Dolores Brine

Activity of Δ8-and Δ9-Tetrahydrocannabinol and Related Compounds in the Mouse

The 11-hydroxy metabolites of Δ8.- and Δ9-tetrahydrocannabinol are more active than the parent compounds when administered to mice by either the intravenous or intracerebral route. Both Δ8- and Δ9-tetrahydrocannabinol are rapidly and extensively metabolized by the liver and not by the brain. The hypothesis that the 11-hydroxy metabolites may be the active form of tetrahydrocannabinol is discussed

Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids

OBJECTIVES To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of the N-oxide forms of these alkaloids to levels of the parent alkaloids. DESIGN Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine. Recognising that the N-oxide derivatives of these alkaloids have also been identified in comfrey preparations, chemical reduction was applied to determine the total quantities of the alkaloids as free bases and as N-oxide derivatives. RESULTS The concentration of symphytine and echimidine varied considerably between teas prepared from leaves purchased from the different vendors of plant material. Moreover, a much higher concentration of symphytine was found in the tea when steps were included to reduce N-oxides prior to analysis. The treatment of pure symphytine with hot water did not generate the N-oxide derivative de novo. CONCLUSIONS Since the pyrrolizidine alkaloids are known to be hepatotoxic, consumption of herbal teas made from comfrey leaves may be ill-advised. The concentration of pyrrolizidine alkaloids in such teas may be underestimated substantially unless the concentration of N-oxides is taken into consideration.

Pyrolysis Products of Heroin

Heating of heroin hydrochloride or of heroin at 250 degrees C led to extensive degradation. Major components of the pyrolysate were identified as heroin, 6-acetylmorphine, N,6-diacetylnormorphine, and N-acetylnorheroin by comparison of mass spectra and 13C- and 1H-nuclear magnetic resonance (NMR) spectra with those of authentic compounds. There was evidence for degradation of the piperidino moiety and the structure 3,4-diacetoxyphenanthrene was proposed for a minor product.

Identification of Cannabinoids and Metabolites in Biological Materials by Combined Gas-Liquid Chromatography—Mass Spectrometry

Studies from several research groups have shown that Δ9-tetra-hydrocannabinol (Δ9-THC) and related cannabinoids, such as can-nabidiol and cannabinol, are extensively metabolized by liver microsomal enzymes (cf. Mechoulam [2] and Paton and Crown [3] for recent reviews). Studies from our laboratories have shown that the major metabolic route involves rapid hydroxylation at carbon 11 followed by further oxidation to the carboxylic acids [4–7]. Minor routes involve hydroxylation at the 8α or 8β positions, or in the side chain singly or in combination with the major routes. The sites of hydroxylation in the THC molecule are shown in Figure 5.1.

APPLICATIONS OF MASS SPECTROMETRY IN CANNABINOID RESEARCH

GC—MS methods are described for the quantitation of Δ 9 -THC, 11-hydroxy-Δ 9 -THC, 11-nor-Δ 9 -THC-9-oic acid and CBN in blood and urine using deuterated internal standards. Linear calibration curves were obtained and levels as low as 0.2–0.5 ng/ml could be measured. Results obtained on different instruments and using both electron-impact and chemical ionization showed good reproducibility. Good correlation was also found with measurements made by GLC or radio-TLC. 11-nor-Δ 9 -THC-9-oic acid could be measured with reasonable linearity from 1 ng/ml to 50 ng/ml. A biphasic elimination pattern was observed following i.v. infusion of 4–5 mg Δ 9 -THC. The peak concentration of 50–60 ng/ml declined rapidly for 15–40 min and then more slowly to a value of 3–5 ng/ml after 24 hours. 11-nor-Δ 9 -THC-9-oic acid also showed biphasic elimination but with a longer half-life. 3“-Hydroxy-Δ 9 -THC was also measured by GC—MS using the 11-hydroxy isomer as internal standard. The elimination of 11-[ 2 H 3 ]Δ 9 -THC was also studied and found to be more rapid than elimination of the unlabelled drug. Finally a GC—MS method was developed for the measurement of paraquat in marihuana smoke as its sodium borohydride reduction product.

CLINICAL STUDY OF FREQUENT MARIJUANA USE: ADRENAL CORTICAL RESERVE METABOLISM OF A CONTRACEPTIVE AGENT AND DEVELOPMENT OF TOLERANCE*

In recent years, the frequent use of marijuana among segments of the American population has become a cause of concern as to whether the drug could significantly affect the health of the users. We will report the effects of marijuana as used by young Americans in a southeastern university town on three unrelated physiologic parameters: adrenal cortical reserve, liver metabolism of a contraceptive drug; and development of tolerance or sensitivity to Ag-tetrahydrocannabinol ( Ag-THC). In this report, we define frequency of marijuana use as the number of cigarettes smoked per year multiplied by the number of years of use. We recognize the faults of this method of measurement, in that it relies on subjective reporting, which might not be accurate, on mathematical averaging, which might not be appropriate, and on a total lack of knowledge of the potency of the marijuana used in terms of AS-THC content. Whatever the disadvantages of the retrospective approach, it has produced significant results in the study of the health consequences of alcohol and tobacco use.