Abuse Liability Profile of Three Substituted Tryptamines

Abstract

The abuse liability profile of three synthetic hallucinogens, N,Ndiisopropyltryptamine (DIPT), 5-N,N-diethyl-5-methoxytryptamine (5-MeO-DET), and 5-methoxy-␣-methyltryptamine (5-MeO-AMT), was tested in rats trained to discriminate hallucinogenic and psychostimulant compounds, including cocaine, methamphetamine, 3,4-methylenedioxymethylamphetamine (MDMA), lysergic acid diethylamide (LSD), (Ϫ)-2,5-dimethoxy-4-methylamphetamine (DOM), and dimethyltryptamine (DMT). Because abused hallucinogens act at 5-hydroxytryptamine 1A (5-HT 1A ) and 5-HT 2A receptors, and abused psychostimulants act at monoamine transporters, binding and functional activities of DIPT, 5-MeO-DET, and 5-MeO-AMT at these sites were also tested. DIPT fully substituted in rats trained to discriminate DMT (ED 50 ϭ 1.71 mg/kg) and DOM (ED 50 ϭ 1.94 mg/kg), but produced only 68% LSD-appropriate responding. 5-MeO-DET fully substituted for DMT (ED 50 ϭ 0.41 mg/kg) and produced 59% MDMA-appropriate responding. 5-MeO-AMT did not fully substitute for any of the training drugs, but produced 67% LSD-appropriate responding. None of the compounds produced substitution in rats trained to discriminate cocaine or methamphetamine. All three compounds showed activity at 5-HT 1A and 5-HT 2A receptors as well as blockade of reuptake by the serotonin transporter. In addition, 5-MeO-AMT produced low levels of serotonin release and low potency blockade of dopamine uptake. DIPT, 5-MeO-DET, and 5-MeO-AMT produced behavioral and receptor effects similar to those of abused hallucinogens, but were not similar to those of psychostimulants. DIPT and 5-MeO-DET may have abuse liability similar to known hallucinogens and may be hazardous because high doses produced activity and lethality.

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…5-MeO-AMT has also been shown to act as a substrate releaser at rat monoamine transporters and the human SERT (Gatch et al, 2011). A recent study showed that 5-MeO-MiPT stimulated 5-HT 2 receptors but did not interact with rat monoamine transporters (Blough et al, 2014), in contrast to its close analog 5-methoxy-diisopropyltryptamine (5-MeO-DiPT), which acted at the SERT (Blough et al, 2014;Sogawa et al, 2007).…”

“…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).…”

“…DiPT is an agonist at rat and human 5-HT 2A receptors and also blocks the rat and human SERT (Blough et al, 2014;Cozzi et al, 2009;Gatch et al, 2011;Nagai et al, 2007). However, interactions with other receptors have not yet been studied.…”

“…DiPT is a ring-unsubstituted tryptamine, similar to DMT. DiPT fully substituted for 5 DMT in discrimination studies (Gatch et al, 2011) but unlike DMT reportedly induces auditory and not visual alterations in humans (Blough et al, 2014). DiPT is psychoactive at doses of 20-100 mg, with effects that last 4-8 h (Shulgin and Carter, 1980;Tittarelli et al, 2015).…”

“…The clinical effects of 5-MeO-AMT reportedly last up to 18 h, and severe toxicity has been associated with this substance (Tittarelli et al, 2015). 5-MeO-AMT is a potent 5-HT 2A receptor ligand and agonist with some selectivity for the 5-HT 2A receptor over the 5-HT 1 receptor (Gatch et al, 2011;Glennon et al, 1990;Tomaszewski et al, 1992).…”