Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA)
- 454 Downloads
The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.
In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.
Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.
ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.
These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.
KeywordsLSD 5-HT2A receptor Lysergamide Psychedelics Head twitch
These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP), Contract No. HHSN-271-2008-00025-C. The NIMH PDSP is directed by Dr. Bryan Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda, MD, USA.
This study was funded by NIDA (R01 DA041336).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Abramson HA, Rolo A (1967) Comparison of LSD with methysergide and psilocybin on test subjects. In: Abramson HA (ed) The use of LSD in psychotherapy and alcoholism. Bobbs-Merrill Company, Inc., Indianapolis, pp 53–57Google Scholar
- Anonymous (2018) Tripping well grounded: an experience with MIPLA (exp111958). Available online: https://erowid.org/experiences/exp.php?ID=111958 [Accessed: August 21, 2018]
- Barrett FS, Preller KH, Herdener M, Janata P, Vollenweider FX (2017) Serotonin 2A receptor signaling underlies LSD-induced alteration of the neural response to dynamic changes in music. Cereb Cortex, in press. https://doi.org/10.1093/cercor/bhx257
- Bennett JP, Jr., Snyder SH (1975) Stereospecific binding of D-lysergic acid diethylamide (LSD) to brain membranes: relationship to serotonin receptors. Brain Res 94: 523–544Google Scholar
- Brandt SD, Kavanagh PV, Westphal F, Elliott SP, Wallach J, Colestock T, Burrow TE, Chapman SJ, Stratford A, Nichols DE, Halberstadt AL (2017a) Return of the lysergamides. Part II: analytical and behavioural characterization of N6 -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ). Drug Test Anal 9:38–50CrossRefPubMedGoogle Scholar
- Brandt SD, Kavanagh PV, Westphal F, Elliott SP, Wallach J, Stratford A, Nichols DE, Halberstadt AL (2017b) Return of the lysergamides. Part III: analytical characterization of N(6) -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD). Drug Test Anal 9:1641–1649CrossRefPubMedPubMedCentralGoogle Scholar
- Brandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, Stratford A, Klein LM, McCorvy JD, Nichols DE, Halberstadt AL (2018) Return of the lysergamides. Part IV: analytical and pharmacological characterization of lysergic acid morpholide (LSM-775). Drug Test Anal 10:310–322CrossRefPubMedGoogle Scholar
- Carhart-Harris RL, Muthukumaraswamy S, Roseman L, Kaelen M, Droog W, Murphy K, Tagliazucchi E, Schenberg EE, Nest T, Orban C, Leech R, Williams LT, Williams TM, Bolstridge M, Sessa B, McGonigle J, Sereno MI, Nichols D, Hellyer PJ, Hobden P, Evans J, Singh KD, Wise RG, Curran HV, Feilding A, Nutt DJ (2016b) Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci U S A 113:4853–4858CrossRefPubMedPubMedCentralGoogle Scholar
- Klein LM, Cozzi NV, Daley PF, Brandt SD, Halberstadt AL (2018) Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs. Neuropharmacology, in press. doi: https://doi.org/10.1016/j.neuropharm.2018.02.028
- Murphree HB, de Maar EWJ, Williams HL, Bryan LL (1958) Effects of lysergic acid derivatives on man: antagonism between d-lysergic acid diethylamide and its 2-brom congener. J Pharmacol Exp Ther 122:55A–56AGoogle Scholar
- Nichols DE (2018) Chemistry and structure-activity relationships of psychedelics. Curr Top Behav Neurosci 36:1–43Google Scholar
- Peroutka SJ (1994) 5-Hydroxytryptamine receptor interactions of D-lysergic acid diethylamide. In: Pletscher A, Ladewig D (eds) 50 years of LSD current status and perspectives of hallucinogens. Parthenon Press, New York, pp 19–26Google Scholar
- Roth BL (2013) National Institute of Mental Health psychoactive drug screening program (NIMH PDSP) assay protocol book, version II. Available online: https://pdspdb.unc.edu/pdspWeb/content/PDSP%20Protocols%20II%202013-03-28.pdf [Accessed: 06 May 2017]
- Schmidt A, Muller F, Lenz C, Dolder PC, Schmid Y, Zanchi D, Lang UE, Liechti ME, Borgwardt S (2018) Acute LSD effects on response inhibition neural networks. Psychol Med 48:1464–1473Google Scholar
- Shulgin AT (2016) Pharmacology notebook 9. Available online: https://www.erowid.org/library/books_online/shulgin_labbooks/shulgin_pharmacology_notebook9_searchable.pdf [Accessed: January 20, 2018]
- Shulgin A, Shulgin A (1997) TIHKAL: the continuation. Transform Press, BerkeleyGoogle Scholar
- Tagliazucchi E, Roseman L, Kaelen M, Orban C, Muthukumaraswamy SD, Murphy K, Laufs H, Leech R, McGonigle J, Crossley N, Bullmore E, Williams T, Bolstridge M, Feilding A, Nutt DJ, Carhart-Harris R (2016) Increased global functional connectivity correlates with LSD-induced ego dissolution. Curr Biol 26:1043–1050CrossRefPubMedGoogle Scholar
- Valle M, Maqueda AE, Rabella M, Rodriguez-Pujadas A, Antonijoan RM, Romero S, Alonso JF, Mananas MA, Barker S, Friedlander P, Feilding A, Riba J (2016) Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. Eur Neuropsychopharmacol 26:1161–1175CrossRefPubMedGoogle Scholar