------------------------------------------------------------------------------- Notes about Adrenochrome ------------------------------------------------------------------------------- Rev Drone Anybody who's read "Fear and Loathing in Las Vegas" with their eyes open has wondered about that andrenochrome scene. What is that stuff? Where do I get that stuff? etc. Well, andrenochrome is 3-hydroxy-1-methyl-5,6-indoline-dione -- made by the oxidation of epinephrine (andrenalin). Now I can see where the hydrogens were abstracted from, and I can generally speculate about the mechnism, but does anyone have the definative word on electron-pushing for this little chemical anomaly? Also, does anyone have experience with this stuff? Johnny Depp sure made it look kewl, and being the young, impressionable lad that I am, I'd sure like to know if it is "all that" or not. ------------------------------------------------------------------------------- Beagle I have no experience with this compound, but of course I am very interested in it. Here are the original refs, in case anyone is willing to follow up on it. The original paper, in which Hoffer obtained "profound psychomimetic symptoms" from as little as 0.5 mg S.C. or I.V.: J. Mental Sci. 100, 29, '54 Later papers where negative results or possible slight effects were obtained by dosages up to 25mg: Am. J. Psychiat. 111, 603, '55 Am. J. Psychiat. 115, 162, '58 Am. J. Psychiat. 116, 454, '59 Lancet ii, 308, '58 I believe that the ultimate athority of Shulgin refered to adrenochrome as "a facinating red herring" in Tihkal. And I really hate to argue with Him. I believe that the original, positive reports were based on experiments with one mentally unstable woman. This was covered in Hoffer and Osmonds The Hallucinogens, I believe. Other reviews are : Hormones, Brain Function and Behavior, p181 1957. Psychotropic Drugs p.10, 1957 Opinions that adrenochrome is not active: Lancet, I 1287, 1960. In Nature 191, 245, ’61 it was pointed out that adrenochrome may have significance as a hallucinogen, since it is an in vitro glutamic acid decarboxylase and cholinesterase inhibitor. It has also been described as having a wide range of other physiological activites, as reviewed in Pharmacol. Rev. 1, 1, ’49 and Fortschr. Chem. Org. Naturstoffe. 14, 217, ’57 Of course, most of this work was done under conditions that would be considered primitive today, and there is not absolute certainty that all research groups were working with the same compound. Originally, adrenochrome was prepared by oxidation of adrenalin with catechol oxidase or silver oxide. The chemistry of its preparation is reviewed in Chem. Rev. 59, 181, ’59. Additionally, adrenochrome semicarbazone has been claimed to have hallucinogenic properties similar to the parent substance: Acta Chem. Scand. 12, 1231, ’58. It certainly would be interesting to apply modern techniques to this mystery and settle it once and for all. Anyone looking for a research project? ------------------------------------------------------------------------------- rev drone Many thanks for the extensive foray into andrenochrome you've offered. I have a few more andrenalin oxidations I can offer. I was told epinephrine was available OTC in a veterinary context, but otherwise is avaiable in bulk through several chemical companies. THe synthesis is a mere one-step reaction, so it looks like the makings of a fun weekend project. Off to the library I go... ------------------------------------------------------------------------------- Beagle I would be glad to hear of any other epinephrine oxidations that you could offer. Also, for another fun fictionalized account of adrenochrome in the vein of H.S. Thompson, see Blood of a Wig, from the book Red Dirt Marijuana and Other Stories, by Terry Southern. I just checked Medline, and low and behold, there has been quite a bit of work done in recent years on the physiological significance of adrenochrome. One article that I saw on the mechanism of this transformation was Biol Signals, 5(5):275-82 1996 Sep-Oct, where it was suggested that the transformation is an enzyme mediated one, and is dependant on H2O2 and O2-. NADH also apparently stimulates the production of adrenochrome, indicating involvement of NADH dehydrogenase. I had no idea that this was still a current topic of research, but there were over 100 cites, just going back to 1986. Further searching of Medline has yielded the following papers relating to adrenochrome and mental function that may prove interesting. I don't have easy access to any of them. If anyone gets them and finds anything interesting, please post. Molecular interactions in the phenomenology of the onset of mental illness. Chem-Biol-Interact. 1973 Jul; 7(1): 1-9 [Chemical interaction between serotonin and adrenochrome. Contribution to the "short circuit" theory of the genesis of mental disease] Riv-Neurol. 1971 May-Jun; 41(3): 182-7 Short circuit theory on the onset of mental illness. Clin-Chim-Acta. 1970 Oct; 30(1): 5-11 ------------------------------------------------------------------------------- Mobius In the book 'Legal Highs' (Adam Gottlieb) I found this monograph concerning Adrenochrome Semicarbazone: Usage: 100 mg is thoroughly dissolved in just enough alcohol, melted fat (butter), or vegetable oil and ingested. Because of its poor solubility in water these must be used to aid absorption. Effects: Physical stimulation, feeling of well-being, slight reduction of thought processes. Contraindications: None noted. Act as a systemic hemostatic preventing capilary bleeding during injury. Adrenochrome causes chemicaly induced schizo- phrenia. Its semicarbazone does not... ------------------------------------------------------------------------------- Teonanacatl I was curious if any of you have looked into the chemistry of adrenochrome...I just happened across a paper by Heacock, and it really interested me, but I haven't been able to find any other literature on it...I realize that it isn't fully an indole..but it is pretty close...you can close this thread if I've gone too far off topic (sorry in that case) ------------------------------------------------------------------------------- Agnememnon Is this what you read? Review as a psychotomimetic agent: R.A. Heacock, Chim. Ther. 6, 300 (1971) How was it? Production: Prepn using Ag2O as an oxidising agent: MacCarthy, Chim. Ind. Paris 55, 435 (1946) Look at the Heacock article. If not that, the only place I know is Thompson's 'Fear and Loathing in Las Vegas.' But who knows how much is based on fact? ------------------------------------------------------------------------------- Teonanacatl Nien... not the same article, which is good now I have something else to look up... sounds a lot like what I was looking for, cause the paper I've been reading mostly goes through it's chemistry (quite detailed...) and I was looking for some reviews of physiological action to round out my knowledge..thanks. Here's the ref for the one I was looking at (old as hell, but looks like the same author...) The Chemistry of Adrenochrome and Related Compounds, R.A. Heacock...damn it! I just realized I did it again... keep forgetting to attach any info on the paper I photocopy...I never learn... I'll look it up again for you (sorry). Only other info I have is that it was "received Jan 2 1959"...so probably a 1959 paper. pp. 182-231. ------------------------------------------------------------------------------- From "Biochemical Journal", Vol 31 part 1, yr 1937, page 609. "XIII. Properties of adrenochrome Adrenochrome is a very unstable substance: it is completely destroyed in 4 min. by 1% hydrochloric acid, and in 40 sec. by 1% ammonia. At pH 7.3 and 37C the red colour disappears in 35 min., and even under the optimium conditions for keeping the solution, at pH 4.0 and 0C, marked decompostion and melanin formation could be observed in 4-5 hours. In the dry crystalline condition adrenochrome could be kept for several weeks, but on standing in a vacuum desiccator it decomposed to give a brown amorphous product. The crystalline substance appears to be a hydrate. The crystals decompose on heating at abot 115-120C. Adrenochrome is very soluble in water and crystallizes from water only on evaporation practically to dryness. It is also readily soluble in methyl alcohol. It is removed quantitatively from the aqueous solution by adsorption on charcoal, and can be eluted again from the charcoal with methyl alcohol." From "The Journal of the Chemical Society", yr 1950, page 1276-1279. "b) (-) -Adrenaline (2 g.) was suspended in water (70 mL) and dilute hydrochloric acid was added dropwise with shaking, until a clear solution was obtained. Silver oxide (8 g.) was added, the mixture shaken vigorously for 5 minutes and then filtered. The aqueous solution of adrenochrome this obtained was stable for about 12 hr at 0C." ------------------------------------------------------------------------------- rev drone The folowing were taken from Beilstein Reaction Reaction ID 352748 Reactant BRN 2368277 4-((R)-1-hydroxy-2-methylamino-ethyl)-benzene-1,2-diol Product BRN 84667 (R)-3-hydroxy-1-methyl-indoline-5,6-dione ------------------------- Reaction Details 1 of 7 Reaction Classification Preparation Reagent silver oxide methanol Ref. 1 1053607; Journal; Ellis; JPETAB; J.Pharmacol.Exp.Ther.; 79; 1943; 364,368; Ref. 2 1053608; Journal; Veer; RTCPA3; Recl.Trav.Chim.Pays-Bas; 61; 1942; 638,643; ------------------------- Reaction Details 2 of 7 Reaction Classification Preparation Reagent silver oxide ethanol Ref. 1 1053607; Journal; Ellis; JPETAB; J.Pharmacol.Exp.Ther.; 79; 1943; 364,368; Ref. 2 1053608; Journal; Veer; RTCPA3; Recl.Trav.Chim.Pays-Bas; 61; 1942; 638,643; ------------------------- Reaction Details 3 of 7 Reaction Classification Preparation Reagent silver oxide methanol formic acid Ref. 1 1053583; Journal; Heacock et al.; CJCHAG; Can.J.Chem.; 36; 1958; 853,855; Ref. 2 1053605; Journal; Sobotka; Austin; JACSAT; J.Amer.Chem.Soc.; 73; 1951; 3077; Ref. 3 1053598; Journal; Harley-Mason; JCSOA9; J.Chem.Soc.; 1950; 1276,1279; Ref. 4 1053586; Journal; Ingle et al.; JPHAA3; J.Am.Pharm.Assoc.; 37; 1948; 375; Ref. 5 1053606; Journal; MacCarthy; CHIEAN; Chim.Ind.(Paris); 55; 1946; 435; ------------------------- Reaction Details 4 of 7 Reaction Classification Preparation Reagent oxygen Other conditions in Gegenwart von Katalysatoren Ref. 1 1053600; Journal; Green et al.; JBCHA3; J.Biol.Chem.; 220; 1956; 237; Ref. 2 1053601; Journal; Chaix et al.; BBACAQ; Biochim.Biophys.Acta; 5; 1950; 472,473; Ref. 3 1053602; Journal; Drevon; Stupfel; C.r.Soc.Biol.; 143; 1949; 271; Ref. 4 1053603; Journal; Blaschko; Schlossmann; J.Physiol.London; 98; 1940; 130-140; Ref. 5 1053604; Journal; Green; Richter; BIJOAK; Biochem.J.; 31; 1937; 598,609; ------------------------- Reaction Details 5 of 7 Reaction Classification Preparation Reagent iron (2+) hydrogen peroxide Ref. 1 1053598; Journal; Harley-Mason; JCSOA9; J.Chem.Soc.; 1950; 1276,1279; Ref. 2 1053599; Journal; Mazur et al.; JBCHA3; J.Biol.Chem.; 220; 1956; 227; ------------------------- Reaction Details 6 of 7 Reaction Classification Preparation Reagent iron (2+) sodium peroxo disulfate Ref. 1 1053598; Journal; Harley-Mason; JCSOA9; J.Chem.Soc.; 1950; 1276,1279; Ref. 2 1053599; Journal; Mazur et al.; JBCHA3; J.Biol.Chem.; 220; 1956; 227; ------------------------- Reaction Details 7 of 7 Reaction Classification Preparation Reagent water iodic acid Ref. 1 1053597; Journal; Correia; Alves; Anais Fac.Farm.Porto; 14; 1954; 101,109; Ref. 2 1053596; Journal; Macciotta; GCITA9; Gazz.Chim.Ital.; 81; 1951; 485,488; Reaction Reaction ID 2106910 Reactant BRN 2212160 4-(1-hydroxy-2-methylamino-ethyl)-benzene-1,2-diol Product BRN 84665 3-hydroxy-1-methyl-2,3-dihydro-indole-5,6-dione ------------------------- Reaction Details 1 of 2 Reaction Classification Chemical behaviour Reagent VOCl2, O2 Solvent H2O Temperature 25 øC Other conditions dependence of rate constant on pH, adrenaline concentration, VOCl2 concentration; ionic strength: 0.100 mol dm%-3& (KNO3) Subject studied Rate constant Ref. 1 5731416; Journal; Jameson, Reginald F.; Kiss, Tamas; JCDTBI; J.Chem.Soc.Dalton Trans.; EN; 1986; 1833-1838; ------------------------- Reaction Details 2 of 2 Reaction Classification Chemical behaviour Other conditions disproportionation during electrooxidation of title compound at carbon-fiber microelectrodes at physiological pH Subject studied Rate constant Mechanism Ref. 1 5925724; Journal; Ciolkowski, Edward L.; Maness, Karolyn M.; Cahill, Paula S.; Wightman, R. Mark; Evans, Dennis H.; et al.; ANCHAM; Anal.Chem.; EN; 66; 21; 1994; 3611-3617;Reaction Reaction ID 2106911 Reactant BRN 2212160 4-(1-hydroxy-2-methylamino-ethyl)-benzene-1,2-diol Product BRN 84665 3-hydroxy-1-methyl-2,3-dihydro-indole-5,6-dione 161691 1-methyl-indole-3,5,6-triol ------------------------- Reaction Details Reaction Classification Chemical behaviour Solvent D2O Time 350 min Temperature 24.9 øC Other conditions Irradiation other sensitizers: methylene blue, rose bengal, fluoresceine, superoxide dismutase; other inhibitors: 1,3-diphenylisobenzofuran, 1,4-diazobicyclo<2,2,2>octane, KN3, NaN3; other solvent: H2O. Subject studied Rate constant Mechanism Ref. 1 5689294; Journal; Kruk, I.; ZPCLAH; Z.Phys.Chem.(Leipzig); EN; 268; 3; 1987; 607-613;Reaction Reaction ID 2106912 Reactant BRN 2212160 4-(1-hydroxy-2-methylamino-ethyl)-benzene-1,2-diol Product BRN 84665 3-hydroxy-1-methyl-2,3-dihydro-indole-5,6-dione 2806381 C9H11NO3 ------------------------- Reaction Details Reaction Classification Chemical behaviour Other conditions Irradiation laser induced oxidation at pH5 at various electrodes; half life of 0-quinone Subject studied Product distribution Ref. 1 5562583; Journal; Skully, Joan P.; McCreery, Richard L.; ANCHAM; Anal.Chem.; EN; 52; 12; 1980; 1885-1889; Reaction Reaction ID 2173865 Reactant BRN 2806381 C9H11NO3 Product BRN 84665 3-hydroxy-1-methyl-2,3-dihydro-indole-5,6-dione ------------------------- Reaction Details Reaction Classification Chemical behaviour Other conditions the half life Subject studied Rate constant Ref. 1 5562583; Journal; Skully, Joan P.; McCreery, Richard L.; ANCHAM; Anal.Chem.; EN; 52; 12; 1980; 1885-1889; Reaction Reaction ID 2199350 Reactant BRN 3201122 (+-)-1-<3,4-dihydroxy-phenyl>-2-methylamino-ethanol Product BRN 5741691 C9H9NO3 ------------------------- Reaction Details Reaction Classification Preparation Reagent K3Fe(CN)6 Solvent acetic acid H2O Time 5 min Temperature 5 øC Ref. 1 5676615; Journal; Kato, Eishin; Oya, Masayuki; Uda, Kozo; Iso, Tadashi; Fujita, Tadashi; Iwao, Jun-Ichi; CPBTAL; Chem.Pharm.Bull.; EN; 29; 7; 1981; 1935-1941; Reaction Reaction ID 3658966 Reactant BRN 6685443 C9H11NO3 Product BRN 84667 (R)-3-hydroxy-1-methyl-indoline-5,6-dione ------------------------- Reaction Details Reaction Classification Chemical behaviour Reagent Fe(NO3)3, KNO3 Solvent H2O Temperature 25 øC Subject studied Rate constant Ref. 1 5856275; Journal; Linert, Wolfgang; Herlinger, Erwin; Jameson, Reginald F.; JCPKBH; J.Chem.Soc.Perkin Trans.2; EN; 12; 1993; 2435-2439; ------------------------------------------------------------------------------- Excerpt from "The Private Sea" by William Braden Chemistry and mysticism [...] The question of religious chemistry has been underscored recently by the wide attention given to the theories, already mentioned, of Dr. Abram Hoffer and Humphry Osmond. Their adrenochrome-adrenolutin hypothesis suggests that schizophrenia may be caused at least in part by defective adrenal metabolism. Very briefly, the adrenal gland secretes the hormone adrenaline, which helps coordinate biological mechanisms in emergency situations, for example, a fist fight or a threatened traffic accident. Heart rate is increased, the blood is sugared up and pumped to the necessary muscles. Adrenaline also may affect the emotions, contributing to anxiety and depression. In the body it turns into a toxic hormone called adrenochrome, which in turn can be converted into either of two other compounds: dihydroxyindole or adrenolutin. It is possible that dihydroxyindole balances off adrenaline to reduce tension and irritability; in schizophrenics, however, adrenochrome is converted primarily into adrenolutin, which also is toxic, and the combination of adrenochrome-adrenolutin results in a poisonous disruption of the brain's chemical processes. That is the theory. And the prescribed antidotes are nicotinic acid (niacin) or nicotinamide (Vitamin B-3). Discussing one of the villains in the piece, the scientists write: "There are few who doubt that adrenochrome is active in animals or in man, and it is now included among the family of compounds known as hallucinogens - compounds like mescaline and LSD-25 capable of producing psychological changes in man." -------------------------------------------------------------------------------