Phenylethylamine, a fragment of LSD, and a number of alkoxyphenylethylamines
have been used by various aboriginal societies as hallucinogens. The best known is
mescaline (4.129), which occurs in a number of cacti (Lophophora, Trichocereus)
native to Mexico. In large doses (300–500 mg) it causes vivid and colorful hallucina-
tions, perception of the environment as unusually beautiful, and increased insight
(“mind-expanding experience”). The effect is increased by attaching a methoxy group
to the ortho position and using alkyl substituents.
The third group of psychotomimetic compounds comprises the cannabinoids,
represented by ∆^9 -tetrahydrocannabinol (THC) (4.130), the principal active ingredient
of marijuana and hashish, produced by the hemp Cannabis sativa. It is not considered
a hallucinogen, is not habit forming, and seems to have no adverse physiological effects
except in habitual consumers of large quantities. Extremely high doses may lead to
paranoid depersonalization.
The emotional propaganda (both pro and con) surrounding cannabinoids notwith-
standing, cannabinoid derivatives—if not THC itself—have interesting therapeutic pos-
sibilities. One of the cannabinoid derivatives in clinical use, nabilone (4.131), has a very
selective antiemetic activity in patients suffering from toxic side effects of cancer
chemotherapy. Other derivatives show anticonvulsant and analgesic activity, and also
decrease ocular pressure in glaucoma. The structure–activity correlations of these com-
pounds have been explored quite thoroughly.
4.5.5 The Clinical–Molecular Interface: Migraine Headache
as a Serotonergic DisorderAlthough migraines produce severe headaches, not all severe headaches are migraines.
As a headache disorder, migraines have distinctive diagnostic criteria. A classical
migraineonsets with an “aura,” which may be brightly colored lights or bright lighten-
ing displays in the visual fields. The pain then occurs as a pounding, pulsatile, throbbing
headache localized to one side of the head and associated with photophobia (dislike
of light), phonophobia (dislike of noise), nausea, and perhaps vomiting. A common
migraine lacks the aura phase. Migraine is a familial problem in 70% of patients and
occurs more frequently in women than in men, with 14–15% of women experiencing
migraine headaches. A complicated migraine headacheis a migraine associated with
neurologic problems, such as weakness over half of the body. In younger women
258 MEDICINAL CHEMISTRY