The hallucinogenic world of tryptamines: an updated review

Abstract

In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N,N-dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD ('legal' alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as 'research chemicals', but can also be sold in 'headshops' and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…However, many synthetic tryptamine derivatives have been synthesized and are recreationally used as novel psychoactive substances (Araujo et al, 2015;EMCDDA, 2014;Helander et al, 2014;Kamour et al, 2014;Shulgin and Shulgin, 1997;Tittarelli et al, 2015;Winstock et al, 2014). Tryptamines share their core structure with the neurotransmitter serotonin (5-hydroxytryptamine ).…”

“…The psychoactive effects of hallucinogens, including those of tryptamines, are thought to be mediated mainly by the 5-HT 2A receptor (Glennon et al, 1984;Nichols, 2004;Titeler et al, 1988;Vollenweider et al, 1998) but may also be modulated by interactions with other targets, including other 5-HT receptors, monoamine transporters, and trace amineassociated receptors (Baumeister et al, 2014;Bunzow et al, 2001;Cozzi et al, 2009;Fantegrossi et al, 2006;McKenna et al, 1990;Nagai et al, 2007;Nichols, 2004;Ray, 2010). Structural alterations of tryptamines have been shown to result in different pharmacological and psychoactive profiles (Araujo et al, 2015;McKenna et al, 1990;Repke et al, 1985;Shulgin and Shulgin, 1997;Tittarelli et al, 2015;Trachsel et al, 2013). For example, compounds that have no substitutions or a 4-hydroxyl group (e.g., DMT or psilocin, respectively; Fig.…”

“…1) produce hallucinogenic effects with relative low potency in man (Repke et al, 1985). Psilocin is orally psychoactive above 5-10 mg, and DMT is active at parenteral doses of 20-100 mg (Araujo et al, 2015;Shulgin and Shulgin, 1997;Studerus et al, 2011;Tittarelli et al, 2015). In contrast, a 5-methoxy group, such as in 5-MeO-AMT ( Fig.…”

“…Different N-substitutions also influenced in vivo potency (Nichols et al, 2015;Repke et al, 1985). The pharmacological profiles of many tryptamines have been studied previously at selected targets (Blough et al, 2014;Gatch et al, 2011;McKenna et al, 1990;Nichols et al, 2015;Repke et al, 1985;Shulgin and Carter, 1980), and new and pharmacologically unknown tryptamine derivatives are constantly emerging on the illicit drug market (Araujo et al, 2015;Corkery et al, 2012;EMCDDA, 2014;Greene, 2013;Helander et al, 2014;Tittarelli et al, 2015).…”

“…LSD and mescaline were included for comparison. Tryptamines have also been shown to interact with membrane monoamine transporters to inhibit their function or release monoamines through the transporter (Araujo et al, 2015;Cozzi et al, 2009;Nagai et al, 2007), similar to 3,4-methylenedioxymethamphetamine (MDMA) and many other novel psychoactive substances (Rickli et al, 2015a;Simmler et al, 2013;Simmler et al, 2014a;Simmler et al, 2014b). Therefore, inhibition of the norepinephrine (NE), dopamine (DA), and 5-HT transporters (NET, DAT, and SERT, respectively) and the release of NE, DA, and 5-HT were also investigated.…”