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Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action

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New Psychoactive Substances

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 252))

Abstract

Recent, well-controlled – albeit small-scale – clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

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Abbreviations

1P-LSD:

1-Propionyl-lysergic acid diethylamide

25C-NBOMe:

N-(2-Methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine

25CN-NBOH:

N-(2-Hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine

25I-NBOMe:

N-(2-Methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine

2C-B:

4-Bromo-2,5-dimethoxyphenethylamine

2C-I:

4-Iodo-2,5-dimethoxyphenethylamine

2C-T-7:

2,5-Dimethoxy-4-propylthiophenethylamine

5-APB:

5-(2-Aminopropyl)benzofuran

5-HT:

5-Hydroxytryptamine (serotonin)

5-MeO-DALT:

5-Methoxy-N,N-diallyltryptamine

5-MeO-DIPT:

5-Methoxy-N,N-diisopropyltryptamine

5-MeO-DMT:

5-Methoxy-N,N-dimethyltryptamine

6-APB:

6-(2-Aminopropyl)benzofuran

AL-LAD:

N 6-allyl-6-norlysergic acid diethylamide

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

bk-2C-B:

β-Keto-2,5-dimethoxy-4-bromophenethylamine

BOL-148:

2-Bromo-lysergic acid diethylamide

CB1:

Cannabinoid 1 receptor

DA:

Dopamine

DIPT:

N,N-Diisopropyltryptamine

DMT:

N,N-Dimethyltryptamine

DOB:

2,5-Dimethoxy-4-bromoamphetamine

DOI:

2,5-Dimethoxy-4-iodoamphetamine

DOM:

2,5-Dimethoxy-4-methylamphetamine

DOPAC:

3,4-Dihydroxyphenylacetic acid

DPT:

N,N-Dipropyltryptamine

IP3 :

Inositol 1,4,5-trisphosphate

LSA:

Lysergamide

LSD:

Lysergic acid diethylamide

LSM-775:

Lysergic acid morpholide

LSZ:

Lysergic acid 2,4-dimethylazetidide

mCPP:

meta-Chlorophenylpiperazine

MDMA:

3,4-Methylenedioxymethamphetamine

mGluR2:

Metabotropic glutamate receptor 2

NMDA:

N-Methyl-D-aspartate

PARGY-LAD:

N 6-Propynyl-6-norlysergic acid diethylamide

PET:

Positron emission tomography

SERT:

Serotonin transporter

TAAR1:

Trace amine-associated receptor 1

TCB-2:

1-(3-Bromo-2,5-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine

THC:

Δ9-Tetrahydrocannabinol

THH:

Tetrahydroharmine

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Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse (R21DA040907) and the Department of Defense (W81XWH-17-1-0329). I express my sincere gratitude to Dr. Nader Moniri and Austen Casey for critically reading and providing feedback on an early draft of this manuscript.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, USA

    Clinton E. Canal

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  1. Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany

    Hans H. Maurer

  2. School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK

    Simon D. Brandt

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Canal, C.E. (2018). Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action. In: Maurer, H., Brandt, S. (eds) New Psychoactive Substances . Handbook of Experimental Pharmacology, vol 252. Springer, Cham. https://doi.org/10.1007/164_2018_107

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