Because of the widespread importance of serotonin, the development of serotonin
antagonists is a continuing area of research endeavor. 5-HT2Cantagonists have been
clinically evaluated as antidepressants; 5-HT 6 antagonists may have clinical utility as
antipsychotics.
4.5.4.4 Serotonergic Drugs as Hallucinogens and Psychotomimetic Agents
These drugs seem to act on central 5-HT neurons in a manner that is not clear. They
decrease the turnover of serotonin, possibly through a presynaptic receptor in the raphe
cells. Since 5-HT is an inhibitory neurotransmitter in many of its actions, the removal
of this inhibition could lead to behavioral changes. However, to discredit this simple
hypothesis, there are a number of LSD derivatives that are not hallucinogens (e.g., the
2-bromo derivative). The effects of LSD are also seen in animals with raphe lesions that
have destroyed the serotonergic neurons.
There are indications that other psychotomimetic agents also act through a central
5-HT mechanism. Four groups can be distinguished:
- Lysergic acid diethylamide and related indolalkylamines
- Phenylethylamines (e.g., mescaline)
- Cannabis derivatives
- Anticholinergics
LSD (4.126) is a rather structure-specific compound. Only the (+)-isomer is active, and
alkylamides other than the diethyl derivative, including some cyclic analogs (the pyrro-
lidide and morpholide analogs), have very low activity. Lysergic acid does contain the
3-indolylethylamine moiety, and it is therefore not surprising that other such structures
are also hallucinogens. Among natural products, psilocin (4.127) and its phosphate
ester, psilocybin, occur in a Mexican mushroom (Psilocybe). Harmaline (4.128), an
alkaloid (from Peganum harmalaand some other plants), and some related compounds
are also effective hallucinogens.
After the ingestion of hallucinogens, a great variety of symptoms may occur, includ-
ing dizziness; perceptual changes of size, time, and distance; visual hallucinations;
mood changes; and potential panic. These effects may last for about 12 hours. Tolerance
develops quickly, and there is cross-tolerance with phenylethylamines but not with
amphetamines. The psychological hazards (“bad trip”) of LSD use are very real; the
physiologically harmful effects, if any, are not clear cut.
NEUROTRANSMITTERS AND THEIR RECEPTORS 257