Acomplia may be dangerous for women of reproductive age

Anandamide is a lipid signal molecule that was the first endogenous agonist for cannabinoid receptors to be discovered.
Cannabinoid receptor type 1 ( CB1 ) is widely distributed in neurons and nonneuronal cells in brain and peripheral organs including sperm, eggs, and preimplantation embryos.

A study by Wang and colleagues, published in the Journal of Clinical Investigation, has demonstrated that a critical balance between anandamide synthesis by NAPE-PLD enzyme and its degradation by FAAH enzyme in mouse embryos and oviducts creates locally an appropriate "anandamide tone" required for normal embryo development, oviductal transport, implantation, and pregnancy.

Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of delta-9-tetrahydrocannabinol ( THC; the major psychoactive constituent of marijuana ), due to enhanced signaling via CB1.

Attempts to understand the mechanisms responsible for the psychoactive properties of THC in marijuana led to the discovery of cannabinoid receptors and their endogenous ligands, the endocannabinoids.
Two subtypes of cannabinoid receptors have been identified to date, the CB1 receptor and the CB2 receptor.

Anandamide signaling via cannabinoid receptors is not restricted to the central nervous system.
It is known that CB1 and CB2 are widely distributed in nonneuronal somatic cells of peripheral organs including those of the reproductive system. This may account for the effects of marijuana and THC on multiple aspects of reproductive physiology.

Aberrant functioning of anandamide signaling systems in embryos and oviducts in women may lead to ectopic pregnancy in the oviduct and/or impaired fertility.
Similar adverse effects may be associated with abuse of marijuana by women of reproductive age.
Reduced peripheral FAAH activity is associated with spontaneous abortion in women.

As the first endocannabinoid to be discovered, anandamide has attracted the most attention from investigators. Similarly, the biological functions of CB1 have been studied much more extensively than those mediated by CB2, because CB1 receptors in the brain are directly involved in the psychoactive effects of THC.

Anandamide signaling presents many potential targets for the development of novel therapeutic drugs. Unfortunately, cannabinergic ligands affect almost every physiological system investigated. Thus, drugs acting on anandamide signaling may produce a wide variety of side effects that would limit their utility. For example, possible medicinal uses of THC are limited by its psychoactive properties.

One strategy for drug development targets specific cannabinoid receptors. The CB1 antagonist Rimonabant ( Acomplia ) suppresses appetite. The EMEA ( European Agency for the Evaluation of Medicinal Products ) recently has approved the use of Acomplia as a weight-loss drug.

An alternate approach targets removal and degradation of anandamide. Basal levels of anandamide in the brain and peripheral organs are quite low. It is rapidly released and degraded locally. Thus, drugs that prevent anandamide reuptake and hydrolysis might be useful clinically.

However, these drugs should be “carefully evaluated to judge their effects on women of reproductive age and those that are pregnant”, says Herbert Schuel, at the University at Buffalo.

Source: Journal of Clinical Investigation, 2006