Discriminative Stimulus Effects of Substituted Tryptamines in Rats

This animal study (n=64) evaluated the hallucinogen-like effects of eight novel substituted tryptamines in rats and characterized their potency and abuse liability according to their substituted side chains. All compounds fully substituted for the discriminative stimulus effects of 0.5 mg/kg DOM without any adverse effects, unlike other tryptamine analogs.

Abstract

“Introduction: Novel synthetic compounds have been available for decades as quasi-legal alternatives to controlled substances. The hallucinogen-like effects of eight novel substituted tryptamines were evaluated to determine their potential abuse liability.

Methods: Male Sprague–Dawley rats were trained to discriminate 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5 mg/kg, i.p., 30 min) from saline. 4-Acetoxy-N,N-diethyltryptamine (4-AcO-DET), 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET), 4-hydroxy-N,N-diethyltryptamine (4-OH-DET), 4-acetoxy-N-methyl-N-isopropyltryptamine (4-AcO-MiPT), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT), 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DiPT), and 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) were tested for their ability to substitute for the discriminative stimulus effects of DOM.

Results: All test compounds fully substituted for DOM with potencies less than or equal to that of DOM. 4-OH-MET, 4-OH-DET, 4-OH-DMT, and 4-AcO-DMT decreased response rate at doses that fully substituted.

Discussion: Because the test compounds produced DOM-like discriminative stimulus effects, they may have similar abuse liability as DOM. 4-Acetoxy substituted compounds were less potent than 4-hydroxy substituted compounds, and the N,N-diisopropyl compounds were less potent than the dimethyl, diethyl, N-methyl-N-ethyl, and N-methyl-N-isopropyl compounds.“

Authors: Michael B. Gatch, Adam Hoch & Theresa M. Carbonaro

Summary

Classic serotonin-mediated hallucinogens such as psilocybin have likely been used for millennia for religious and divinatory purposes. However, novel synthetic hallucinogens are still coming onto the market, including 4-AcO-DET, 4-OH-MET, 4-OH-DiPT, 4-AcO-DMT, and 4-AcO-DIPT.

Classic hallucinogens act at serotonin (5-HT) receptors, particularly 5-HT2A, but also have effects on 5-HT1A, 5-HT2A, and 5-HT2B receptors.

4-OH-DMT (psilocin) is the active metabolite of the well-known hallucinogen psilocybin, and has similar but not completely overlapping behavioral effects to psilocybin. Some of the parent compounds, DMT, DET, and DiPT, have been reported to produce hallucinogen-like discriminative stimulus effects.

Assessment of abuse liability incorporates several factors, including similar chemical structures and mechanisms of action to known drugs of abuse, behavioral effects common to known drugs of abuse, and confirmatory tests of subjective effects and rewarding/reinforcing effects.

■ RESULTS AND DISCUSSION

All of the test compounds substituted for the discriminative stimulus effects of DOM. The potencies were less than or equal to that of DOM.

Rats did not change their response rate following any dose of 5-MeO-MiPT, 4-AcO-MiPT, or 4-OH-DiPT. However, two rats failed to earn a food pellet following the highest dose of 4-OH-DET and 4-OH-DMT.

These findings agree with earlier findings that substituted tryptamines can produce DOM-like discriminative stimulus effects, and with the fact that psilocybin is converted to 4-OH-DMT in the body, so direct administration of 4-OH-DMT would also fully substitute for the discriminative stimulus effects of DOM.

Eight novel substituted tryptamines produced discriminative stimulus effects comparable to those of DOM, suggesting that they may have similar subjective effects as hallucinogenic tryptamines. Additionally, the hypothesis that psilocin is the behaviorally active metabolite of psilocybin was supported by the full substitution of psilocin in DOM-trained rats.

Standard operant behavior-testing chambers were connected to IBM-PC compatible computers via LVB interfaces and programmed in Med-PC for Windows, version IV to collect data.

27 rats were trained to discriminate ()-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, i.p.) from saline using a two-lever choice methodology. They received 60 training sessions and were used in substitution tests once they achieved 9 of 10 sessions at 85% injection-appropriate responding for both the first reinforcer and total session.

Rats were tested for substitution in DOM-trained rats with 4-AcO-DET, 4-OH-MET, 4-AcO-MiPT, 5-MeO-MiPT, 4-AcO-DMT, 4-AcO-DiPT, and 4-OH-DiPT. The dose effect of each compound was tested from no effect to full effect or rate suppression (20% of vehicle control) or adverse effects.

Drug discrimination data were obtained by administering a volume of 1 mL/kg of various test compounds to rats. The potencies of the test compounds were calculated by fitting straight lines to the linear portion of the doseresponse data for each compound by means of OriginGraph.

The authors declare no competing interests and thank Andrew Tourigny for the artwork.