KARL L.R. JANSEN and COLIN J. PRAST
Department of Anatomy, University of Auckland Medical School, Private Bag, Aucklund (New
Zealandl
(Accepted January 4, 1988)
sirs,
Mitragyna speciosa Korth. (“kratom”, “biak”) is a Southeast Asian tree,
the leaves of which provide several alkaloids of considerable interest and
seemingly contradictory properties. In 1836, Low (Burkill, 19351 described
the use of kratom by native Malayans as an opium substitute when opium
itself was unavailable or unaffordable. Holmes (18951 identified kratom as M.
speciosa and its use as a substitute for opium was again noted. In 1907,
Wray described how it may be smoked, chewed or drunk as an infusion with
opium-like effects regardless of the method of administration (Wray, 1907al.
Large doses were claimed to result in stupor while frequent indulgence led
to an “indolent life”. He expressed the hope that an active principle would
soon be isolated and its usefulness to medicine assessed (Wray, 1907bl.
Samples of the leaves were sent to the University of Edinburgh where, 14
years later, Field (19211 isolated two new alkaloids: mitragynine (from M.
speciosa) and mitraversine (from M. pu~tifoZial. Burkill (19301 recorded the
uses of kratom as wound poultice, cure for fever and suppressor of the
opiate withdrawal syndrome.
The first formal pharmacological investigations were carried out at the
University of Cambridge. Grewal 0932al performed a series of experiments
on animal tissues and found mitragynine to be a central nervous system
stimulant rather than depressant. He wrote that in this respect it resembled
cocaine and noted widespread use in Thailand to increase work efficiency,
tolerance of hot sun and that addicts were claimed to be thin with distended
stomachs, unhealthy complexions, dark lips and dry skin (Grewal, 1932b).
Grewal subsequently administered mitragynine to five men and again
observed a cocaine-like effect, discovering that in the leaf form much less
alkaloid was required. Fifty milligrams of pure mitragynine acetate produced
nausea and vomiting in some subjects.
The 1930s saw increasing French interest in M. africana (Raymond-Hamet, 19341. Further alkaloids were isolated, including mitranermine which could
lower the core temperature of guinea pigs by up to 1.6OC (Perrot et al.,
19361. It was hoped that the new alkaloids would replace quinine. Thuan
(19571 was first to report a case of addiction in the medical literature. He
presented a chronic user who had a marked withdrawal syndrome on
attempted cessation, never increased his use, remained in good health, did
not lose weight, and was mentally and physically “quite normal” (Thuan,
19571. Thuan quotes Marcan (1929,1934) as stating that the kratom habit does
not have a bad reputation like opium smoking, nor does it cause any change
in the physical condition of the addict or his character. The effects were
again said to be “like cocaine” and the problem a common one in Malaya.
In the 196Os, modern analytic methods were applied to the Mitragyna
genus alkaloids (Shellard, 19741. It soon became apparent that these were
indoles and oxindoles having a closed or open E ring with substitution
occuring at the C9 position (Beckett et al., 19661. Twenty-two alkaloids were
isolated from M. speciosa alone, the exact content varying with time and
location. Mitragynine (Fig. 11 is the dominant alkaloid, and exclusive to M.
speciosa (Shellard, 19741. The methoxyl group is at position 4 of the indole,
rendering mitragynine analogous to the 4-substituted indole psychedelics,
e.g. psilocybin and lysergic acid amide (Beckett et al., 1965; Shulgin, 1972;
Emboden, 19791.
The resurgence of interest in the 1960s had been spurred by a search for
non-opiate analgesics. Macko et al. (19721 found mitragynine to be
comparable with codeine as an analgesic and cough suppressant in the dog
and that. unlike codeine at equivalent doses, it did not cause emesis or
dyspnoea. There was no opiate-like addiction syndrome, or antagonism by
nalorphine, negligible anti-cholinergic action and minimal effect on gastric
motility at analgesic levels. Futhermore, it had little effect on the blood
pressure of dogs, was only hypotensive in cats at high doses and was much
less of a respiratory depressant than codeine. Chemically unrelated to any
