Metabolism of the drug by the body exerts an important influence on the psychopharmacologic effect of marihuana. Many laboratories in many countries have been examining the metabolism, of the cannabinoids using in vitro liver microsomal enzyme preparations.

With the recent availability of radiolabeled Delta 9 and Delta l THC, cannabinol and cannabidiol much activity has occurred in vivo in animals. A comprehensive review of these areas including studies of absorption, disposition, excretion, metabolism and stimulation-inhibition of metabolism is beyond the scope of this report. Readers interested in further details in this area are referred to an excellent comprehensive review by Lemberger (1972).

From animal and in vitro studies it appears that the liver rapidly changes Delta 9 and Delta 11 THC in a similar manner by hydroxylation to 11-OH THC. This compound appears to be as potent or possibly more potent pharmacologically than the parent compounds This metabolite appears to be, rapidly hydroxylated to 8-11 dihydroxy Delta 9 THC (7-11 dihydroxy All THC) which is inactive. The 8-OH Delta THC appears to be a minor active metabolite (Christensen et al., 1971; Burstein et 1970; Ben-Zvi et al., 1970; Foltz et al., 1970; Wall et al., 1970,71; Nilsson et al., 1970).

These metabolites are excreted primarily into the bile and then to the feces. Some evidence exists for an enterohepatic circulation returning the drug to the blood. (Miras and Coutselinis, 1970; Klausner and Dingell, 1971)

Another metabolic pathway appears to be present resulting in a series of acidic metabolites excreted primarily in the urine (Agurell et al, I., 1970). Recently, Burstein and Rosenfeld (1971) isolated and identified a majo r rabbit urinary metabolite, 11-carboxy-2'-hydroxy-Delta 9 THC. They postulate that other acidic metabolites might be esters or amides of this compound (Figure 7).

Recently, Nakazawa and Costa (1971) demonstrated that A' THC was metabolized by lung microsomes forming two unidentified products not found in liver homogenates.

Lemberger et al. (1970, 1971, 1972) and Galanter et al. (1972) have performed metabolic studies in mail using intravenous, oral and smoked Delta 9 THC. These studies indicate that the THC disappears from the plasma in two phases.

The initial rapid phase has two components and represents metabolism by the liver and redistribution from the blood to the tissues. The slower second phase represents tissue retention and slow release and subsequent metabolism.

The plasma 1/2 life of THC was significantly shorter in daily users than nonusers at both the first component of phase one (10 minutes versus 13 minutes) and phase two (27 hours versus 56 hours). Tissue distribution was similar in daily and nonuser (1/2 life 2 hours).

Therefore, immediate metabolism of THC and subsequent metabolism is more rapid for daily user than the non-user implying specific enzyme induction. THC persists in the plasma for a considerable period of time, at least three days, with a half life of 57 hours for nonusers and 28 hours for daily users.

The presence of 11-hydroxy THC and more polar metabolites in the plasma of both users and nonusers within 10 minutes indicates that the metabolite probably accounts for the pharmacological activity of marihuana, not THC.

Further metabolism of the 11-hydroxy THC to more polar inactive 8-11 dihydroxy A' THC metabolite occurs more rapidly in users than nonusers. During the first few hours after injection, unchanged THC, its polar metabolites and nonpolar metabolites in the plasma, decline rapidly and then level off as they are distributed to the tissues. THC persists in the plasma, for at least three days, and both users and non-users excrete metabolites in the urine and feces for more than a week.

Delta-9-THC is extensively metabolized to more polar compounds which were excreted in the urine and feces. Urinary excretion and biliary excretion (reflected a day later in the feces) was greatest during the initial 24 hours, then gradually tapered off. All THC is metabolized since no unchanged THC was excreted in the feces or urine. No difference in total cumulative excretion was observed but a significantly larger percentage of the metabolites were excreted in the urine of users than nonusers. About 40-45% of the metabolites were collected in the feces in both groups in one week. Urinary excretion in this period accounted for 30% in daily users and 22% in nonusers. (Lemberger et al., 1970, 1971, 1972)

Perez-Reyes et al. (1971) found a similar pattern of excretion of metabolites after oral administration.

Urine contained no Delta 9 THC, only a small quantity (3%) of 11-hydroxy THC and 90% more polar acidic compounds as yet unidentified. (Lemberger, 1971). Preliminary studies by Burstein and Rosenfeld ('1971) suggest that these human acidic urinary metabolites are identical to the 11-carboxy-2' hydroxy THC found in rabbits.

In man, Lemberger et al. (1971, 1972) found that 11-OH THC and 8-11-OH THC were primarily excreted in the feces. Twenty-two percent of the metabolites in the feces were unchanged 11-hydroxy THC and slightly less were 8-11-dihyd-roxy THC. The remainder were unidentified more polar compounds, perhaps conjugates of these metabolites.

All user subjects (Lemberger et al., 1970, 1971, 1972) but no non-user noted a high after intravenous injection of the 0.5 mg dose of Delta 9 THC. This would be a dose range of 5 to 7 micrograms/kg. Highs have been noted by Kiplinger et al. (1971) with smoking THC to deliver a dose of 6.25 micrograms/kg. The high for some lasted up to 90 minutes. Thus, the plasma levels of Delta 9 THC and its metabolites seen after intravenous injection suggest that psychopharmacologic effects are seen in the first component of the rapid phase and terminated by redistribution and metabolism after the initial phase. The 11-hydroxy Delta 9 THC would be present at this early phase and is probably responsible for the activity of Delta 9 THC in marihuana.

Further evidence that the 11-OH Delta 9 THC is responsible for marihuana's effect was seen in oral and inhalation studies. By the oral route, blood levels of unchanged THC were relatively low compared to the radioactivity levels of the metabolic products at the time of peak subjective effect. While the blood level of unchanged THC at the peak oral effect was identical to that after intravenous injection of the 0.5 mg. dose, the psychologic, effect was much more pronounced after oral administration of the larger 20 mg. dose of THC. Again after inhalation, the plasma levels of the metabolites correlate temporally with the subjective effects but the plasma levels of unchanged Delta 9 THC do not. (Lemberger, 1970, 1971, 1972; Galanter, 1972)