2C-E

The only person whose death can be attributed to 2C-E without co-ingestion was not killed by its pharmacology: he was killed by a label. The powder was sold as 2C-I. It is a psychedelic phenethylamine of the 2C series, an agonist at 5-HT2A and 5-HT2C receptors with affinities of the same order as serotonin itself, and that is very nearly all that is known of it: almost nothing has ever been measured in a human, a single prospective study in ten subjects, no plasma concentration published to date, no imaging in the living, no tolerance data. Almost everything that circulates about it is reputation, not data.

The mix-up that killed, and why it is enough to kill

Blaine, Minnesota, March 2011. A product bought on the internet, advertised as 2C-I, identified on analysis as 2C-E; the Minnesota Bureau of Criminal Apprehension seized a bottle containing 8.9 g. Ten individuals aged 16 to 23, tachycardia, two patients with a systolic pressure above 220 mmHg, eight in severe agitation with delirium and hallucinations. Outcomes: one death, one severe case, eight minor cases. The dead man is a 19-year-old who had insufflated the product, marked agitation about an hour later, then cardiac arrest. The dose was not measured, no blood or urine concentration was published, and the autopsy speaks of drugs of the 2C category in the plural, without naming a molecule.

The arithmetic of the substitution is simple, and it is what should be retained. The common dose of 2C-I is 10 to 25 mg by the oral route, that of 2C-E 10 to 15 mg, and the heavy band for 2C-E begins at 25 mg. The transposition was twofold, molecule and route: on the nasal table for 2C-E, the heavy band begins at 10 mg. A dose chosen for 2C-I, taken by the nose, therefore represents one to two and a half times the threshold of the nasal heavy band for 2C-E. Two white powders identical to the eye, and the route made the substitution worse.

The second incident in the same file contained no 2C-E at all. August 2011, Oregon: two men drank a liquid bought from the website of a Chinese chemical company and believed to be 2C-E. Cyanosis at fifteen minutes, treatment for refractory methaemoglobinaemia and haemolytic anaemia. The FDA identified aniline, an industrial solvent.

Practical consequence, and it is the most solid point on this page: no field reagent separates one 2C from another. 2C-E, 2C-I and 2C-T-7 are indistinguishable without instrumental analysis, and 2C-I carries in addition its own confusion with 25I-NBOMe. Get it analysed, dose by volume rather than on a pocket scale, and do not transpose a dose from one molecule of the series to another, or from one route to another.

Pharmacology

The affinities measured in HEK cells expressing the human receptors (Eshleman and colleagues 2014): 5-HT2A Ki 4.50 ± 0.71 nM, 5-HT2C Ki 5.4 ± 1.1 nM, 5-HT1A Ki 1190 ± 250 nM. The 5-HT1A to 5-HT2A ratio is about 260 to 1: 2C-E is a near-pure 5-HT2 agent, with no 5-HT1A component relevant at active concentrations. On the inositol phosphate pathway, EC50 of 18.0 ± 5.9 nM at 5-HT2A and 65 ± 11 nM at 5-HT2C.

At the monoamine transporters, hDAT, hSERT and hNET, affinity and potency are above 10 µM, with no releasing efficacy. 2C-E is neither a releaser nor a reuptake inhibitor, contrary to a formulation that circulates everywhere and whose history is traceable: Nagai and colleagues 2007 measure and write that 2C-E, 2C-I and 2C-C influence reuptake only weakly; a later review cites Nagai, drops the word weakly and adds dopamine, which both sets of measurements exclude; the abstract of the only human study inherits the formulation without its qualifier, which the introduction of the same article nevertheless keeps. Nor is it an MDMA-type agent, despite full substitution in the rat trained on MDMA, nor a stimulant: it does not substitute for methamphetamine and it depresses locomotion in the mouse at medium and high doses. The psychostimulant designation that lingers in several toxicological databases, right into a CDC publication, is a class inheritance.

One point deserves to be set apart without being inflated. 5-HT2B agonism is the established mechanism of drug-induced valvulopathy, and Rickli and colleagues 2015 place 5-HT2B among the targets bound by the 2C molecules. But no value specific to 2C-E has been read, the tables of that article remaining inaccessible, the only sentence available bears on the whole family and gives most of the Ki and EC50 values below 1 µM, which is modest, and the known valvulopathies presuppose prolonged daily exposure. A conceivable mechanism, not quantified here, a clinical consequence never observed.

On the elimination side, MAO-A and MAO-B are, on human isoenzymes, the major enzymes of the deamination of 2C-E, CYP2D6 intervening only marginally (Theobald and Maurer 2007): this is the foundation of the whole interactions section. In the other direction, 2C-E is perhaps a weak MAO inhibitor. Wagmann and colleagues 2019 measured, across the 2C compounds, IC50 values running from 10 to 125 µM at MAO-A and from 1.7 to 180 µM at MAO-B. These ranges carry no denominator as long as the article is read only in abstract, and the value specific to 2C-E is in a table that has not been read. No data allow one to say whether 2C-E is an MAOI in the clinical sense; the authors decline to rule out a contribution.

What has been measured in humans, and that is ten people

Papaseit and colleagues 2020, an uncontrolled observational study, without placebo: ten experienced users, capsule brought by themselves, in a private club in Barcelona with a psychiatrist present, actual doses of 6.5 to 25 mg. The authors write that the changes in mood were more marked than the perceptual changes: intensity 46 ± 17 out of 100, high 48 ± 23, liking 51 ± 30, and a different bodily sensation at 46 ± 23, the only perceptual variable without a dose-effect relationship, therefore present even at a low dose. A dose-effect relationship does appear, by contrast, on the perceptual and hallucinatory items, and below 10 mg several are at exactly zero, unreal surroundings and auditory hallucinations. Bad effects peak at 8.4 ± 10 out of 100 and the substance was judged well tolerated: the reputation of a bodily and difficult molecule therefore rests on the duration and the somatic load, not on a measured subjective toxicity. On the cardiovascular side, an Emax for heart rate of +33 ± 19 bpm and for systolic pressure of +15 ± 5.8 mmHg in the 15 to 25 mg group, which the authors themselves declare non-significant, summarising their result as a mild to moderate rise in heart rate with no change in blood pressure. These two figures are not to be quoted without that qualifier.

The only kinetics in existence concerns saliva: Cmax 5.8 ± 6.4 ng/mL, individual range 0.93 to 21.54, Tmax 2 h, all ten subjects positive at 4 h and only five at 6 h. No dose-concentration relationship could be established, and the subject who took the lowest dose showed the highest concentrations and the most intense effects, with no explanation from the authors. Neither plasma half-life, nor bioavailability, nor volume of distribution is known. There exists besides a body of user reports on Erowid, which is to be consulted there and not copied out.

Duration, dose, and a steep curve

The figures carry their origin with them, because those origins are not of the same nature. Shulgin, in PiHKAL entry 24, gives a single range of 10 to 25 mg for 8 to 12 h, drawn from unblinded bioassays conducted by himself and his circle, and states that the range is deliberately wide. The Erowid tables, a synthesis of user reports which explicitly presents itself as not being a recommendation, give, by the oral route, a threshold at 2 to 5 mg, a common band at 10 to 15 mg, strong at 15 to 30 mg, heavy at 25 to 40 mg, for 6 to 10 h; PsychonautWiki gives neighbouring bands.

Three things to see in this disorder. The bands overlap: the 25 to 30 mg zone is rated simultaneously strong and heavy by Erowid. Shulgin's upper bound is the lower bound of Erowid's heavy band, and Shulgin rules against himself, since it is precisely at 25 mg that he describes anxiety and sweating within a few minutes, then what he calls a toxic psychosis with voices commenting on his worst fears, resolved in some twenty minutes, and that he concludes that the dose-response curve of 2C-E is steep. The top of his normal range is already, in his own case, the place where the experience tips over. Finally the duration varies from 6 to 12 h depending on the sources, and the only human study stopped measuring at 6 h: it cannot settle the matter.

By the nasal route, no measured human data exist, and it is the route of the only death without documented co-ingestion. Two exact statements, without arithmetic: 10 mg by the nose is already rated heavy by Erowid whereas 10 mg by mouth is rated common there, the same figure in two opposite bands; and both tables place the threshold of their nasal heavy band, 10 mg for Erowid and 14 mg for PsychonautWiki, at or below the upper bound of the oral common band, 15 mg.

Tolerance: no data, neither human nor animal. What circulates is extrapolated from the fast tolerance of the classical 5-HT2A psychedelics. A plausible and unverified extrapolation, and no quantified reset interval can be given.

Harm reduction

MAO inhibitors, the only risk with a direct mechanistic foundation. MAO-A and MAO-B being the principal elimination routes, an MAOI closes the exit and the concentration rises: the documented risk is an overdose by blockade of clearance, not in the first instance a serotonin syndrome, since 2C-E does not load the synapse with serotonin. Dean and colleagues 2013 write it word for word, MAOIs may increase serum concentrations of 2C compounds and increase the risk of toxicity. This covers the antidepressant MAOIs, the MAO-B inhibitors, moclobemide, and two non-psychiatric MAOIs that are often forgotten, linezolid and methylene blue. Also belonging here, through their beta-carbolines, are Syrian rue and ayahuasca, as well as AMT, another established MAO inhibitor in this corpus whose quantified potency is not verified. Honest level of evidence: mechanism established in vitro, no published human case of 2C-E with an MAOI of any kind. It is a class extension and that has to be said. Two neighbouring reference points: for 2C-I the mechanism is clearer still, CYP2D6 not being involved at all, hence with no fallback route; for 2C-T-7, conversely, the only published direct test is negative, a team having co-incubated the 2C-T compounds with MAO inhibitors with no effect on cytotoxicity whereas the same manipulation does aggravate that of mescaline and 2C-B. Caution, then, and never an established fact.

SSRIs and serotonin syndrome: theoretical in one direction, mechanistic in the other. The combination of 2C-E plus an SSRI has never been studied nor reported. Without inventing anything: a potent 5-HT2A agonist plus a reuptake inhibitor creates a stacking effect whose outcome is not predictable, and the reverse is also possible, SSRIs being able to blunt the effects of psychedelics; neither of the two claims has a source specific to 2C-E. The clearest case in the family concerns 2C-I: a 19-year-old man who had insufflated it, recurrent seizures, a hyperadrenergic picture, a diagnosis of serotonin syndrome, prolonged respiratory failure, complete recovery. A class transposition, to be announced as such.

The convulsive load is the transversal fact of this corpus, and 2C-E is one of the four that do not carry it: seizures figure among the common features of 2C intoxications, without any case on 2C-E alone having been published. It is a position that its kinship makes fragile rather than reassuring. Ten of the fourteen substances carry this signal, some on counted human cases, others on an animal signal, an isolated case or an unquantified clinical mention, and the two closest relatives of 2C-E are in the first group: 2C-I, whose two published severe cases are convulsive states, and 2C-T-7, with seizures in two of its three deaths. Two members of this list taken together therefore lower the threshold twice over, and 2C-E is sold precisely under the names of two of them. Outside the set, tramadol and lithium, the latter being the only medicine to which a death in this corpus has been imputed. The lithium warning rests on an analysis of online user reports, 47% of 62 reports involving seizures against 0 out of 34 for lamotrigine: solid in its direction, weak in its figure, and none of these reports concerns 2C-E. For stimulants and MDMA, the rationale is cardiovascular and hyperthermic, with no series specific to 2C-E; the only supporting point in the corpus is a neighbouring one, the DEA attributing two of the three deaths from 2C-T-7 to concurrent consumption of MDMA, including one case with 200 mg.

Signs that should send you to the emergency department: hyperthermia, increasing agitation, rigidity, seizures, severe tachycardia and hypertension, repeated vomiting, dark urine or falling urine output, and a failure to return to normal beyond the expected duration. A point of vocabulary that matters: the excited delirium framework, on which the reference review relied, rests on a 2009 white paper of the American College of Emergency Physicians, and the ACEP withdrew its approval in October 2023. The signs remain true, it is the named entity and its explanation that no longer hold. Describe the signs, do not invoke the syndrome.

In hospital, ask for urine. In a mass poisoning of 29 people in Hamburg, 2C-E was confirmed in 7 urine samples out of 11 and in none of the 29 blood samples, at urinary concentrations of 1.5 to 183 µg/L. A caveat inseparable from the case: the Bromo-DragonFly present in the same event was found, for its part, in 11 urine samples out of 11 and 17 blood samples out of 29, which suggests a dominant exposure to Bromo-DragonFly rather than a blood invisibility specific to 2C-E. The recommendation to take urine is the authors' own and it holds. More broadly, across this whole corpus, a negative screen excludes nothing: saying what was taken and keeping the bag materially changes the management. That management is supportive, rapid sedation, fluid loading and control of hyperthermia, benzodiazepines first line. Ketamine is proposed as an alternative chemical restraint, with a caveat to be quoted alongside it: airway compromise including laryngospasm and hypoxia, and worsening of tachycardia and hypertension. Neuroleptics are suspected of aggravating panic and the visual symptomatology, but the same review concludes that their benefit prevails for undifferentiated agitation, haloperidol plus lorazepam having proved superior to either alone, with a caveat in patients with a long QT.

Populations, all of them deduced from the mechanism and never measured on 2C-E: people on an MAOI of any kind, on lithium, at risk of seizures, and carrying a cardiovascular condition. On pregnancy, breastfeeding and adolescence, no data exist. On a psychotic or bipolar history, class caution and nothing else. An American cross-sectional study finds, in users of novel psychedelics compared with users of classical psychedelics only, a higher probability of suicidal thinking and suicidal planning over the past year; the same authors write that this use was associated neither with psychological distress nor with suicidality compared with no use, and 96.9% of that group had also used classical psychedelics. Association, not causation.

What is not established and is nonetheless read. It is not established that 2C-E causes a leukoencephalopathy: the only case in the world is that of a 26-year-old man in Dallas, urine positive for 2C-E but also for benzodiazepines and THC, an empty zolpidem bottle at the scene, no quantification anywhere, seen in good health twelve hours earlier, and authors who write that this agent probably contributed, a formulation that is not causal even if their title asserts more. To their credit, they examine and explicitly rule out the hypoxic-ischaemic hypothesis. There is besides no usable LD50, human or animal, and any lethal-dose figure that circulates is without a source. Honest count: two deaths in all involve 2C-E, neither of them with a measured dose or concentration, and only one of the two is the subject of a peer-reviewed case report, precisely the more confounded one. The rarity of deaths does not prove harmlessness for a molecule whose prevalence of use is not negligible, between 8.55% and 25.7% depending on the surveys and the populations questioned.

On legal status, 2C-E is placed in United States Schedule I, 21 CFR 1308.11 paragraph (d), DEA code 7509. In France it appears by name in annex IV of the order of 22 February 1990 setting the list of substances classified as narcotics, which contains in addition a generic clause covering ring-substituted phenethylamine derivatives.

Sources

• E. Papaseit and colleagues (2020), acute effects of 2C-E in humans, observational study, Front Pharmacol (n = 10; the whole of the prospective human pharmacology available; full text and tables read).
• A.J. Eshleman and colleagues (2014), behavioural and neurochemical pharmacology of six phenethylamines, Psychopharmacology (principal quantitative source; full text read, numerical tables not re-read at verification, the page putting up a captcha).
• D.S. Theobald and H.H. Maurer (2007), MAO and cytochromes involved in the deamination of the 2C compounds, Biochem Pharmacol (abstract read): mechanistic basis of the MAOI interaction.
• B.V. Dean, S.J. Stellpflug, A.M. Burnett, K.M. Engebretsen (2013), review of the synthetic phenethylamines, J Med Toxicol (full text, tables and bibliography read). Caveats to keep: its table of deaths is entitled Deaths from 2C reported in the media and carries the note that accuracy cannot be verified; its table 1 contains a visible misprint; it attributes to PiHKAL a 16 mg account that does not appear in entry 24, a bibliographic ghost not to be propagated; and its excited delirium framework rests on a white paper disavowed since.
• A. Rickli and colleagues (2015), receptor interaction profiles of the NBOMe derivatives of the 2C compounds, Neuropharmacology (abstract read, tables not read: this is where the 5-HT2B point comes from, and no value specific to 2C-E could be seen).
• L. Wagmann and colleagues (2019), interactions of the 2C compounds with human monoamine oxidases, Drug Test Anal (abstract read, value specific to 2C-E not read; the IC50 ranges are to be quoted on their own, without a denominator, as long as only the abstract has been read).
• F. Nagai and colleagues (2007), effects of psychoactive drugs on monoaminergic neurotransmission, Eur J Pharmacol (abstract read): origin of the claim, thereafter copied out without its qualifier, that the 2C compounds inhibit reuptake.
• J. Sacks, M.J. Ray, S. Williams, M.J. Opatowsky (2012), fatal toxic leukoencephalopathy, Proc Bayl Univ Med Cent and M.J. Van Vrancken, R. Benavides, F.H. Wians (2013), identification of 2C-E in urine, Proc Bayl Univ Med Cent. The same patient, not to be counted twice.
• S. Iwersen-Bergmann and colleagues (2019), mass poisoning with 2C-E and Bromo-DragonFly, Int J Legal Med (abstract read): urinary concentrations, absence of detection in blood, recommendation to take urine.
• A. Bosak, F. LoVecchio, M. Levine (2013), recurrent seizures and serotonin syndrome after ingestion of 2C-I, J Med Toxicol (abstract read): concerns 2C-I, an explicit class transposition.
• CDC (2012), severe methaemoglobinaemia and haemolytic anaemia from aniline bought as 2C-E, Oregon, MMWR 61(5):85-88, PMID 22318470 (abstract read through the PubMed record, full page not read).
• S.M. Nayak and colleagues (2021), co-administration of classical psychedelics and lithium, analysis of online reports, Pharmacopsychiatry (abstract read): a body of user reports, not a clinical series, and nothing specific to 2C-E.
• J.D. Sexton and colleagues (2019), prevalence and epidemiological associations of the novel psychedelics, J Psychopharmacol (abstract read): cross-sectional study, to be quoted with its null result.
• D. Luethi and M.E. Liechti (2018), in vitro profiles and prediction of reported human doses, Int J Neuropsychopharmacol (full text read, supplementary tables not read): documents the circularity of the dose figures, estimated from erowid.org, psychonautwiki.org and tripsit.me.
• A. Shulgin and A. Shulgin, PiHKAL, entry 24, 2C-E, 1991, archived with permission by Erowid (page read): dose 10 to 25 mg, duration 8 to 12 h, steep dose-response curve at 25 mg. The nickname Eternity is attached there by Shulgin to another compound, the 5-ethoxy homologue; its migration to 2C-E is asserted by no source.
• Erowid, 2C-E Vault, dose and fatalities pages (read): oral and nasal dose tables, the latter marked tentative by Erowid; a single pharmacological death listed. The body of experience reports is to be linked and read there, its licence forbids reproduction.
• PsychonautWiki, 2C-E (read): community wiki, no peer-reviewed source for its dose figures, which the page states itself.
• 21 CFR 1308.11 (d), 2C-E entry, DEA code 7509 (read on the Cornell LII mirror), and order of 22 February 1990, annex IV, 2C-E entry read directly on Legifrance.
• J.M. Topeff, H. Ellsworth, L.A. Willhite, S.A. Bangh, E.M. Edwards, J.B. Cole (2011), case series of symptomatic exposures including one death after exposure to 2C-E, Clin Toxicol 49:526. Conference abstract not read; it is the only indexed publication carrying the Blaine death, and its clinical figures are known only through their transcription in Dean and colleagues 2013. National Drug Intelligence Center, 2C-E Causes Death in Minnesota: PDF not opened, contents unknown.
• Gil-Martins and colleagues (2024), cytotoxicity of the 2C-T compounds and the role of the MAOs: source not read here, reported by the 2C-T-7 file of this same corpus. It carries the only published direct test of aggravation by MAO blockade, and it is negative on the 2C-T compounds, positive on mescaline, 2C-B and 2C-N. Cell cytotoxicity at 24 h, which does not refute a plasma accumulation.