William M. McIsaac

A biochemical concept of mental disease.

Evidence strongly favors an abnormal serotonin metabolism as an etiologic factor in some forms of mental disease, and it is possible that under certain circumstances a harmala alkaloid, endogenously produced, could cause a psychotic state; such a state would tend to be chronic because of a chemical feedback mechanism. Although only a theory, this hypothesis provides the fascinating motivation to fulfill Thudichums dictate to study the normal brain chemistry “to its uttermost detail” so that eventually we may be able to isolate the “poisons fermented within the body” which are responsible for insanity.

Marihuana: importance of the route of administration

Conventionally marihuana is used, or rather abused, by inhalation. In this respect it more closely resembles tobacco than alcohol with which it has most often been compared from a behavioural point of view. Yet, surprisingly enough, most experiments on the pharmacological, neurochemical, or behavioural effects of marihuana have relied on an intraperitoneal administration of extracts of cannabis or pure l-A9tetrahydrocannabinol (A9-THC), the major psychoactive constituent. In working with synthetic A9-THC (Idanpaan-Heikkila, Fritchie & others, 1969) we were impressed by its great water insolubility which led us to question just how well it might be absorbed via the various conventional routes of administration. TritiatedAg-THC with a specific activity of 250 pCi/mg was synthesized (Idanpaan-Heikkila, Fritchie & others, 1969) and administered to rats in Tween-80 as a suspension intraperitoneally and intravenously. Animals were killed at various times and autoradiographs prepared using the technique previously described (Ullberg, 1968 ; IdanpaanHeikkila, Vapaatolo & Neuvonen, 1968). 3H-A9-THC administered intraperitoneally remains in the abdominal cavity, with little absorption and distribution to other tissue, including the CNS (Fig. 1A and B). The same dose given intravenously was distributed throughout the body, including the CNS, within 5 min (Fig. 1C). Preliminary experiments also indicated good absorption and distribution after inhalation (Ho, Fritchie & others, 1970). Adiscrepancy exists between the known effective dose in man (100-250 pg/kg range inhaled) (Isbell, Gorodetzsky & Jasinski, 1967 ; Weil, Zinberg & Nelsen, 1968), and that used in most animal studies-10-25 mg/kg, and even as high as 00 mg/kg (intraperitoneally).

6-Methoxy-1,2,3,4-tetrahydro-β-carboline–α serotonin elevator1

THERE is evidence that serotonin metabolism is disturbed in depression and in some forms of mental retardation. It has been reported that depressed patients have a low cerebrospinal fluid level of 5hydroxy indoles and low urinary excretion of tryptamine (ASHCROFT, CRAWFORD, ECCELSON, SHARMAN, MCDONGALL, STANTON and BINNS, 1966; COPPEN, 1968). These levels return to normal with clinical improvement. It has been postulated (LAPIN and OXENKRUG, 1969) that in depression tryptophan pyrrolase is stimulated by elevated blood levels of corticosteroids with the result that tryptophan metabolism is diverted from serotonin production towards increased formation of kynurenine. Since blood corticosteroids are elevated in depression as a result of excitation of the amygdala, on which serotonin acts as an inhibitor, it seems possible that a vicious cycle may occur. Alleviation of depression by administration of 5-hydroxytryptophan to elevate brain 5-HT levels has been reported (COPPEN, SHAW and FARRELL, 1963). and the antidepressant activity of M A 0 inhibitors is enhanced by administration of tryptophan. Any compound which could preferentially elevate brain levels of 5-HT, therefore, should prove useful to explore the etiology of depression and might also have potential merit as a therapeutic agent. In our studies of the neurochemical effects of an extensive series of compounds synthesized in our laboratories we were intrigued to find that 6-methoxy-l,2,3,4-tetrahydro-fi-carboline(6-MeOTHBC) had such an effect. This paper reports our findings in detail.

Metabolism of harmaline in rats

Abstract The distribution and metabolic fate of [3H]harmaline-HCl were studied in rats. Thirty min after subcutaneous injection, high radioactivity was found in the small intestine, liver, adrenals, kidneys and lungs. A rapid turnover and elimination was evident after the first hour, as most of the tissues, except the liver, kidneys and intestines, had decreased nearly 50 per cent in levels of radioactivity. About 40 per cent of the harmaline was bound to human serum or rat serum proteins in vitro. The blood levels, however, were low at all times in vivo. The peak concentration in the brain occurred at 1 hr postinjection. The major route of excretion of harmaline and its metabolites was through the kidneys; a total of 62 per cent of the injected dose was excreted in the urine during 96 hr as compared to only 11·5 per cent in the feces over the same period. The major fate of harmaline in rats was demethylation to form harmalol, which was predominantly excreted as the glucuronide conjugate. Six to 10 per cent of the radioactivity was identified as the sulfate conjugate of harmol, which was formed by the dehydrogenation of harmalol. During the first 8 hr, unchanged harmaline in the urine amounted to about 25 per cent; however, this decreased to only 7 per cent during the 8–24 hr period.

Neuropharmacological study of Δ9- and Δ8-l-tetrahydrocannabinols in monkeys and mice

Abstract In monkeys, Δ8- and Δ9-THC were both active at 0.5 mg/kg. Animals receiving intravenously 0.5 and 2 mg/kg doses of both isomers exhibited changes in behavior. At 10 mg/kg, the animals became catatonic and uncoordinated. Both cannabinols caused a decrease in serotonin and norepinephrine in various discrete areas of the brain. It is possible that these neurochemical changes were related to the behavioral effects. In mice, after intravenous injection Δ8-THC exerted a greater effect on brain concentrations of serotonin and norepinephrine than the Δ9 isomer; although the latter is more potent behaviorally. Some differential effects of the two isomers on brain amine levels in specific areas might indicate that not only may there be a difference in potency between the two compounds, but that they might each have a qualitatively different spectrum of psychopharmacological action.

10-Methoxyharmalan, a Potent Serotonin Antagonist Which Affects Conditioned Behavior

10-Methoxyharmalan, an alkaloid obtained by the cyclodehydration of melatonin, itself a derivative of serotonin, is a more potent serotonin antagonist than harmaline and is only slightly less active than lysergic acid diethylamide. It has a similar, yet slightly greater, effect on behavior as that of harmaline and is the most potent serotonin derivative, so far tested, that affects the avoidance-escape behavioral reflex

Metabolism of 6-Methoxytetrahydro-β-Carboline in Rats

1. Thirty minutes after intraperitoneal injection of 6-methoxytetrahydro-β-carboline, rapid uptake by the lungs, liver, kidney, adrenals, brain and spleen was observed, and by 6 h the radioactivity in most tissues except liver and testes had decreased to less than half of the max. values.2. Approximately 71% of the administered dose was found in the urine within 72 h, as compared to a total of 9% that appeared in the faeces over the same period of time. After oral administration, rats excreted 64 and 14% of the administered dose in 72 h in the urine and faeces, respectively.3. The major metabolic pathway for 6-methoxytetrahydro-β-carboline was hydroxylation of the 7-position and demethylation of the 6-methoxy group. The two metabolites, 6-methoxy-7-hydroxytetrahydro-β-carboline and 6-hydroxytetrahydro-β-carboline were excreted in urine in nearly equal amounts, almost entirely as glucuronide and sulphate conjugates with the latter predominating. The presence of conjugates of the two metabolites in the bile...

Biological activities of some 5-substituted N,N-dimethyltryptamines, α-methyltryptamines, and gramines

SummaryThree series of derivatives of N,N-dimethyltryptamine, α-methyltryptamine and gramine bearing substituents of varying electronic nature on the C-5 position were tested for acute toxicity, effect on barbiturate sleeping time, antireserpine effect, swim maze, variable interval conditioned behavior, and inhibition of monoamine oxidase. No correlation could be made between the electronic effects and their pharmacological activities. It was thus suggested that there exist different pharmacological receptors for the tryptamines and gramines.

Relation of pharmacological and behavioral effects of a hallucinogenic amphetamine to distribution in cat brain.

The hallucinogen 2,5-dimethoxy,-4-methylamphetamine, also known as STP, accumulates in specfic areas of cat brains. The unchanged compound was detected in the brain for at least 6 hours, whereas its behavioral effects lasted for about 4 hourS. The coincidental pharmacological and behavioral effects of the compound apparently indicate a relation between the anatomical distribution and action.

Effects of 6-methoxy-1,2,3,4-tetrahydro-β-carboline on the regional and subcellular distribution of serotonin in mouse and rat brains

Abstract 6-Methoxy-1,2,3,4-tetrahydro-β-carboline (6-MeO-THBC), which exerts its effect specifically on brain serotonin (5-HT), caused substantial increase of the amine in all the discrete areas of the rat brain. Since norepinephrine levels were unchanged, the increase in 5-HT was evidently not due to inhibition of monoamine oxidase activity. Subcellular distribution studies in mouse brain showed a significant increase in the particulate fraction of “bound” 5-HT by 6-MeO-THBC. The compound slowed the disappearance of intracisternally injected [ 3 H] 5-HT from the rat brain but had no effect on the level of [ 3 H] 5-hydroxyindoleacetic acid. Increased binding of the 5-HT was suggested as a possible mechanism for the effects of 6-MeO-THBC on brain 5-HT.