself more. It's got potential I guess. I think this would make a great beginner or entry level psychedelic for someone who wants to carefully wade into that realm.

16. MPT: I am still running trials on this, I hope to have a report up soon. A base tryptamine that was uniquely offered as a fumarate salt. I am mostly too lazy to rig up something to vape tryptamines, though learning how to work a crackpipe has opened that front up a little more. But this I could just eat, which was nice. I've been undershooting my doses due to a lack of information on this one, working up to an experience that I think would be worth reporting on. The last was fairly intense, but remarkably non-visual at all. I stupidly took bromazolam the night before however, and I wonder if that diluted the experience. It's interesting and draws me in to investigate further, so it benefits from that. Hoping to run another trial soon but I have a lot on my plate currently :)

17. 4-HO-DiPT: Another standard eh psychedelic. Like 4-HO-MALT. If you ingest this, you will definitely have a brief psychedelic experience replete with the typical trappings. But there frankly wasn't much about this drug that made it stand out amongst the hundreds of other psychedelic experiences I've had. It does its job and it does it well, but I didn't find it particularly novel or interesting. I'm sure you could coax something profound out of a higher dose of it, but I didn't have any particular compulsion to explore that. 

18. 3-F-PCP: We're reaching an inflection point in the list, where compounds are just so-so, very neutral, or have their positives equally weighted by negatives. 3-F-PCP is the former. Just a really nondescript intense and neutral dissociation that battered like a storm for a short span of time. Not too interesting, not too profound, just left me dazed and stupid. Some people seem to like this drug, most don't though. If raw dissociation is your speed and you want something shorter and less potent than O-PCE then why not. 

19. BOD: A fast and furious psychedelic, hot and stimulating. It reminds me a lot of psychedelic amphetamines despite not being one at all. It was a fun and novel compound, great for socializing, great for humor. Maybe it ranks low because I haven't seen my best friends I did this with in months and I miss them. But it also had a heavy bodyload, particularly in urinary effects, that lingered long after the pleasant effects wore off and that has turned me off from revisiting it. 

20. Norflurazepam: A very neutral benzodiazepine, it doses high and despite being billed as having a long half life, it seems about the same duration as clonazepam for me. Perhaps the lingering half life just means you'll stay well for longer if you're trying to taper off. This drug is billed as a golden standard for tapering after all, if you can't get your hands on Diazepam. Diclazepam fulfills this role too, but more on that later. Norflurazepam is for me, near indistinguishable from Diazepam, but a bit more incapacitating and sedating, which is why I'll rank it a notch higher than Diazepam.

21. Diazepam: Neutral as a benzo, it's nice on its own but its this far down the list because it doesn't serve my main utility with benzos at all- the ability to cut through the comedown of a stim or psych or disso and put me to sleep. This cuck of a compound just shies to the background and lets stims rage through me in a haze until the sun rises. Just have to know when to use it right. Maybe if I pushed doses high enough I would get to sleep but 30 mg had me feeling plenty off base. I'm glad I got to finally encounter the "gold standard" of benzodiazepines though, as it was really just through a stroke of fortune.

22. Eutylone: Eh. It's a good roll, and its extremely cheap. Only problem is I don't much like rolling. A bit too many stimmy side effects for my taste, but if someone wants to feel good with some other people for very little cash then this should more than meet their needs.

23. Diclazepam: I don't know what to make of this. Some people say you aren't supposed to feel it, it just keeps you well if you have a habit. Other say you can absolutely get fucked up in Diclazepam, and say the latter have all been getting bunk product. I brought it up for discussion and people came from both camps very passionately. No conclusion was reached. I personally do not feel anything from Diclazepam beyond excessive salivation, even at doses exceeding 8 mg. But that's just one batch- perhaps it is one of the "bunk" batches- who knows! This is the true neutral baseline point of the list, because I question if it feels like anything at all. Everything below this has the negative effects outweigh the positives.

24. O-DSMT: My introduction to the world of opioids seems to point towards them not being a class of drug that is very compatible with me. I seem quite sensitive to the itching side effect, even with plenty of antihistamines administered. It was extremely uncomfortable. The high was nice, but the horrendous skin tearing itching took away from it. It's not a bad drug I don't think, just not for me. If you are into opioids and want to catch a fix without nodding off all the way then it would probably serve you well.

25. 5-MeO-MALT: To this drug's credit, it is, at the very least, very interesting and novel. But also extremely uncomfortable. I would've liked to honestly explore further into this one but it felt like my body, particularly my heart, could not handle diving in deeper. It's important to listen to your body and when it's telling you to stop and I'm glad I did. Just sad I can't really plumb the depths of this compound, it seems like it has interesting things to offer. Perhaps someone else with a better body could. Made for a fun tryptamine in a crackpipe experience.

26. 3-FMA: With stimulants I'm mostly seeking effectiveness along an axis of motivation, lucidity, and heightened awareness. This thing plays with the levels in all the wrong ways. It's definitely stimulating, but instead of focusing on the tasks at hand, I find myself compulsively falling into cycles of procrastination and distraction. Not useful at all, just a waste of time. I'm just fidgety and compulsively refreshing my social media feeds for hours, then feeling bad about it after. 

27. Bromazolam: I had really high hopes for this one, its sad that it ended up towards the bottom of the list, because now I have more than I know what to do with. I heard lots of positive experiences especially with regards to its recreational value. It was purportedly euphoric and very anxiolytic and quite hypnotic too. All things I sought to varying degrees. And it did provide that, in spades- things this far down the list though have the negatives outweigh the positives, and Bromazolam was just so amnesic- an effect that would linger for multiple days, that I really want no part of it in my life anymore. I found myself unexpectedly and inadvertently missing days I would have liked to remembered, which I don't really like- very little discussion online mentioned the drawn out amnesic effects even after most of the other effects had faded, but in bringing it up  for discussion a handful of people corroborated this. So be warned! And this serves as a warning to me that drugs are very subjective and not to get my expectations too high. 

28. Clonazolam: This is the end of the road for many a benzo addict- extremely potent and long lasting, it really just fits the needs of those who need to maintain a heavy habit and absolutely no one else. This shit makes me sleep through every alarm while being blacked out for like 3 days, and then I'm dozing off the whole time. I don't mind a drawn out benzo but this one is just so sedating that I'm more or less useless until its left my body. I can't see myself using this unless I had exhausted every other option financially and had to keep a habit up, which is I guess what draws so many people into this chemical.

29.  α-PCYP: Absolute garbage. I usually restrain myself from dismissing any drugs with broad strokes like that, but corresponding with others who have used this, I think it's fair terms to speak of this drug. Bottom of the barrel cathinone for those seeking a fix. 20 minutes of fun then a day or two of feeling like absolute shit, and it makes everything smell like cum. Apparently a lot of this is standard for pyrovalerones which makes me wonder what the fuck but to each their own. But also its generally held in low regard even amongst its sketchy pyrovalerone cousins. Maybe I'm a cuck about stims but I genuinely wondered if I had done permanent damage to my body after using this. There's a reason its so cheap.

30. BTCP: Probably toxic for your liver. I snorted it and it hurt a ton and I had a stinging sniffling pain in my sinuses for the rest of the day. Dumb dumb dumb. Yielded a neutral useless stimulation that was overshadowed by the discomfort. Was given this for free with a bigger order, and I can see why the vendor wanted to just be rid of it. Tried for the sake of trying, will never touch again, even in an emergency. 

31. 5-MeO-MET: I just felt like I had poisoned myself. Nothing profound or interesting to offer beyond a physical sensation of being poisoned. Maybe my body is just sensitive but I'm not eager to investigate further. Would like to hear other's thoughts on this and hear if anyone has anything positive to say but for now, to me, this drug has absolutely no redeeming qualities. BTCP and α-PCYP ultimately felt awful but for some period of the experience had something to offer me at least. This had nothing, at any point, that felt of value. Would probably rank among the most uncomfortable, dysphoric, irredeemable substances I've put in my body, next to Glaucine.

I also tried 2-Methyl-AP-327 with barely discernible effects- though recent reports on its consistent toxicity has made me wary of delving further into it. I also tried blue lotus in a smoking blend mixed with cannabis- effects were subtle and barely discernible. A gentler high than usual, though I only tried it once with the help of a friend, hard to really say much more on it.

I would also like to give an honorable mention to kratom and 3-HO-PCE, which I revisited in earnest this year after merely sampling them in years before. Kratom provides a nice high but more importantly provides relief from the pain in my spine and neck and the resulting tension headaches. Still haven't mastered consuming it without almost vomiting however. 3-HO-PCE I initially dismissed due to sampling an early batch that has now been tested and shown to be either inert or heavily diluted with some sort of filler or inert byproduct. I gave it another chance, and it proved itself to be a unique and intense dissociative in its own right- still not really one to my liking, it would probably fit between 5-MeO-DPT and 4-HO-MALT on this list- but definitely something worth trying and exploring. It's not for everyone but it has its adherents, just like any drug.

To all readers, thank you for reading, thank you for the kind words occasionally offered, hit me up at nervewing@protonmail.com if you ever want to chat or have any questions or whatever, here's to another year of being altered.

New Drugs: Dioxolanes

Generalized structure of a Dioxolane compound with NMDAr antagonist activity

Coming back to add a third addition to my series on the structure activity relationships of various compounds, I first touched on Arylcyclohexylamines and Diarylethylamines.

Dioxolanes dioxolanes how I would love to meet a dioxolane on the street some day! I have written a good bit on thesecompounds in the past. A good generalized but detailed introduction to this class of chemicals can be found in that article! These are curious characters that I personally believe hold a lot of potential. An untapped mineral vein, gleaming in the dark-

Overall, dioxolanes are fairly unpredictable when modified and there seem to be a range of cryptic patterns or lack thereof with their SAR, rife with exceptions and anomalies. It is for now, very hard (for me at least) to conjecture what may or may not be active.

Dioxolanes never had the distinction of making it to the recreational market. I have no knowledge of what the clandestine chemistry scene around dissociatives was like in the early 2010s but it seems like the only jump to a different class of molecules was driven by a UK ban on aryclyohexylamines. At that point there was a buffet of available options for the enterprising novel psychoactive chemical developer- The diarylethylamines ultimately took the prize, but the dioxolanes must have been considered then. Why did they remain relegated to the dustbin of history?

Only two were ever tested on humans and most literature on developing other Dioxolanes uses them as standards. These are Etoxadrol and Dexoxadrol.

When one delves into the medical literature on dioxolanes they encounter a lot of interesting comments on dioxolanes-These are excerpts pulled from my article on them, the citations can be found there!

“Open eyed hallucinations were not observed in post recovery, though subjects observed a "dream state" while anesthetized

"None of these dreams carried connotations of unhappiness to the individual; in fact, the majority were described as pleasant and/or unusual experiences. Consistent ideas of depersonalization, primarily of malinterpretations of self anatomical configurations, were a prominent symptom”

"The side effects caused due to the medication of Dexoxadrol are quite unusual and dangerous. It causes hallucinations and nightmares in the users. It has been reported that Dexoxadrol creates unpleasant conditions before the users. The dreams that came after the usage of this medicine range from pleasant to frightening. In dreams, it seems as they are in some other world that has no relation to the reality. But in most users, the results are outstanding rather than insane."

In most literature these effects can seem alarming, dysphoric, perhaps not particularly appealing. Perhaps it was this that turned research chemical designers off from developing them any further. Sensations described as vivid “dreams” or “nightmares” along with open eyed hallucinations were frequent. I hypothesize however, that what were referred to as dreams or nightmares were actually akin to dissociative “holes”- semiconscious states heavily laden with visuals, even visuals that bore a narrative- if this is the case then these would certainly be very interesting substances! It believe that at the time the medical literature simply lacked the vocabulary to do define those states as such. Other effects of the dioxolane experience were defined as “PCP-like”, while other side effects noted as concerning seemed to be exact descriptions of the qualities of a typical dissociative experience.

Nonetheless, this research was shortly after PCP had become an unexpected problem child in the world of anesthetic development. Seeing similar effects, it was possible that researchers quickly aborted trials and swept this class of chemicals under the rug to avoid repeating the trials and tribulations that came about through the lifespan of PCP. Meanwhile, the questionable, though I argue dated, descriptions of the experience from the contemporary literature may have turned future research chemical developers off from exploring this class of compounds further. Not only may they be very intriguing, but so far most have shown to be sufficiently potent, with dosages from 10-50 mg across the family depending on the compound and ROA. I personally believe that it is worthwhile to give this class of chemicals another shot!

So how do you go about designing novel chemicals in this class?

First, I must share the disclaimer I always share when dispensing this kid of information-

The safety profiles of the dioxolanes is entirely unknown. The only reference we have for doses is via IV, active doses by common oral, rectal, and intranasal means are entirely unknown. They have only seen limited human trials with only 2 compounds, which leaves a lot of unknowns. It is known that an accidental overdose of over 6x the intended dose was not fatal, though it yielded a long and difficult experience [7]. It appears that it is well tolerated for acute toxicity with minimal dangerous side effects. The effects of chronic use and chronic toxicity of dioxolanes is entirely unknown and this should be approached with the utmost caution. The risk of accidentally producing toxic byproducts from improper synthesis is also entirely unknown to me.

A warning about dissociatives in general, sources cited in this article:

“There are also a number of ways chronic toxicity is reported to present with NMDA antagonists, mainly neurotoxicity and cytotoxicity. In terms of neurotoxicity, there are the infamous Olney’s lesions, a form of brain damage, that has been observed in other animals, though they have still not officially been observed in humans yet [43]. However, a recent study reportedly observed some form of damage in the brain of extremely frequent users of ketamine [44]. The other main reported symptom that indicates toxicity is urinary toxicity [45, 46], supposedly a result of damage to the epithelial cells lining the bladder caused by direct toxicity from ketamine metabolites. This has so far only been officially reported with ketamine, though there are anecdotal reports of it occurring in frequent users of other dissociatives. There is also a potential for cognitive dysfunction from extreme repeated use of dissociatives, mostly in the form of “brain fog” and memory loss, though there is some literature on the matter [47].

 

These substances also carry the risk of generating dangerous behaviors that can be damaging to one’s life circumstances and relationships, both through the dangerous interplay of prohibition and substance, and in properties inherent to the chemicals themselves. One key risk is addiction- while physical dependence to dissociatives is significantly more rare than with other classes of substance, it is entirely possible and psychological dependence is commonly reported. Frequent usage significantly increases the chance of toxic effects or cognitive dysfunction presenting. Other substances, such as PCP, are notorious for causing intense mania that can push into psychosis, which can lead to violence, damaging relationships, and legal trouble. All of these risks are real and it is up to the user to determine what methods personally work best for mitigating them, including total abstinence if necessary.

 

I would suggest, in a perfect world (keep in mind this is all very handwaved, this actual process can be expensive, difficult, and extremely time consuming)- First, doing a virtual docking simulation of the compound. This of course is not a surefire way to determine activity, but can perhaps give warning of possible unexpected activity or help to rule out certain options as being less viable. The compound can be synthesized from there, at which point it must be properly characterized via NMR and GC/MS analysis. From there, an in-vitro receptor affinity study can be done to confirm or deny certain targeted activities in nerve cells in comparison to familiar reference compounds, like PCP, Ketamine, MK-801 or Morphine. The safest step from there would be in-vivo studies in animals, also compared to a control group of reference compounds. Behavioral tests can be done for comparison to any references, and drug substitution tests can help indicate similarity to the references. There is a huge variety of animal tests that can be done in combination with each other and with various controls to really narrow down possible mechanism of action depending on what a researcher has at their disposal. In-vivo tests also help to determine an mg/kg dosage range and possible acute or chronic toxicity, or even an LD-50. Only after it has been presumed nontoxic and its likely activities have been characterized should one even consider human testing. This must also be done in the context of extremely precise doses, titrated upwards from a microgram range, with the subject physically monitored by a healthcare professional. If you want to get really fancy, this can be performed in a double blind test with a placebo.

 

Of course not all those processes or resources are available to every researcher. Those are all long, difficult, expensive processes that may require specialty equipment, facilities, and faculty. Many researchers of psychoactive compounds have opted to skip some or most or all of those steps, and prohibition absolutely makes obtaining any of those resources extremely difficult. I would recommend approaching with maximum caution, but I’m also not the boss of anyone and can’t make anyone do anything, and understand how the spirit of curiosity can sometimes overcome a lack of available resources. Ideally a team of researchers could easily have infrastructure to efficiently run multiple compounds through that gauntlet of safety determinations. But this world is less than ideal. Please just for the love of god, be safe, be smart, be responsible.”

Here’s a handy flowchart to assist you!

For an enlarged version of this image: https://i.imgur.com/3v6qKnx.png

For a download of a pdf of this chart: https://gofile.io/d/h05j2m

 

What are the exact details of the SAR of this class of compounds and why did I include what I did? Let’s get into it.

Working our way down from the top of the molecule-

 

Starting with the amine: In the dioxolanes that have seen in vivo usage, this is a 2-piperidine. One attempt was made however, to replace this with a simple primary amine on an ethylamine chain extending from the dioxolane. In this case, a trans analogue of etoxadrol with an ethylamine was one of the only compounds to show any activity, and it was much less than that of base etoxadrol [1]. Even more promising was the 2S, 4R enantiomer of this same compound, which saw increased potency, though not quite as much as etoxadrol [1]. This has broader implications for potentially attempting other amines beyond the standard 2-piperidine. It appears there needs to be at least 2 carbons between the dioxolane ring and the nitrogen to conserve activity- necessitating an ethylamine. While the primary ethylamine has been demonstrated to be active in vitro, a secondary ethylamine (as seen in the standard piperidine ring) may also be active, yielding an immense variety of potentially active variations. Beyond that, a tertiary amine appears inactive [6].  A Pyrollidine instead of a piperidine has also been attempted but was found to be inactive [6]. So it all seems quite fickle and hard to predict.

Working with a piperidine however, many other little tidbits are known. For one, the nitrogen must remain as a secondary amine- as mentioned above, adding substitutions to turn it into a tertiary amine greatly decreases activity [6]. Secondly, NMDAr antagonist effects are conserved (and potency either retained or increased!) with very specific substitutions on the 4 position of the piperidine ring. It seems to be fickle for which substitutions it’ll accept however. So far it has been demonstrated that a Dexoxadrol substituted with a 4-Fluorine on the piperidine is even more potent in vitro than Dexoxadrol alone [3]. A Difluoro substitution also appeared sufficiently active [3]. A Hydroxy group is also tolerated [2]. The 4-fluoro and 4-Hydroxy analogues of Dexoxadrol have been named WMS-2539 and WMS-2508 respectively. Meanwhile, a double bonded oxygen, forming a 4-piperidone, is hardly active, as is a 4-methoxy group, as is any kind of 4-amino group [5] [2]. This makes it hard to guess what can and cannot be placed there (for me at least). Perhaps other halogens would work, either in mono- or di- form. Perhaps a methyl group though it seems unlikely that anything extending beyond that would remain active, ass activity on those substitutions is hypothesized to be correlated with bulk be (by my conjecture) that a substitution larger than ~30 u will not be tolerated (though multiple substitutions can still be affixed to the same spot, even if they cumulatively have a mass greater than 30 u!). The amino substitution has less bulk than that- but perhaps there is something in the unique properties of the nitrogen that precludes activity. As for substitutions on other parts of the piperidine ring? They haven’t been attempted and so far no one knows how they might behave.

Next we move on to the next component- the eponymous Dioxolane ring. Several studies attempted to expand the dioxolane ring to a 6-member Dioxane ring. It was apparent that this greatly decreased activity in most circumstances [1] [6] [5]. The Dioxolane ring is important.

There is of course always an exception- if the piperidine ring is replaced with an ethylamine with a primary amine at the end, then NMDAr antagonist activity is yet again retained. This suggests an entirely new class of compound closely related to the dioxolanes called the dioxanes- a 6 member 2-oxygen ring (as a 1,3-dioxane) with an ethylamine chain instead of a piperidine [5].

Structure of a hypothetical 1,3-dioxane based compound with a primary amine

So now we move onto the next options at our disposal- an aromatic ring and some other functional group bonded to the same quaternary carbon on the dioxolane ring. Etoxadrol sees that functional group as an ethyl, while dexoxadrol sees a second phenyl ring. In all drugs that have been attempted in vivo, the aromatic rings were phenyl rings. However, one example that showed NMDAr antagonist activity in vitro and equivalent or slightly less potency to etoxadrol was an analogue of etoxadrol with the phenyl ring replaced with a thiophene, just as the thiophene would differentiate TCP from PCP. The 2-Thiophene showed less potency than the 3-Thiophene [6]. So in any variation of a dioxolane, it is feasible to replace the lower phenyl ring with at the very least a thiophene, if not other aromatic rings. As activity can be conserved with two aromatic rings bonded to the same spot, different aromatic rings could even be mixed and matched if it was synthetically feasible. The bottom line however is that there must be at least one aromatic ring. As for the other spot on that carbon?

The golden standard has been a simple ethyl group. One study demonstrated in vitro that other alkane chains, from a propyl to a butyl, also conserved an appreciable amount of activity [5]. The most potent compounds had the phenyl ring matched with either a propyl or isopropyl group [5]. It is unknown what else may be possible: Halogenated groups, ethers and thioalkanes, esters, other aromatic rings, various heterocycles- there’s nothing that indicates to me that these wouldn’t be possible!

The last option for modification is adding substitutions to the aromatic ring (in this case, and rather by default, a phenyl ring). 2-Cl, 3-Cl, 2-F, 3-F, 3-OH, 2-OH substitutions retained an appreciable level of activity [5] [6]. Activity doesn’t seem consistent across position no matter the class of substitution-the hydroxy substitution (already fairly impotent), sees an even further drop in activity on the 3-position, as does a Fluorine substitution (though they still show an appreciable level of activity, the drop in potency is still remarkable!) [5] [6]. Substitutions on the 4 position were consistently inactive [5]. This suggests that the main suite of substitutions seen on dissociatives will conserve activity if on the 2 and/or 3 position variably, one way or another. Perhaps the usual alkanes, and alkoxy groups could also retain activity there. The most off-the-wall substitution that saw retained activity was working a diphenylazepine (that is 2 phenyl groups on an aromatic 7 member ring) onto the R1 and R2 positions [6]. 

As far as stereochemistry is concerned, it appears that only the (+)-enantiomer of any enantiomeric compound is active as an NMDA antagonist. Racemic mixtures will see the potency cut in half and the (-)-enantiomer has so far been demonstrated as inactive [4].

 

As for nomenclature? No logical patterns have been established- the 2 named compounds (Etoxadrol and Dexoxadrol). have an informal naming structure, with one of them, Dexoxadrol indicating that it is merely the dextro-isomer of the parent compound, Dioxoadrol. The names give little indication of structure, beyond the mention of an ethyl group in Etoxadrol. Thus for compounds developed further, a new nomenclatural scheme will have to be developed.

The name can be prefixed with the relevant substitutions that have been added to the molecule. The suffix -oxadrol, can be kept, and if a piperidine as the amine is assumed to be the “default”, then modifications of the amine can be worked into this name. So if there’s an N-propyl tertiary amine, for example, the compound would bare the suffix of “N-propyloxadrol”. The two moieties on R1 and R2 can then be worked into the name. The name of the R1 aromatic ring should always come second. Thus, Etoxadrol would in this schematic be renamed to Etphenyloxadrol. Dexoxadrol would be Diphenyloxadrol. If for example, a methoxy group or a chlorine was paired with say, a thiophene, the names would respectively be Methoxythiophenyloxadrol or Chorothiophenyloxadrol. If you were to pair these with, for the sake of example, a sec­-butyl secondary amine, they would yield the unwieldly names Methoxythiophenyl-N-sec-butyloxadrol or Chlorothiophenyl-N-sec-butyloxadrol respectively.  If an oxane ring is used instead of a dioxalane, the suffix can be modified from -oxadrol to -oxanadrol.

 

Sources and Further Reading:

[1]- Aepkers M, Wünsch B (2005) Structure-affinity relationship studies of non-competitive NMDA receptor antagonists derived from dexoxadrol and etoxadrol. Bioorg Med Chem. 13(24):6836-49.

[2]-Banerjee A, Fröhlich R, Schepmanna D, Wünsch B (2010) Synthesis and NMDA receptor affinity of dexoxadrol analogues with modifications in position 4 of the piperidine ring. Med. Chem. Commun. 1:87-102

[3]-Banerjee A, Schepmann D, Köhler J, Würthwein E-U, Wünsch B, (2010) Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists. Bioorganic & Medicinal Chemistry 18(22):7855-7867

[4]- Jacobson AE, Harrison EA, Mattson MV, Rafferty MF, Rice KC, Woods JH, Winger G, Solomon RE, Lessor RA, Silverton JV (1987) Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties. Journal of Pharmacology and Experimental Therapeutics 243(1):110-117

[5]- Sax M, Fröhlich R. Schepmann D, Wünsch B (2008) Synthesis and NMDA Receptor Affinity of Ring and Side Chain Homologues of Dexoxadrol. European Journal of Organic Chemistry: 6015-6028

[6]- Thurkauf A, Mattson MV, Richardson S, Mirsadeghi S, Ornstein PL, Harrison EA Jr, Rice KC, Jacobson AE, Monn JA (1992) Analogues of the dioxolanes dexoxadrol and etoxadrol as potential phencyclidine-like agents. Synthesis and structure-activity relationships. J Med Chem. 35(8):1323-9

[7] -Wilson RD, Traber DL, Barratt E, Creson DL, Schmitt RC, Allen CR (1970) Evaluation of CL-1848C: a new dissociative anesthetic in normal human volunteers. Anesth Analg. 49(2):236‐241.