Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Abstract

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy.

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…The pharmacological profiles of psilocin and LSD are particularly interesting because both substances currently receive high interest as research tools and potential therapeutic substances in psychiatry (Geyer, 2015;Halberstadt, 2015;Kupferschmidt, 2014). Clinically, the acute effects of psilocybin last shorter than those of LSD but are qualitatively very similar (Passie et al, 2008).…”

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

“…and NBOMe drugs (Braden et al, 2006;Halberstadt, 2015;Halberstadt and Geyer, 2014). receptor affinity correlates with hallucinogenic drug potency in humans (Halberstadt, 2015;Titeler et al, 1988), and NBOMe drugs can be expected to be extremely potent hallucinogens in vivo.…”

“…receptor affinity correlates with hallucinogenic drug potency in humans (Halberstadt, 2015;Titeler et al, 1988), and NBOMe drugs can be expected to be extremely potent hallucinogens in vivo. Indeed, higher incidences of hallucinations and delusions have been reported in patients with NBOMe compared with 2C drug intoxication (Forrester, 2013(Forrester, , 2014Srisuma et al, 2015).…”

“…Indeed, higher incidences of hallucinations and delusions have been reported in patients with NBOMe compared with 2C drug intoxication (Forrester, 2013(Forrester, , 2014Srisuma et al, 2015). suggesting that additional ligand-receptor interactions contribute to receptor activation (Halberstadt, 2015;Nichols, 2004). Additionally, marked discrepancies between inositol phosphate hydrolysis activation and other in vitro assays and the in 13 vivo effects of hallucinogens in laboratory animals or humans are well recognized (Nichols, 2004;Saez et al, 1994;Villalobos et al, 2004).…”

Legally flawed, scientifically problematic, potentially harmful: The UK Psychoactive Substance Bill

“…The properties of Salvia have been studied for many years, but if it were newly emerging onto the market it would be difficult to make predictions about its psychoactive effects. In contrast to classic serotonergic hallucinogens, its primary active constituent -salvinorin A -possesses unique pharmacology at kappa opioid receptors (Grundmann, Phipps, Zadezensky, & Butterweck, 2007), is not self-administered by rats given access to it (Serra et al, 2015), is aversive in mice (Zhang, Butelman, Schlussman, Ho, & Kreek, 2005) and is not detected by simple pre-clinical behavioural assays of hallucinogen-like activity (Halberstadt, 2015). Without evidence from clinical or robust naturalistic studies, psychoactivity and human use of salvinorin A would be difficult to predict by comparison with existing drugs.…”