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Notes about Adrenochrome

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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.
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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?
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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...
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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
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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...
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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)
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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?
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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.
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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."
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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; 638,64
3;
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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; 638,64
3;
-------------------------
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; 30
77;
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; 47
2,473;
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;
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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
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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;
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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."
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