Do classical hallucinogens act as 5-HT2 agonists or antagonists?

There has long been controversy over whether the classical hallucinogens behave as serotonin (5-hydroxytryptamine [5-HT]) agonists or antagonists. Now that there is evidence that many of the effects produced by these agents involve a 5-HT2 mechanism, a new controversy has arisen: do they behave as 5-HT2 agonists or as 5-HT2 antagonists? A review of the existing literature suggests that where a 5-HT2 mechanism has been implicated (such as in phosphoinositide turnover, contraction of certain smooth muscle, rat-paw edema, head-twitch behavior, discriminative stimulus effects, hyperthermia, platelet aggregation, and in various other effects), the classical hallucinogens are most likely acting via an agonist, or at least via a partial agonist, mechanism. A partial agonist mechanism would explain why classical hallucinogens occasionally appear to act as antagonists. Furthermore, in certain instances, and due to their nonselective nature, indolealkylamine hallucinogens may be able to modulate their own 5-HT2-mediated effects by simultaneous costimulation of 5-HT1 receptors. These agents can also modulate the agonist effects of other, more selective 5-HT2 agonists. Nevertheless, it is very unlikely that the classical hallucinogens are acting as pure 5-HT2 antagonists.