Obscure and Unknown: Antibiotic Hallucinations

*WARNING* I'm forgoing the usual disclaimer again. The effects on humans have by now been well documented. My justification for inclusion in this series is in the body of the text. Under NO circumstances should you attempt to take these drugs to intentionally induce hallucinations. The experience is considered a form of neurotoxic psychosis. Furthermore, taking antibiotics when not prescribed can cause LASTING DAMAGE TO YOUR IMMUNE SYSTEM.

The title says it all- Antibiotics? Antibiotics are hallucinogens? I've taken antibiotics and I haven't tripped!
It is well established but little discussed that many antibiotics are capable of, in rare instances, causing a set of side effects known "Antibiotic Associated Encephalopathy" which are clinically defined as a form of neurotoxicity. A subset of Antibiotic Associated Encephalopathies are described as "Type II" or "Psychotic", according to a classification scheme offered in Bhattacharyya et al. 20161. This cluster of presents from only a few specific classes of antibiotics, which will be detailed here.
In the footnotes of my post on Mefloquine I lay out that Hallucinogen (capital H) refers to the traditional trifecta of Psychedelics-Dissociatives-Deliriants, substances that at the right dose, will consistently induce hallucinatory effects. There is the much broader term "hallucinogen" (little h) which refers to the much broader spectrum of drugs that will incidentally induce hallucinations in some cases, such as cannabinoids, alcohol, regular stimulants, or the antibiotics discussed here.

Perhaps most interesting about antibiotic induced hallucinations is that each class of drug or each specific substance seems to yield a specific image in each of their hallucinations- such as insects, worms, or helicopters. It should be noted that the visual hallucinations are almost always accompanied with a state of acute psychosis and delusional paranoia.

Several different classes of Antibiotic have been documented to cause hallucinations in some patients. Though these effects are not seen in the vast majority of patients treated with antibiotics (as they are among of the most prescribed used drugs in the world), they have a higher incidence in patients with risk factors such as being elderly, being a young child, having history of CNS damage, or having a history of kidney problems2. Overall, psychotic symptoms present in about anywhere from .9-11% (varying depending on substance) of antibiotics patients. Thankfully, in almost all cases psychotic side effects subside with cessation of the medication.

I would like to reiterate- these PSYCHOTIC effects present as a subset of clinically defined neurotoxicity- that is damage to the nervous system. This is not anything anyone should intentionally induce under ANY circumstances. The experience is a distressing delirious psychosis of which hallucinations are only one component. Furthermore, due to the low incidence of hallucinatory side effects (coupled with the fact that most incidences occurred in those with risk factors) it is likely that you cannot predict the effects well enough to reliably induce hallucinations, though you would likely rack up other negative side effects in doing so. Lastly and most importantly, taking antibiotics when not prescribed is EXTREMELY UNADVISED as any medical professional can tell you and can cause PERMANENT IMMUNE SYSTEM DAMAGE.

The different types of antibiotics that will be detailed here are Fluorouinolines, Carbapenems, Cephalosporins, Macrolides, Sulfonamides, and Penecillins.

Fluoroquinolones

A variety of Fluoroquinolone antibiotics (I was too lazy to draw my own molecules this time)

You may remember the Quinolines from my article on Mefloquine. You may also be familiar with quinolines for being in the news a lot lately, name Chloroquine and Hydroxychloroquine (HCQ), touted as dubious cures for COVID-19. Quinoline is a base for a diverse array of substances- Mefloquine, Chloroquine, and HCQ all fit under the umbrella of antimalarial quinolines. Quinoline derivatives that contain a Fluorine in the structure along with a 4-ketone are referred to as Fluoroquinolones, a scaffold that serves as the basis for some of the most widely used antibiotics today. They include Ciprofloxacin, probably the most widely used antibiotic. The Fluoroquinolones are also probably the group in which hallucinatory side effects are most commonly seen.

Hypotheses for the method of action of Fluoroquinolones antibiotic induced neurotoxicity include GABA receptor inhibition and NMDA receptor agonism, though it is still not fully understood. It is also suspected that it weakens the blood-brain barrier in a way that may increase sensitivity to other medicines in a way that causes neurotoxicity1.

Specific Fluoroquinolones cited for psychotic side effects are Ciprofloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Grepafloxacin, Trovifloxacin, and Moxifloxacin2.

Let's look at some specific case studies.

Ciprofloxacin

Ciprofloxacin

Ciprofloxacin (Cipro) is indicated for a wide range of bacterial infections for many different organ systems. It is one of the most commonly prescribed antibiotics and is cheap and readily available around the world. So its fairly surprising to learn something used so widely can cause hallucinations. Those effects are nonetheless very rare.
One case report cites an otherwise healthy 27 year old woman who presented with an eye infection. She was prescribed Ciprofloxacin eye drops3. She was prescribed 1 drop in each eye once an hour. 30 minutes after her third dose, she reported "well defined visual hallucinations" and "poorly defined auditory hallucinations", reminiscent of the creepy indistinct mumbling of Mefloquine. The exact nature of the visual hallucinations is not described. These symptoms subsided 24 hours after she stopped treatment.
This case report mentioned young women as being vulnerable to these psychotic side effects. One interesting component is that she could clearly remember all of the hallucinations, which is unlike the amnesiac delirium induced by drugs like anticholinergics or even other quinolines like Mefloquine.

Ofloxacin (Levofloxacin)

The (-) Isomer of Ofloxacin, Levofloxacin

Ofloxacin is also indicated for a wide variety of bacterial infections. It is a racemic mixture of it's two stereoisomers, Levofloxacin (-) and Dextrofloxacin (+). Oftentimes, only the (-) isomer is used as a medication. As there are multiple reports of Levofloxacin inducing hallucinogens and none of Dextrofloxacin doing so, it can be assumed that the Levofloxacin isomer is wholly responsible for the hallucinations in racemic Ofloxacin.

It is one of the quinoline antibiotics most commonly cited in inducing psychotic hallucinatory side effects, though the vast majority of these cases only present in young children around the age of 4 or 5.There exist several case reports about Ofloxacin-induced psychosis.

The first case report presented in a 4 year old girl. She was prescribed 100 mg of Ofloxacin orally twice a day to treat gastroenteritis. She soon complained of:

"snakes in her room and felt ants crawling up her arms which she brushed off. She commented that her father had a helicopter in his hand and was putting it in a bag. She reported that strangers were standing in the room and looking at her"4

These extremely distressing effects were found to be a result of the girl inadvertently being given 800 mg of Ofloxacin, an adult sized dose by any measure. Psychotic symptoms subsided after 72 hours.

Another case study of a 5 year old girl being treated with 50 mg twice daily of Ofloxacin presented:

"the child woke up screaming, telling that she could see large ants crawling all over the bed and in the room. She also alleged that she could see a scooter and helicopter flying in the room with bright headlights"5

This also subsided with time, and this patient could also clearly remember the course of her hallucinations.
One last case with a 6 year old boy being treated with 400 mg a day for 3 days saw:

"insects crawling all over the walls. His mother woke up and turned on the lights to find that there were none. He also complained of hearing voices which were not audible to others of a group of people who weren’t in the room. He also felt insects crawling all over his body. He also reported seeing a ghost sitting on his 10 months old sister"6

The (-) isomer, Levofloxacin, when used alone seems to only affect elderly patients. A 52 year old woman reported "seeing people who are not there"7, A 79 year old woman "became confused, irritable, and disoriented to time, place, and person. She had optic and acoustic hallucinations"8, and 50 year old man "experienced visual hallucinations of people in his hospital room. Gradually his confusion worsened and he became more violent in nature."9. A younger patient, 19 years old, reported exclusively tactile hallucinations "a feeling of insects crawling over his face, chest, and upper limbs with itching."10 All of these patients saw symptoms subside with cessation.

Something interesting about the Ofloxacin hallucinations is the common themes seen throughout- specifically patients describing seeing or feeling insects crawling on them and oddly enough, seeing helicopters. Hallucinated insects or spiders are commonly reported with anticholinergic deliriants like DPH or Scopolamine. This is interesting as Quinolines are not known to have anticholinergic activity. This may suggest that multiple receptor pathways are able to induce a similar delirious state.

Carbapenems

The generalized structure of a Carbapenem

Carbapenems are antibiotics typically reserved for treatment resistant bacterial infections. They are classified as β-lactams, a family of antibiotics defined by their binding to the penicilin sites on bacteria, destroying their cell walls.
The neurotoxic effects of Carbapenems are most commonly unerstood as an epilepsy-like encephalopathy. Psychotic symptoms and hallucinations only present in a fraction of the few cases in which neurotoxic effects are seen. This is likely also a result of GABA inhibition/NMDA agonism1.
The specific substance cited for hallucinations in this family is Ertapenem.

Ertapenem

Ertapenem

Ertapenem (Invanz) is prescribed for a variety of bacterial infections. While multiple case studies vaguely cite hallucinations as a component of Ertapenem induced psychosis, such as one with 1g daily dosage11. One other case study however features more vivid descriptions of the experience. In this case, the patient was a 58 year old man, who described:

"On multiple occasions, the presence of his close friends was perceived as real and he engaged in sensible conversation, only to notice their actual absence after a brief period of time. Others episodes included seeing text messages on his switched-off cell phone, and pouring tea into an absent cup, again, noted by the patient shortly afterwards. These were also well noted by family members and were initially thought to be generalised “confusions”, to the degree that the patient was constantly unsure if he was hallucinating or not. He was not delusional, remained conscious throughout and recalled these episodes in vivid detail as real events, which caused significant distress to him and the family."12

The symptoms typically presented about 4 hours after a dose of Ertapenem, and per usual symptoms went away after discontinuation. It was observed that they returned when doctors attempted to put him on a lower dose of the drug.

Cephalosporins

Generalized structure of a Cephalosporin

Cephalosporins are another class of  β-lactams antibiotics that have a similar mechanism of action to penicillin. They are derived from the fungus genus Acremonium, formerly called Cephalosporium, from which they get their name. Oddly enough, the fungus and resulting compounds were first discovered in a sewage outfall in a harbor- not the type of place you'd expect a livesaving antibiotic to come from. They are indicated to treat a few specific species of bacteria vulnerable to this type of compound. Cephalosporin neurotoxicity typically presents as seizures, though in rare cases, psychotic hallucinatory delirium can occur13. They present most frequently in patients with decreased kidney function. 

The specific Cephalosporins resposible for hallucinations are not well documented. An article about medication induced delirium cites cephalosporins as frequently being associated with antibiotic hallucinations but it doesn't clarify past that14. In fact my impetus for writing this entire article was someone in a group chat giving an anecdotal report of experiencing hallucinations from Cefdinir as a child, though I could find nothing on it in the literature.

Cefdinir

Macrolides

Various Macrolide Antibiotics

Macrolides are molecules based on a very large ring, with 14-16 members, to which 2 sugars are attached. They are used to treat respiratory and soft tissue infections (one of which, Azithromycin, has also been dubiously reported by certain demographics to be a component of a "miracle cure" cocktail of drugs for COVID 19). The mechanism of action for Macrolide neurotoxicity is suspected to be downregulation of CYP3A4, typically as a result of the chemical not being properly filtered by the kidneys. This may lead to a buildup of the unmetabolized drug, which may in turn cause psychotic effects through some unknown mechanism15. This is still not wholly understood and is for now, mostly conjecture.
Psychotic effects are primarily seen in Clarithromycin, and in extremely rare cases, Erythromycin15.

Clarithromycin

Clarithromycin (Drawn slightly differently from above)

Clarithromycin is another essential medicine used for a variety of serious bacterial infections. The delirious hallucinations that present as in Clarithromycin psychosis seem to share a common element of involving swarms of worms. In one case study, a 71 one year old woman taking 500 mg of Clarithromycin reported, on the 16th day of her dosage regimen, "seeing worms over her body and in her surrounding environment".15 Another 49 year old male patient also reported hallucinating worms13. As in previous cases, this subsided with the cessation of the medication

Sulfonamides

Sulfonamide

The Sulfonamide is a very basic functional group that is featured in the structure of a wide variety of drugs with a wide variety of uses. They are often broadly referred to as Sulfa drugs. The first ones developed were antibacterial antibiotics however. Sulfonamides are not prescribed as frequently as other antibiotics due to a relatively high incidence of allergies or side effects. Psychotic side effects are very are and have only been seen in one medication- a combination of Trimethoprim and Sulfamethoxazole (TMP-SMZ). The mechanism for how this medication induces psychosis is still unknown. One hypothesis suggests that it's connected to how the drugs inhibit metabolism of folic acid16.

Trimethoprim-Sulfamethoxazole

Trimethoprim (top) and Sulfamethoxazole (bottom)

Trimethoprim-Sulfamethoxazole (TMP-SMZ) is a combination antibiotic prescribed for a variety of bacterial infections. Both drugs are very rarely prescribed on their own, as they are both known to work best in the presence of the other. In this combination, Sulfaethoxazole is the sulfonamide likely responsible for the psychiatric side effects, though it isn't prescribed on its own frequently enough to determine whether it bears the sole responsibility for that. TMP-SMZ is notorious for its psychotic effects, both in their acuteness and frequency. One study found that 11.9% of HIV patients being treated with TMP-SMZ for pneumonia had psychotic side effects17.
A 74 year old woman being treated with TMP-SMZ (160 mg/80 mg) twice daily began to wander from her room, and within 3 days she reported:

" seeing artificial snow outside her window, felt that the hospital was falling apart, and described seeing plaster falling off the walls."18

In another stranger case, an alarmingly young 19 year old woman with a history of spina bifida was found:

"staring at the wall of her hospital room and shouting inappropriate words while seeming to follow imaginary objects on the wall with her eyes."19

Perhaps the most alarming case report however, was an 18 year old male who had attempted suicide with a gunshot to the face. This was after beginning a regiment of TMP-SMZ for an infection.

"On the day of admission, the patient “saw” his deceased paternal uncle, himself a victim of suicide. The vision audibly reassured him, “It is okay to shoot yourself.” Shortly afterward"16

This last case particularly highlights the massive dangers in medications with psychotic side effects. Psychosis can push people into paranoid delusional states where they harm themselves or others. This is further exacerbated if it occurs alongside already existing mental illnesses.
As with all other antibiotics, symptoms subdsided with the cessation of the medication.

Penicillins

Generalized structure of a Penicillin

Penicillin is well known as one of the first and most widely used antibiotics to be developed, derived from the Penecillium food molds. Because of its widespread use, many bacteria have developed resistance to it, and it has a relatively high incidence of allergies, thus a whole plethora of other antibiotics, including Penicillin analogues, have been developed since.
Psychotic side effects in Penecillins have a range of causes. In Penicillin G Procaine, the psychosis inducing agent is most likely the procaine, due to its pharmacological similarity to Cocaine, and may be akin to a sort of stimulant psychosis (minus the contribution of sleep deprivation)1. As Penicillins are classified as β-lactams, the other psychiatric effects they have can be attributed to the same method of action as the Carbapenems and Cephalosporins. We will look specifically at Penicillin G Procaine, and Amoxycillin. Ampicillin is also cited to produce hallucinations though there were few case studies on it.

Penicillin G Procaine

Penicillin G Procaine

Penicillin G Procaine is another combination antibiotic. Penicillin G Procaine is an injectable drug combined with procaine (also known as novocaine), a local anesthetic, as penicillin can cause pain at the site of injection.
As mentioned before, Penicillin on its own doesn't present with Psychotic side effects. However, the Penicillin G Procaine cocktail is well established as doing so- so established in fact that the effect is referred to as "Hoigne's Syndrome". In one case study, a 3 year old girl receiving injections reported:

" bugs on her arms and snakes in the room. She attempted to remove bugs from her body. These hallucinations continued, with several brief interludes, all night"20

This closely matches the hallucinations seen in all of the other antibiotics. It's curious that animals humans seem to viscerally fear like snakes and insects and spiders seem to present so commonly in these delirious states. In another case, a 49 year old male reported:

" that the normal sounds in the emergency room became amplified with a reverberating quality, and he had a strong feeling of impending doom. He thought a male nurse wore facial make-up and had paper-mach6-like skin on his arms. Inspection of his own arms revealed that they too had an artificial-appearing texture. Visual illusions and hallucinations stopped within twenty minutes of onset. He then thought the staff were alien beings involved in a conspiracy to use him for organ transplants and drug trials."21

This case study details the extensiveness of psychotic effects and how acutely they can affect every part of the patient's existence. It is worth remembering that psychotic antibiotic effects aren't only hallucinations, but full-blown paranoia and delusions.

Amoxicillin

Amoxicillin

Amoxicillin is another multi-use antibiotic that is very widely prescribed. It has the same mechanism of action as other penicillins. What is interesting about amoxicillin is that it induces hallucinatory side effects independent of an additive like Procaine. This suggests that Penicillin may still be in part responsible for the hallucinatory effects of that combination courtesy of its action as a β-lactam. Unfortunately, most of the case reports on Amoxicillin induced psychosis are inacessible, even through sci-hub.
A case study worksheet presenting a hypothetical situation however, summarizes them, with patients aged 30-63 demonstrating tactile, auditory, and visual hallucinations and agitation. 22





Antibiotic induced psychotic hallucinations are no picnic, they are not any sort of recreational hallucinatory experience and don't occur frequently enough to even be considered for that role. Rather, they are a form of neurotoxicity that must be considered in clinical settings. In almost all case studies, doctors attempted to treat the psychotic symptoms with antipsychotics, with little effect. The psychotic symptoms always eventually subsided with cessation of the offending antibiotic.

Sources and Further Reading:
1-Bhattacharyya S, Darby RR, Raibagkar P, Castro LNG, Berkowitz AL (2016) Antibiotic-associated encephalopathy. Neurology 86(10)
2-Grill MF, Maganti RK (2011) Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol. 72(3):381‐393
3-Tripathi A, Chen SI, O'Sullivan S (2002) Acute Psychosis Following the Use of Topical Ciprofloxacin. Arch Ophthalmol. 120(5):665-666
4-Bhattacharya, A, Sharan R., Praharaj SK (2017). High Dose Ofloxacin-induced Bimodal Hallucinations in a 4 Years Old Child. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 15(4)
5-Bisht M, Kumar A (2019) Ofloxacin Induced Visual Hallucinations in Pediatric Patient. Ann Pharmacol Pharm. 2(11): 1062
6-Desousa A, Chaudhari P, Karia S, Nilesh S (2019) Ofloxacin induced hallucinations in a 6 years old child: A case report. Telangana Journal of Psychiatry 5: 64-65. 
7-Raffaelli V, Cantoni G, Nucera1 G, Marino P (2018) Levofloxacin-induced visual hallucinations: A case report and review of the literature. Journal of Health and Social Sciences 3(1):85-89
8-Kogan Y, Elias N, Paz A, Odeh M (2018) Acute Delirium Associated With Levofloxacin. Journal of clinical medicine research 10(9):725–727
9-Moorthy N, Raghavendra N, Venkatarathnamma PN (2008) Levofloxacin-induced acute psychosis. Indian journal of psychiatry 50(1):57–58
10-Maharani B, Jafrin AL, Bai, KV, Sivagnanam G. (2019) Levofloxacin-induced tactile hallucination and acute anxiety reaction. Indian journal of pharmacology 51(2):123–125
11-Sutton SS, Jumper M, Cook S, Edun B, Wyatt MD. (2017) Ertapenem-Induced Encephalopathy in a Patient With Normal Renal Function. J Investig Med High Impact Case Re. 5(1)
12-Kong V, Beckert L, Awunor-Renner C (2009). A case of beta lactam-induced visual hallucination. The New Zealand medical journal 122: 76-77. 
13-Mattappalil A, Mergenhagen KA. (2014) Neurotoxicity with antimicrobials in the elderly: a review. Clin Ther. 36(11):1489‐1511
14-https://www.aao.org/eyenet/article/medication-related-visual-hallucinations-what-you-
15-Ma TK, Chow KM, Choy AS, Kwan BC, Szeto CC, Li PK (2014) Clinical manifestation of macrolide antibiotic toxicity in CKD and dialysis patients. Clinical kidney journal 7(6): 507–512
16-Parashar S, Roy N, Osuagwu FC, Khalid Z, Tinklepaugh M, Mehr S, Dillon JE (2016). Trimethoprim-Sulfamethoxazole-Induced Psychosis Culminating in Catastrophic Self-Injury: A Case Report. The primary care companion for CNS disorders 18(1)
17-https://www.uspharmacist.com/article/nonpsychotropic-medicationinduced-psychosis
18-Gregor JC, Zilli CA, Gotlib IH (1993) Acute psychosis associated with oral trimethoprim-sulfamethoxazole therapy. Can J Psychiatry 38(1):56‐58
19-Saidinejad M, Ewald MB, Shannon MW (2005) Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 115(6)
20-Robertson Jr. CR (1985) Hallucinations After Penicillin Injection. m J Dis Child.139(11):1074
21-Cummings JL, Barritt CF, Horan M (1986) Delusions induced by procaine penicillin: case report and review of the syndrome. Int J Psychiatry Med. 16(2):163‐168
22-Murphy MB, Alcera LC, Gill JK, Dunn J (2008) The Inexplicably Suicidal Patient. Current Psychiatry 7(11):73-82

Obscure and Unknown: Dioxolane dissociatives

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

For today's entry of obscure and unknown we will be looking at an entire family of well established hallucinatory dissociatives, once tested for their potential for anesthesia. These drugs are well documented for their hallucinatory effects, though they were all aborted early in their development and only appeared in receptor assays after limited human trials were abandoned. Their fate was sealed for their propensity to give patients "nightmares", a term that was misused when in actuality, subjects experienced vivid closed-eyed hallucinatory episodes. Drawn out anesthesia and rare psychotic effects also spelled death for these compounds, as this was probably reminiscent of the trials and tribulations of testing PCP as an anesthetic. These are the Dioxolanes, namely Etoxadrol, Dexoxadrol, WMS-2539, and WMS-2508. 

The generalized structure of a Dioxolane dissociative

The Dioxolane name refers to the basis of these structures, the Dioxolane molecule, a 5-member ring with 3 Carbons and 2 Oxygens on the 1 and 3 positions (In the diagram above its the ring in the center that looks like it has a little ovo face goin on. Kinda looks like the face of a little bug or somethin). It is worth noting that Dioxolane refers to a much broader chemical family derived from this simple molecule and the vast vast majority of Dioxolanes are not psychoactive. The four known to be dissociatives have a common structure, with a piperidine on the 2 position of the Dioxolane ring and a phenyl ring attached to the 5 position. They vary in having another group attached to the 5 position, and two have a substitution on the piperidine ring. It is unknown if the Dioxolane group retains its dissociative effects with other substitutions at either the 2 or 5 position, or if the entire Piperidine-Dioxolane-Phenyl structure must be retained to conserve those effects.
As of now the pharmacophore (active constituent) of NMDA antagonists is not fully understood, though several structural activity relation studies have attempted to determine where Dioxolanes fit into this picture1,2.

So just what are these substances like? Let's delve into their variations, starting with the most well studied Dioxolane in humans, Etoxadrol.

Etoxadrol

Etoxadrol

Etoxadrol is a very simple iteration of the basic Dioxolane dissociative structure, with the substitution position being occupied by a simple ethyl group.
This is the one Dioxolanes to carry the distinction of having human trials. It was investigated as a potential novel anesthetic in the early 1970's, in a similar development trajectory as better known dissociatives like ketamine and PCP. Indeed, initial trials in primates showed a very similar physiological profile to ketamine, with about double the potency and a greater duration3.

It was also initially tested on humans around the same time in a set of volunteers. Volunteers were found by word of mouth (Imagine you're at the university of Texas in 1970 and a friend asks if you want to volunteer for a medical study and you find yourself dosed with a brand new dissociative.... if only....)
A .75 mg/kg IV dose produced profound full anesthesia for an 1-1.5 hours. Open eyed hallucinations were not observed in post recovery, though subjects observed a "dream state" while anesthetized4.

"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 symptom4"

Sounds familiar?
So this would likely mean Etoxadrol doses at about 30 mg intravenously for desired effects. It is unknown what other ROA's are active, though recreational doses of ketamine IV are around 50 mg, so it can be expected that Etoxadrol would likely also see a 1/2 drop in potency in other ROA's, yielding perhaps a 50-60 mg insufflated dose, if that ROA is safe and active. Oral doses would probably be higher than that.
One volunteer however, found the experience frightening, and a had a prolonged panic reaction.

So etoxadrol is definitely interesting- why have we never seen it?
Another human study elucidated some of the "side effects" of this drug. This study saw patients experience a lasting anesthetic afterglow which some complained about. Patients were difficult to communicate with, offering one word answers5.
Most importantly though, a whopping 20% of patients in this study reported "adverse or threatening dreams", a new and funny way to say "nightmare". These nightmares commonly featured memories from the patient's lives. I find it odd that their full sleep cycles were being tracked after the study, but a later statement elucidates what is really going on-

"Such mental aberrations frequently persisted up to 18 to 24 hours. However, they were voluntarily controlled by most of the patients and could be reinstituted if the patient closed his eyes."

So this isn't a sleeping nightmare, but rather an awakened closed-eyed hallucinatory state, the sort that may be familiar to those who have delved deep into dissociatives. I believe that they simply didn't have the terminology to describe it or recognize it as such back then and simply labeled them as "dreams". It is interesting that the imagery invoked in this state however, had such vivid and coherent connection to the patient's memories. It certainly sounds like an interesting experience! (Except for one patient,  "who had inadvertently been given 4.65 mg/kg) this effect lasted for 6 days." oops.)
 Half of the patients reporting these "nightmares" also reported a psychotic state where they found their thoughts and actions difficult to control. All these symptoms considered, this sounds like a powerful dissociative similar that invokes vivid closed eyed hallucinations at high doses.

Etoxadrol isn't seen because studies were halted after this trial, citing concerns about the "nightmare" effects. It seems like a very similar side effect profile to PCP, which had gained widespread use before those effects had it struck from medical practice. By then it had built enough reputation to develop as a street drug. This likely wasn't seen in Etoxadrol because studies were cut off so early into its development, before it had any chance to develop a wider reputation (and this was probably informed by what had happened with PCP). All signs point to this being an interesting and relatively safe recreational substance.

Dexoxadrol

Dexoxadrol

Dexoxadrol is the other well known Dioxalane dissociative. Dexoxadrol is the (+) enantiomer of the generalized molecule Dioxadrol, with the (-) enantiomer being called Levoxadrol. Levoxadrol has been demonstrated as being inactive however6.
Dexoxadrol is probably the most studied and best understood of the Dioxalanes, being thorouhgly studied in vitro and in animal trials, but still having little history of human testing. Thankfully the one human trial is remarkably detailed.

The earliest reports on Dexoxadrol describe it as a psychomimetic anesthetic, both a stimulant and depressant. These reports predate the term "dissociative anesthesia" and the connection between NMDA antagonism and dissociative effects. A 1965 study was the first and only human trials performed on the drug, with subjects being given a 20 mg oral dose. 5/74 subjects reported interesting side effects described as such:

"one complained of feeling “dopey, weak, and helpless”; one complained of light-headedness and numbness and was observed to weep; one complained of light-headedness, itching, of having “no feeling,” being “drunk,” and of “not being here.” Of the other 2 patients, one stated that she felt drunk, and said that she was “not entirely present.” She also said that her “hands had no real feeling” and seemed a bit numb. Four hours after the dose, all that remained was a slight light-headedness.  The final patient was very upset, wept, and tried to get out of bed. She found it difficult or seemed unwilling to explain what was the matter. She said that her upper limbs seemed numb and as if they did not quite belong to her. There was no similar feeling in the lower limbs. She tried to bite her left arm several times as if to convince herself that it really belonged to her.7" 

This all sounds like the constellation of typical effects from dissociative anesthetics, which frankly can be quite distressing in those not expecting them. The authors classified this drug as a psychotomimetic anesthetic for these reasons. This study also mentioned that when tested in animals, it increase their sensitivity to noxious stimuli.

All other studies were done in vitro or in animals. Dexoxadrol was found to elicit the same reaction as PCP in drug discrimination tests with monkeys6. Another study in monkeys studied the rate at which monkeys would self-administer the drug (in addition to Etoxadrol) to determine addictive potential- the reinforcement pattern between PCP, Etoxadrol and Cocaine was very similar, indicating that Etoxadrol triggered pleasurable effects in the monkeys and they sought more. They also repeated dosing of Dexoxadrol, though this was more erratic8. A study in rats noticed that Dexoxadrol increased body temperature9.

So here we see Dexoxadrol as perhaps less euphoric than Etoxadrol, though very similar to both (and PCP). Indeed the subjective effects described by patients for Dexoxadrol seem a tad more distressing, though this was also people with no frame of reference for such experiences in 1965. It seems that 20 mg was a low oral dose as it only triggered hallucinatory effects in a small proportion of subjects. An oral dose that users may find "recreational" would probably be in the range of 30-50 mg orally.
An (extremely) dubious vendor who lists Dexoxadrol on their site meanwhile (not linked), describes it as such:

"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."

That sums it up well it seems, and it would be very interesting to try.

WMS-2539

WMS-2539 was a result of several studies to develop analogues of dexoxadrol. This one is distinguished by having a fluorine on the 4 position of the piperidine ring. This substance has never been tested in humans or animals, but receptor assays have demonstrated that it is at least very potent, with it's potency lying about halfway between MK-801 and Dexoxadrol10. So if you consider a dose of MK-801 ~ 500 ug, then a dose of WMS-2539 may be in the range of 10-15 mg. Though I am not the best at math.

WMS-2508

WMS-2508 is another analogue that was determined to be a powerful NMDA antagonist, with an OH group substituted onto the 4 position Piperidine. This had a Ki value of 44 nm, which was within an active range relative to the compound it was being compared to, MK-801. I cannot speculate on a possible dosage for this one, but the authors found it highly promising and supposedly quite potent11.

Sources and Further Reading:
1-Sax M, Wünsch B (2006) Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity. Curr Top Med Chem. 6(7):723‐732
2-Thurkauf A, Mattson MV, Richardson S, Mirsadeghi S, Ornstein PL, Harrison Jr. EA, 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):1323‐1329.
3-Hidalgo J, Dileo RM, Rikimaru MT, Guzman RJ, Thompson CR (1971) Etoxadrol (CL-1848C) a new dissociative anesthetic: studies in primates and other species. Anesth Analg. 50(2):231‐239.
4-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.
5-Frederickson EL, Longnecker DE, Allen GW. (1976) Clinical investigation of a new intravenous anesthetic--etoxadrol hydrochloride (CL-1848; U-37862A). Anesth Analg. 55(3):335‐339
6-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
7-Lasagna L, Pearson JW (1965) Analgesic and Psychotomimetic properties of Dexoxadrol. Proc Soc Exp Biol Med. 118:352‐354.
8-Brady KT, Woolverton WL, Balster RL (1981) Discriminative Stimulus and Reinforcing Properties of EtoxadroLand Dexoxadrol in Monkeys. Journal of Pharmacology and Experimental Therapeutics 220(1):56-62
9-Pechnick RN, Wong CA, George R, Thurkauf A, Jacobson AE, Rice KC (1989) Comparison of the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Neuropharmacology 28(8):829‐835
10-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
11-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

Obscure and Unknown: Butyl Tryptamines Part 2: NBT, 4-HO-DiBT, 4-HO-DsBT, and the Vast Future

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

I set out to write about the butyl tryptamines, and it ended up making for an extremely long article, so I split it in two. You can read part 1 here. The first entry explores in depth some of the substances mentioned in the writings of Alexander Shulgin. As I mention there, I'm wary to just pick and choose obscure chemicals only mentioned in his seminal works PiHKAL and TiHKAL, as there is nothing I can say about them that he hasn't already said better. His work on butyl tryptamines as a coherent group however, I found worth noting and expanding upon. 

Now we will look at ones mentioned in other literature, before I go on a wild ride of speculating other potential compounds- as it turns out there are many many variations on how you can assemble 4 carbons with all sorts of other tryptamine substitutions. The specific compounds looked at here are NBT, 4-HO-DiBT, and 4-HO-DsBT. These ones have 0 history of human use and all information on them is purely speculative and extrapolated from animal studies. The effects they have in humans simply will never be known for sure until they are tried.
In the last section I also speculate on which potential compounds show the most promise as interesting psychedelics.

As I said in the last part, I am well aware of Shulgin's assessment that "Butyl is futile" as a dismissal of Butyl compounds as simply being so high dosing and lacking in interesting effects that they perhaps are not worth pursuing. While I certainly trust his judgment on that, I decided to still write about them at length because they are still an interesting variation on the theme of tryptamine substitution, lend some interesting observations with respect to structure-activity relations, and prevent a vast field of possibilities for various combinations of substitutions, many of which have never been attempted and may yield unexpected interesting effects.

NBT

NBT

Meet N-Butyltryptamine, or NBT. This was first synthesized in 1964 for Brimblecome et al's study into tryptamine derivatives4. The paper only mentions in passing that NBT has psychotomimetic properties similar to that of NET and DBT, which are both extremely obscure so this is fairly meaningless4. The effects of NET in humans are unknown. N-methyltryptamine is demonstrated to be an odd non-visual psychedelic so NET and this chemical may be similar in that regard (and as mentioned earlier, Shulgin noted odd non-visual and perhaps empathogenic activity in other N-butyl variations). A similar behavioral response in an open field test (where behavior in an empty space is closely observed) was also observed between NBT, NET, DBT, and DiPT4.
The later 1972 study by Leonard and Shallice noted that no behavioral effects were observed at a dose of 10 mg/kg5. It was also observed that NBT decreased the amount of serotonin in the brain5.
These perhaps indicate a substance that is active only at higher doses but may not be entirely fun or enjoyable. The results of the few studies done on it don't paint a definitive picture so its hard to say with certainty either way what the effects of this drug may be in people.

4-HO-DiBT & 4-HO-DsBT

4-HO-DiBT (left) and 4-HO-DsBT (right)

Now we get into some of the variations on the straight chain butyl-tryptamine theme. Both of these compounds are the 4-HO analogues (see last entry on last post for what the 4-HO denotes). Shulgin hypothesizes on the base structures seen here- DiBT he presumes may not be active because of the dense tangle of interfering carbons in the Di-isobutyl structure. He sees more promise in the cleaner and more stable looking DsBT. He notes that 4-HO-DsBT comes in liquid form at room temperature- an oil that didn't crystallize2.

Only one study in history has produced and observed the effects of these compounds other than Shulgin. This was a pharmacological assay done by Mckenna et al. in 1990. This was a simple receptor affinity study done with a number of tryptamines, some familiar some very obscure. In its lineup of obscure analogues was 4-HO-DiBT and 4-HO-DsBT.

This study determined the inhibition constant (IC50) for the compounds on the 5-HT1A, 5-HT2A, and 5-HT2B receptors, 3 of the receptors whose activation is responsible for the constellation of effects in the psychedelic experience. Most important of these for contributing to the psychedelic state is the 5-HT2A receptor. The IC50 is a value that denotes the concentration of a compound required to activate a receptor- the higher the value is, the less potent a substance is likely to be (though this isn't always a direct correlation, there are all sorts of complicating factors). The two compounds of interest, 4-HO-DiBT and 4-HO-DsBT showed an IC50 of 260±60 and 39±10 respectively (on the 5-HT2A receptor). What does this mean? Well when we look at the IC50 of other compounds in this study that are known to be psychedelic, we can paint a larger picture: Psilocin (6.0±.5), 4-HO-MiPT (13±4), 5-MeO-DMT (5±1), and DMT (75±16).

So this tells us that 4-HO-DiBT and 4-HO-DsBT both activate the receptor necessary for a psychedelic experience to a meaningful degree. This tells us that both compounds are much less potent than most other familiar psychedelics and likely require a much higher dose than others. This tells us that Shulgin's prediction based purely on structure- that 4-HO-DiBT would be significantly less potent than 4-HO-DsBT, is correct.

This does NOT tell us with certainty whether these are actually psychedelic when ingested by humans, what the quality of the experience is actually like, what the possible toxicity is, or what the exact dosage or duration may be. Those are simply things that can only be found out with further in-vivo study. The effects in a test tube can only tell us so much.

Vast Possibilities
4 carbons man.... 4 carbons can be arranged in so many different ways the amount of possible iterations is dizzying. Let's take a look at what all is possible. I have drawn most of the possible variations for base tryptamines utilizing the -butyl group in some way. This is just purely based on what substitutions have already been invented and created for tryptamines. There is a near-infinite amount of possibilities.

Now look at all of these 50 compounds and multiply by 3 for the 3 major substitutions possible on the base structure (4-HO, 4-AcO- and 5-MeO), and we get 200 possible compounds. Yikes.
ow.
That's a lot to think about and a lot to speculate on. Too much in my opinion.

Some of these definitely show more promise than others, some can be presumed inactive or even physically impossible to produce. It serves to warn that the next section is purely SPECULATION based on the tidbits of information known about butyl tryptamine and patterns observed with respect to chemical structure and psychoactive effects in other similar familiar compounds. The real effects these will have on people can be roughly predicted, but are impossible to know with certainty until they have been tried (through titration!) by people. There are always surprises and new patterns.
The dibutylated variations are a good place to start.

Dibutylated Tryptamines- the way to go?

The Dibutylated structures serve as a good basis to work from due to ease of production. DBT has been demonstrated to very likely be active (albeit at a high dose), and the 4-HO analogue shows promise. What about the others? As mentioned before, Shulgin speculates on the possible activity of these in his entry for 4-HO-DBT. He saw the most promise in DsBT, as that had the least "tangled" mess of carbons on the nitrogen in the middle. He speculated that the di-isobutyl groups in DiBT would clash together, making it less active, and lastly that DtBT had so much crowding around the nitrogen that it might literally be impossible to make as the atoms would all be bonking into one another. The 4-HO analogues of DiBT and DsBT have been demonstrated to be active (though not very potent) in vitro, though their activity in humans is yet to be seen. A dicyclo- substituted tryptamine in any form has never been attempted, and I am doubtful if such a thing is physically possible from the two tense constrained ringed structures. There can be no conjecture on what effects such a drug would even have as there are absolutely zero existing analogous examples. Thus, DBT, DiBT, and DsBT all show promise as base structures.

The big limiting factor we run into when speculating on compounds is crowding- too many carbons stuffed too close to that active nitrogen renders the compound inactive or simply physically impossible. Most of the -tBT variations are thus, probably unlikely. I am going to arbitrarily guess that the crowding becomes too much for the molecule or the body to handle past having an ethyl group next door. There exists zero information on effects a cyclobutyl group would have in a tryptamine, and it is for now impossible to predict as there are no structural-activity relationships recorded that would even offer hints as to how those might behave- but more likely such molecules would be unstable or exceedingly difficult to produce. If the effects of a cyclobutyl group are to be studied, it should be done with a much simpler substitution on the nitrogen, so I am tossing anything past an ethyl group into the reject pile for now too. Furthermore, it seems that the longer the chains are and the more carbons are involved in the overall formula, the less active and less potent the chemical will be. So the shorter we keep it, the more promising everything is. With this in mind, it's likely that we cannot expect much from the following compounds:

BiBT, BtBT, DiBT, iBiPT, iBsBT, iBtBT, sBiPT, tBsBT, PtBT, DtBT, tBiPT, tBALT, PcBT, BcBT, DcBT, cBiPT, cBiBT, sBcBT, tBcBT, cBALT, and cBcPT.

The (probable) rejects

I'm not saying that these should all be dismissed as inactive or impossible, but they are more likely than not going to be subpar experiences that require extremely high doses and may have a litany of uncomfortable side effects. And some may indeed be physically impossible to make.

Despite the fact that the rule seems to be the less carbons, the more promising the effects, the N-x tryptamines with the lowest amount of carbons out of this series are also fairly lackluster in effects. NBT is questionably active, NsBT may perhaps be interesting as an empathogen, and NtBT was barely active. The activity of NiBT is still unknown. Whether these substances yield interesting substituted analogues is unknown, as substituted N-x-tryptamines have never been made, even with simpler variations like NMT, NET, or NPT (with the exception of 5-MeO-NMT, whose effects in people are still undocumented). Nonetheless, substitutions of N-x-tryptamines should be explored in ones with something simpler than weird butyl groups first.
NsBT or some substituted analogue may be interesting however.


So the next step up from there is likely the most promising, the Methyl-Butylated tryptamines.

friends perhaps?

Shulgin had already demonstrated that MBT was active, albeit in very high doses. To gauge the effects of the other variations, we can look to the tryptamines a step down- the propyl tryptamines. Dipropyltryptamine, DPT, with two straight chains the least potent of the base tryptamines commonly available, dosing into the 100s of mgs. Diisopropyltryptamine, DiPT, meanwhile, has the same amount of carbons but in a much tighter arrangement, and is considerably more potent (with extremely unique auditory effects). So perhaps having a long straight chain involved does something to the potency. Perhaps MiBT, MsBT, and MtBT may be more potent than MBT due to the this effect, but this is just raw speculation and I don't know for sure. But in general, many base tryptamines are less recreational, potent, or interesting than their 4-HO and 4-AcO counterparts, and in the world of butylated tryptamines, I think these substitutions are where they would shine the most. Ethyl substitutions may also prove fruitful. The one standing example of mixing an ethyl group with a higher order of carbon chain is EPT, which has two very interesting and useful analogues in 4-HO-EPT and 4-AcO-EPT. Ethylisopropyltryptamine (EiPT) has also been attempted, and though little information exists on it, the few reports show promise. As mentioned before, the effect of a cyclobutyl group is completely unknown and nearly impossible to predict, so that's a big question mark for now. However, there exists one 4-HO substituted tryptamine that has a cyclopropyl group in its base structure 4-HO-McPT, which is a fairly lackluster and higher dosing psychedelic. I wonder if the extremely tense cyclopropyl group would be hydrolized into an isopropyl, serving as prodrug to 4-HO-MiPT, in which case a cyclobutyl would be hydrolyzed into a sec-butyl group. For now I am leaving McBT and EcBT out of consideration, until any information on such compounds at all is attained.
Nevertheless, based on that, out of all the butylated tryptamines that are possible, I believe the  following compounds may prove the most interesting psychedelics of the bunch:

4-HO-MBT, 4-AcO-MBT, 4-HO-MiBT, 4-AcO-MiBT, 4-HO-MsBT, and 4-AcO-MsBT
and with the ethyl variants,
4-HO-EBT, 4-AcO-EBT, 4-HO-EsBT, and 4-AcO-EsBT.
or if you want to see it illustrated:

The goods

I didn't include 4-HO or 4-AcO analogues of MtBT or EtBT, because the stability and activity of the tert-butyl groups in tryptamines in any context is still almost entirely unknown. The only one to ever have been manufactured and tested was NtBT (which doesn't have another carbon stuck to the nitrogen to worry about) (and which was also found to be brief and lackluster). All of the others have never been manufactured in human history, and of course have never been tested under any circumstance, and the one that was made and tested did not show much promise.
EiBT analogues were also not included for the sake of being thoroughly crowded around the nitrogen.

Also seen as possible substitutions are the various butyl groups combined with an Allyl group and a cyclopropyl group. For both Allyl Tryptamines and Cyclopropyltryptamines, no examples exist of other substitutions beyond a methyl group (namely in the MALT series and the McPT series), so it is entirely unknown what effect paring them with even longer and more complex chains may have. For both examples, the products are considered fairly mild and lackluster, so it follows that building them up with even longer and more complex chains may further reduce interesting effects. But of course it cannot be known or predicted until it is tried.

Of course, the base structures for most of these have never been manufactured in human history or been tested, so their baseline activity is simply not known for now. Some unforseen structural anomaly in one of these benign seeming compounds could end up rendering it and all of its analogues completely inactive. Once again, we don't know until we make it and try.


As the various carbon chains get longer, it can be expected that activity and potency will further decrease, though not to the point where they are rendered totally inactive. They might just prove to not be particularly fun or interesting.

Now looking at the effects of known Butyl tryptamines, one might think "They dose so high and they don't sound particularly exciting. Why bother?" Well, a lot of the compounds explored in this entry are speculation based on structure or animal trials, we really don't know what truly unique effects in humans will arise from these chemicals until we try them. Who could've predicted the unique auditory effects of DiPT just by looking at the molecule? All sorts of idiosyncratic effects could be hiding in this infinite variety, just waiting to be discovered. Furthermore, the low potency seems a curse, but it could perhaps be a blessing- in a world of irresponsible researchers who don't use scales or misuse scales, perhaps it could prove helpful to have high-dosing failsafe psychedelics that have a broad margin of error, where a 20-30 mg discrepancy in dose won't really be noticeable.

It's unlikely that we will ever encounter these however- from a market perspective, there really isn't much payoff. Large amounts of product are needed for the desired effects, meaning it will likely be more expensive for the end user. Production of some, especially the sterically fussy ones that crowd around the nitrogen may be very difficult and complicated, and the products may be fairly unstable or difficult to work with (indeed 4-HO-DsBT is an oily liquid at room temperature)2. And furthermore, the effects may be so lackluster that they don't really have much broad appeal to market beyond their novelty for intrepid psychonauts. I would personally love to see and sample some of these, but perhaps that is just a pipe dream.

Sources and Further Reading:

1-Shulgin A, Shulgin A (1997) DBT. TiHKAL: The Continuation 
2-Shulgin A, Shulgin A (1997) 4-HO-DBT. TiHKAL: The Continuation 
3-Shulgin A, Shulgin A (1997) 4-HO-MBT. TiHKAL: The Continuation 
4-Brimblecombe RW, Downing DF, Green DM, Hunt RR (1964) Some pharmacological effects of a series of tryptamine derivatives. Br J Pharmacol Chemother 23(1): 43–54.
5-Leonard BE, Shallice SA (1972) The effects of some tryptamine derivatives on brain monoamines and their precursor amino acids. Neuropharmacology 11(3):373‐384.
6-Mckenna DJ, Repke DB, Lo L, Peroutka SJ (1990) Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes. Neuropharmacology, 29(3): 193-198

Obscure and Unknown: Butyl Tryptamines Part 1: MBT, DBT, NsBT, NtBT and 4-HO-DBT

*WARNING* The substances mentioned in this series have little to no record of human use, and thus the effects they have on humans are either poorly understood or entirely unknown. Much of what this information is simply hypotheses based on animal trials or very small human sample sizes. Very little information exists about their acute or long-term toxicity. Under no circumstances should any of these substances be ingested by a human outside of a clinical setting where psychological and physiological effects can be closely monitored and extremely precise doses can be prepared and TITRATED. DO NOT seek any of these out if you do not have access to those resources.

Last two entries covered fairly dark areas in the history of drug development and testing. Today we will be looking at much more benign substances with much more benign histories- the butyl tryptamines. This post is very long. I'm splitting it into 2 parts. You can read part 2 here.

The basic tryptamine structure

To those familiar with tryptamines, you may be aware of the base structure of the tryptamine (if you're already familiar you can skip this section)- the indole (This is a phenyl (hexagon) ring connected to a pyrrole (pentagon) ring- if you're unfamiliar with organic chemistry you can just look the terms up it's fairly straightforward!), with an ethylamino (2 carbons and a nitrogen with the corresponding hydrogens filling space, labeled as NH2 on the diagram) attached to the pyrrole. The psychedelic tryptamines are constructed by attaching carbons to that nitrogen out on the end of that ethyl carbon chain. Say you attach 2 methyl (single carbon) groups, then you have DiMethylTryptamine, or DMT. If you remember the progression of carbon groups, it goes Methyl (1), Ethyl (2), Propyl (3) and Butyl (4). And we have seen various transmutations and combinations of most of those extensions on the market, with various other substitutions (Not to mention once you have >3 carbons you can rearrange them so they aren't just straight chain! This can yield Isopropyl groups, which are Y shaped, offering even more variation). Methylethyltryptamine (MET), Diethyltrytamine (DET), Methylpropyltryitamine (MPT), Ethylpropyltryptamine (EPT) and Dipropyltryptamine (DPT) (+ a number of isopropyl variants) have become the basis for a number of popular research chemicals, with new variations on those themes being developed and produced every year. So the logical next step is adding yet another carbon, forming a Butyl group. 

The many ways you can arrange 4 carbons. I don't know why sec-butyl is highlighted, this was the only good picture I could find and I didn't feel like making a diagram myself

This offers us such specimens as Dibutyltryptamine, Methylbutyltryptamine, Ethylbutyltryptamine, Propylbutyltryptamine, and then, oh god butyl groups can also be arranged into isobutyl and sec-butyl and tert-butyl forms (And the not pictured square shaped ring cyclobutyl form), expanding possible combinations by a whole other factor and a whole new mouthful of chemical nomenclature (Can you say Isobutylisopropyltryptamine?)! Yikes. An absurd magnitude of possible permutations aside, what are these chemicals like? Why haven't we seen them for sale anywhere, or seen any interest or curiosity in them? The case for most that have been attempted is lackluster but definitely present activity it seems. I will be looking at some of the variations that have been attempted and forgotten throughout history, along with speculating about some that have never been tried in humans or ever manufactured at all in human history.

Those that have a history of human usage come almost exclusively from the man, the myth, the legend, Alexander Shulgin, as documented in his seminal work TiHKAL (Tryptamines I have Known and Loved). I want to avoid delving too much into substances only explored in his works, because frankly there is nothing I could say on them that he hasn't already said better than I ever could. So I want to use that as a basis to look into some other related substances! The compounds Shulgin produced and tested which I will be looking at for part 1- MBT, DBT, NsBT, NtBT, and 4-HO-DBT. Part 2 of this post will look into the documentation on some other variations- NBT, 4-HO-DiBT, and 4-HO-DsBT, and from there, I will look at the vast field of other possibilities...

I am well aware of Shulgin's assessment that "Butyl is futile" as a dismissal of Butyl compounds as simply being so high dosing and lacking in interesting effects that they perhaps are not worth pursuing. While I certainly trust his judgment on that, I decided to still write about them at length because they are still an interesting variation on the theme of tryptamine substitution, lend some interesting observations with respect to structure-activity relations, and prevent a vast field of possibilities for various combinations of substitutions, many of which have never been attempted and may yield unexpected interesting effects.

MBT

MBT

The simplest butylated tryptamine explored by Shulgin was MBT, Methylbutyltryptamine. This sees a single methyl group and a looooong butyl group attached to the nitrogen. 
Shulgin observed some properties in this one that I think set an important benchmark for all butylated tryptamines- Most importantly the dosage. You can go read the full entry in TiHKAL yourself, but with respect to doses he observes:

"(with 130 mg, orally) "Perhaps a subtle intoxication at two hours, and certainly nothing at five hours."

(with 175 mg, orally) "Some mild incoordination and concentration difficulties, all trivial, and a good sleep and a good day the next day."

(with 250 mg, orally) "At 75 minutes there was the prompt development of an intoxicated state primarily characterized by fine motor impairment. Nothing remotely resembling any type of hallucination. Appetite was normal and food and water were consumed without difficulty. Most activities were uninteresting, even dull. The effects lasted about five hours."

(with 400 mg, orally) "It hit an just over an hour, and it quickly became difficult to keep both eyes focused on the point of gaze. There was no actual double vision, but things were not quite right. In a few more minutes an apparent motion became apparent with fixed objects, and shortly thereafter there was a faint 'retinal circus' that was reminiscent of DMT but less compelling. Subject matter could not be chose, but rather came on its own. At this point, walking required great concentration, and lying on a bed was a much better choice. Music seemed to encourage the drifting of thoughts, but all the eyes-closed effects faded quite quickly. I felt overheated, sweat a lot, was intensely dehydrated, and drank quantities of water all night, and still felt dehydrated. Urine output was low. Not my choice of drug; the intoxication is too much for the visual stuff."

"

So this indicates that the effects are frankly mild and a bit uninteresting, but definitely there. There are notable uncomfortable physical and incapacitating effects. The psychedelic effects at the highest dose seem just barely past threshold even as physical effects increase. The overall duration given is 4-6 hours. 

What's most noteworthy is the extremely high dosage of this drug- other unsubstituted tryptamines (MET, DET, DPT, MiPT, DiPT) yield mild experiences at doses of around 20-100 mg. Dosing any of them at 400 mg would be an overwhelming all-consuming experience, while for this one it seems lacking and gentle. Shulgin notes that it might be worthwhile to attempt different routes of administration for this one such as vaporization or IV (or perhaps insufflation!), or to combine it with an MAOI like P. harmala.

DBT

DBT

No this is not Dialectical behavioral therapy, but Dibutyltrytamine, or rather if you took the tryptamine molecule and gave it some gnarly horns. Shulgin manufactured this one, and mentioned that it showed a lower potency than DMT or DET when injected intramuscularly at 1 mg/kg. He at the very least doesn't note that it's completely inactive. He says there are further details under his entry for DMT, but this was a dead end. So the quality and precise effects of the DBT experience are still mostly a mystery.

Some other researchers however, delved into the possibilities of DBT in animal trials. A very recent study looked into 4 very odd substituted tryptamines, including DBT5. This study looked into the Head Twitch Response in mice- this is a diagnostic test to determine if a drug is active as a 5-HT2A agonist, the mechanism of action responsible for psychedelic effects in humans. Essentially, if the specific HTR is observed, it means that that compound is highly likely (though not certainly) to be hallucinogenic in humans, and that that mouse is highly likely (though not certainly) having a little mouse trip.

The results of this study were fairly analogous with the response demonstrated by known hallucinogenic tryptamines, indicating that DBT has a very high likelihood of being hallucinogenic in humans. So this definitely shows promise!

Another study by Brimblecombe et al from 1964 also looked at animal responses to a variety of tryptamines6- something interesting that this study noted was that there seemed to be a definite maximum dose of the more complex (more carbons stuck to the nitrogen) tryptamines-It seemed that it worked as a negative feedback loop, with a high enough concentration of the molecule preventing its own metabolism. This is an effect not observed in other psychedelics, and means that if a high enough dose is taken, no effects may be felt at all before the drug is excreted, unmetabolized. In rats, this dose was 50 mg/kg, which would be a dose in the range of multiple grams for humans. While this seems like a horrendous overdose of any psychedelic, it wasn't shown to be toxic in rats.

It is most likely however, that DBT would dose very high relative to other tryptamines. This study showed an active dose in rats was around 5 mg/kg, which would be a range of 300-400 mg in a human. Dose may also be inferred from structure- The current active psychedelic with the most carbons and hydrogens attached to the ethyl-amino chain is DPT, with 6 carbons and 14 hydrogens sticking out. This is also the highest orally dosing base tryptamine, with a common dose in the range of 150-250 mg. Take a step down to DET (4 carbons, 10 hydrogens). Thus it should follow that DBT, with 8 carbons and 18 hydrogens should dose higher. There doesn't seem to necessarily be an exact linear progression to this pattern so a precise dose wouldn't be known, but it would most likely be at least >100 mg for light effects. As with any base tryptamine, it would probably have a fairly short duration, from 5-6 hours at the longest.

NsBT & NtBT

NsBT (left) and NtBT (right)

Some new naming conventions come into play. The N- denotes that a simple hydrogen is stuck to the nitrogen in lieu of the usual carbon structure. The -sB- and -tB- denote the sec-butyl and tert-butyl variants of the 4-carbon butyl design, respectively, as there are many ways to rearrange 4 carbons.

Both are mentioned in passing by Shulgin, lacking their own entries, in the commentary on another drug, NET (N-ethyltryptamine). 

On NsBT he states:

"...the hydrochloride [salt melts] at ... 175-177 °C ... Interestingly, NSBT is one of the two mono-substituted tryptamines that just might have CNS activity. It has shown a generalized and somewhat diffuse intoxication with several studies covering the 25 to 75 milligram range. Short lived, intellectual excitement with some modest sensory enhancements. Promising, and a lot of erotic horniness, but no plus threes, yet."

While on NtBT He states:

"In the 5 to 20 milligram area, there is a light-headed intoxication that is a totally pleasant buzz, but nothing more profound than that. Wouldn't it be fascination of it turned out that all of the mono-tryptamines (the NRT's) were GHB-like intoxicants, and totally devoid of psychedelic activity. That would be a true challenge to the SAR crowd. I was told many years ago that NTBT was extremely potent when smoked, but I never received any particulars, and I must leave that as a baseless rumor."

This demonstrates both may be interesting stimulants, intoxicants, aphrodisiacs fitting the bill for drugs defined as Empathogens. They would be interesting to explore further. No other information exists beyond that.


4-HO-DBT

4-HO-DBT

Now we get into substitutions- for those who don't know a substitution is where you take the base tryptamine molecule as defined by what's stuck to that nitrogen (xxT) and add things to other parts of it. Most tryptamines show effects with either an -OH or -AcO group stuck to the 4 position, or an -MeO on the 5 position (see the first image on this article). These substitutions usually increase potency and duration of the tryptamine and yield all variety of unique experiences.

So what can we expect from 4-HO-DBT? A tryptamine with greater oral activity, potency, and a longer duration than DBT. Shulgin made this one too, but curiously only tried it once at 20 mg, a dose where he observed no activity. He then tossed this one aside. I find this curious, because the butylated tryptamines have a clear pattern of being significantly less potent than other tryptamines, yet he didn't even bother to try a higher dose than is standard for most other smaller 4-HO tryptamines. But he was also a very busy man with a lot of drugs to test so I don't hold it against him. 

The wikipedia article for this substance interestingly enough has an uncited claim that this was sold on the rc market and a few anecdotal reports note that it is indeed active, if a bit uninspiring at doses well past 20 mg (though it doesn't specify doses). I could not dig up any of these reports however. A cursory search did find this substance in the stock of some dubious surfaceweb vendors that I have never heard of whom I'm not sure I trust, but even if they're fake listings they are likely imitating a time it was on the market, because why else list this extremely obscure substance? 

If you have by chance encountered this substance, please contact me and share your knowledge. Some amount of people out there have tried this and frustratingly none of them saw fit to share any of what they've learned with the rest of us. If you are consuming a drug for which there is 0 information available online, I believe you are OBLIGATED to share whatever information you have gained from your experiences with the rest of the community, whether it be descriptions of the experience or at the very least information on dosage and duration.




Part 2 coming after the jump.... It will look beyond Shulgin at some of the other butyl tryptamines that have been attempted, and then into the future of infinite possibilities...
You can continue if you'd like.

Sources and Further Reading:
1-Shulgin A, Shulgin A (1997) MBT. TiHKAL: The Continuation 
2-Shulgin A, Shulgin A (1997) DBT. TiHKAL: The Continuation 
3-Shulgin A, Shulgin A (1997) NET. TiHKAL: The Continuation 
4-Shulgin A, Shulgin A (1997) 4-HO-DBT. TiHKAL: The Continuation 
5-Abiero A, Ryu IS, Botanas CJ, et al. (2019) Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice. Biomol Ther (Seoul) 28(1):83‐91
6-Brimblecombe RW, Downing DF, Green DM, Hunt RR (1964) Some pharmacological effects of a series of tryptamine derivatives. Br J Pharmacol Chemother 23(1): 43–54.
7-Leonard BE, Shallice SA (1972) The effects of some tryptamine derivatives on brain monoamines and their precursor amino acids. Neuropharmacology 11(3):373‐384.