Natural Cannabinoids

A serious problem in the early Western medicinal use of C. sativa, mainly as a tincture, was its highly variable activity and inconsistent results. Medicinal preparations have to handle several particularities due to the structure of the active ingredients of C. sativa. The identity of the main active constituent of C. sativa, A9-tetrahydrocannabinol (INN dronabinol) remained unknown until 1964 [128] standardized C. sativa preparations were not available. The plant itself is found in several different chemotypes, which added to the unpredictable nature of early medicinal preparations. 

Cannabinoids are highly lipophilic compounds making bioavailabihty very dependent on the formulation and the mode of administration. Cannabinoid occurrence in the plant is predominantly in the form of the carboxyhc acids, which are pharmacologically totally different and rather unstable, decarboxy-lating over time to their active neutral form. The carboxyhc acids, although not active at the CB receptor, nevertheless add to the overall effect as they possess antibiotic and anti-inflammatory effects. 

Last but not least the identification of THC as the main active constituent of C. sativa was preceded by an almost total ban on the plant as a narcotic drug, practically ending medicinal research. 

the 20th century actually led to an almost total disappearance of C. sativa for medicinal purposes. The only source for THC, which became the focus of scientific research, was fhe rafher fedious exfracfion and purification from confiscated hashish or marihuana. In 1972 the first commercially viable total synthesis of A9-THC was established and it became the first cannabinoid available as a modern medicine in the form of soft gel capsules (the active ingredient being called dronabinol from tetrahydrocannabinol) under the trade name Marinol for the prevention of nausea and vomiting during cancer chemotherapy. 

Interestingly this indication resulted from the observation of marihuanasmoking patients rather than from pharmacological research. 

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After the discovery of specific endocannabinoid receptors, the amount of scientific literature quickly rose and not only new potential indications were established, but also the mechanisms for the already known effects were clarified. Although the most prominent effect of C. sativa is clearly related to THC and its activity at the CBl receptor, most other natural cannabinoids are not active there. Today two other natural cannabinoids CBD and THCV are the focus of medicinal research. 

There are over 400 constituent compounds in marijuana. More than 60 of these are pharmacologically active cannabinoids, of which 4 are the most important. The most psychoactive is delta-9-tetrahydrocannabinol (A-9-THC). The other three important natural cannabinoids are A-8-THC, cannabinol and cannabidiol (Kumar et al., 2001). In addition, some of the metabolites of THC, such as 11-hydroxy-A-9-THC, are also psychoactive. As a consequence and contrary to many other drugs, the metabolism of THC in the liver does not decrease intoxication, rather it prolongs it. 

Navarro M, Rubio P, de Fonseca FR. (1995). Behavioural consequences of maternal exposure to natural cannabinoids in rats. Psychopharmacology (Berlin). 122(1) 1-14. 

Like all plants. Cannabis sativa L. forms a huge number of chemicals. Many of these have been identified.None of them, except the cannabinoids are specific for this plant and none of these non-cannabinoids has been found to contribute to the cannabinoid effects. Ffowever, very few have been directly tested together with cannabinoids for any biological effects. Recently, ElSohly and Slade, published a comprehensive review. Up to date, 70 natural cannabinoid compounds were documented. Althogether, they record 419 constituents nitrogenous compounds (27), amino acids... 

ElSohly MA, Slade D, Chemical constituents ofmarijuana The complex mixture of natural cannabinoids. Life Sci 78 539—548, 2005. 

The X-ray crystal structure of A1 -tetrahydrocannabinolic acid B is reported,362 and one of the previously reported (Vol. 4, p. 75) dihydrobenzofurans from the citric acid-catalysed condensation of orcinol with menth-4-en-3-ol is shown to be (256) by X-ray analysis.363 G.c.-m.s. assay of A -THC-OMe allows the detection of 1 ng mP1 plasma of A -THC.364 The mass spectral fragmentation of A -THC, A6-THC, and some isomeric cannabinoids to the prominent m/e 231 ion has been examined.365 Miniaturized syntheses of 32 natural, or potentially natural, cannabinoids are reported in connection with their chromatographic analysis.366... 

Petitet F, Jeantaud B, Reibaud M, Imperato A, DubroeucqMC (1998) Complex pharmacology of natural cannabinoids evidence for partial agonist activity of A9-tetrahydrocanna-binol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 63 PL1-PL6... 

Finally, it should be noted that cannabidiol, a natural cannabinoid that does not activate cannabinoid receptors, suppresses lithium-induced conditioned rejection reactions in a rat model of nausea (Parker et al. 2002) and also potentiates the antiemetic effect of ondansetron andA -THC in the musk shrew (Kwiatkowska et al. 2004). 

Nahas G, Trouve R (1985) Effects and interactions of natural cannabinoids on the isolated heart. Proc Soc Exp Biol Med 180 312-316... 

As with the natural cannabinoids, the metabolism of nabilone appears to be extensive and complex. Of particular interest are the primary metabolites - the reduction products of the 1-oxo moiety. While in rats both enantiomers present in the racemate were reduced in vitro and in vivo to the (IS)-alcohol, in dogs one of the enantiomers gave both the (lS)-ol and the (l/ )-ol. The pharmacokinetic picture also differed. While the total carbinol metabolites accounted for 90% of metabolites in dog plasma after 24 h, in humans even after 8 h only 10% were carbinols. However, the doses administered were not fully comparable. These differences in metabolism (or possibly related ones) seem to account for a difference in toxicity. Rats, monkeys and apparently humans differ in their metabolism (and toxicological profile) from the dog, in which some deaths were observed upon prolonged administration [ 162]. 

Bueb, J.L., Lambert, D.M., Tschirhart, E.J., 2001. Receptor-independent effects of natural cannabinoids in rat peritoneal mast cells in vitro. Biochim. Biophys. Acta 1538, 252-259. 

Scientific research during the 1990s made great strides in understanding how THC and other cannabinoids act in the human body. One of the most important findings of this research was the discovery that the brain and other parts of the body contain cannabinoid receptor sites, places where cannabinoids can change the chemistry of that region. (Researchers also found natural cannabinoids in the human body, which explains why the body has cannabinoid receptor sites in the first place.)... 

For many years scientists have known that in men, marijuana use also causes reduced fertility. A 2000 study conducted by scientists from the University of Buffalo found definite evidence that marijuana use has caused infertility in some men. This research proved that cannabi-noids, both the body s natural cannabinoids and THC from marijuana, can prevent sperm from functioning normally. High concentrations of cannabinoids, for instance, can cause sperm to be less effective at fertilizing eggs. This fact led scientists to conclude that heavy marijuana users may jeopardize their fertility. How often this happens is still unknown, but the lead scientist in the University of Buffalo study stated, The increased load of cannabinoids in people who abuse marijuana could flood the natural cannabinoid-signal systems in reproductive organs and adversely impact fertility. This possibility may explain observations made over the past 30 to 40 years that marijuana smoke drastically reduces sperm production in males. ... 

A -THC is the single most potent natural cannabinoid interacting with CB receptors, and the isolation of analogs, coupled to the synthesis of several derivatives, have highlighted the most important pharmacophoric portions of this molecule. 

A number of synthetic compounds, completely unrelated to the structure of natural cannabinoids have been found to act as CB and/or CB2 antagonist/ inverse agonist. The most important member of this class of compounds is rimonabant (29), a diarylpyrazole derivative [57], approved for the treatment of obesity and as an aid in the cessation of cigarette smoking, but later withdrawn from the market because of the severe depression it could induce in sensitive patients. A number of structural motifs significantly different from the p3razole system have been proposed for CB2 selective antagonists, as exemplified by the quinoline derivative 30. 

Availability due to the potential for abuse, there is legal debate about the therapeutic use of natural cannabinoids. It is to be noted that use of cannabinoids may be habit-forming and possibly lead to abuse of other substances. This may not be the case for peripherally selective agonists. Currently CB receptor agonists are only available for experimental analgesic trials. 

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