Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Eur J Pharmacol. 2024 Mar 5;966:176329. doi: 10.1016/j.ejphar.2024.176329.
Epub  2024 Jan 20.

The novel non-hallucinogenic compound DM506 
(3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and 
anxiolytic-like activity in mice by a mechanism involving 5-HT(2A) receptor 
activation.

Arias HR(1), Rudin D(2), Hines DJ(3), Contreras A(3), Gulsevin A(4), Manetti 
D(5), Anouar Y(6), De Deurwaerdere P(7), Meiler J(8), Romanelli MN(5), Liechti 
ME(2), Chagraoui A(9).

Author information:
(1)Department of Pharmacology and Physiology, Oklahoma State University College 
of Osteopathic Medicine, Tahlequah, OK, USA.
(2)Divison of Clinical Pharmacology and Toxicology, Department of Pharmaceutical 
Sciences, University of Basel, Basel, Switzerland; Division of Clinical 
Pharmacology and Toxicology, Department of Biomedicine, University Hospital 
Basel and University of Basel, Basel, Switzerland.
(3)Psychological and Brain Sciences, University of Nevada, Las Vegas, NV, USA.
(4)Department of Chemistry, Vanderbilt University, Nashville, TN, USA; Center 
for Structural Biology, Vanderbilt University, Nashville, TN, USA.
(5)Department of Neurosciences, Psychology, Drug Research and Child Health 
Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 
Italy.
(6)UNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal 
Differentiation and Communication (NorDiC), Rouen Normandie University, 76000, 
Mont-Saint-Aignan, France.
(7)Centre National de la Recherche Scientifique, Institut des Neurosciences 
Integratives et Cognitives d'Aquitaine, UMR, 5287, Bordeaux, France.
(8)Institute for Drug Discovery, Leipzig University Medical School, 04103, 
Leipzig, Germany.
(9)Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen, 
France; UNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal 
Differentiation and Communication (NorDiC), Rouen Normandie University, 76000, 
Mont-Saint-Aignan, France. Electronic address: abdeslam.chagraoui@univ-rouen.fr.

The anxiolytic and sedative-like effects of 
3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic 
compound derived from ibogamine, were studied in mice. The behavioral effects 
were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, 
open field test, and loss of righting reflex (LORR) test. The results showed 
that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in 
naive and stressed/anxious mice, respectively. Repeated administration of 
5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. 
Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was 
inhibited by a selective 5-HT2A receptor antagonist, volinanserin. 
Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the 
transition from a highly alert state (fast γ wavelength) to a more synchronized 
deep-sleeping activity (δ wavelength), which is reflected in the 
sedative/anxiolytic activity in mice but without the head-twitch response 
observed in hallucinogens. The functional, radioligand binding, and molecular 
docking results showed that DM506 binds to the agonist sites of human 5-HT2A 
(Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors and activates them with a potency 
(EC50) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and 
behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared 
to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for 
the first time that the non-hallucinogenic compound DM506 induces anxiolytic- 
and sedative-like activities in naïve and stressed/anxious mice in a dose-, 
time-, and volinanserin-sensitive manner, likely through mechanisms involving 
5-HT2A receptor activation.

Copyright © 2024 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.ejphar.2024.176329
PMID: 38253116 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest We wish to 
confirm that there are no known conflicts of interest associated with this 
publication and there has been no significant financial support for this work 
that could have influenced its outcome.


2. Fitoterapia. 2023 Sep;169:105602. doi: 10.1016/j.fitote.2023.105602. Epub 2023
 Jul 7.

Central nervous system activity of a Tabernaemontana arborea alkaloid extract 
involves serotonergic and opioidergic neurotransmission in murine models.

González-Trujano ME(1), Páez-Martínez N(2), Krengel F(3), Martínez-Vargas D(4), 
León-Santiago M(5), Cruz-López B(6), Puentes-Guerrero JM(1), Díaz-Cantón JK(5), 
Reyes-Chilpa R(7), Guzmán-Gutiérrez SL(8).

Author information:
(1)Laboratorio de Neurofarmacología de Productos Naturales, Dirección de 
Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría "Ramón de la 
Fuente Muñiz", Calz. México-Xochimilco 101, Col. San Lorenzo Huipulco, Ciudad de 
México 14370, Mexico.
(2)Sección de Posgrado e Investigación, Escuela Superior de Medicina, Instituto 
Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Col. Casco de 
Santo Tomas, Ciudad de México 11340, Mexico; Laboratorio Integrativo Para el 
Estudio de Sustancias Inhalables Adictivas, Dirección de Investigaciones en 
Neurociencias, Instituto Nacional de Psiquiatría "Ramón de la Fuente Muñiz", 
Calz. México-Xochimilco 101, Col. San Lorenzo Huipulco, Ciudad de México 14370, 
Mexico.
(3)Laboratorio de Fitoquímica, Departamento de Ecología y Recursos Naturales, 
Facultad de Ciencias, UNAM. Av. Universidad 3000, Circuito Exterior s/n, 
Alcaldía Coyoacán, CP 04510, Ciudad Universitaria, CDMX, Mexico.
(4)Laboratorio de Neurofisiología del Control y la Regulación, Dirección de 
Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría "Ramón de la 
Fuente Muñiz", Calz. México-Xochimilco 101, Col. San Lorenzo Huipulco, Ciudad de 
México 14370, Mexico.
(5)Instituto de Química, Universidad Nacional Autónoma de México, Ciudad 
Universitaria, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, 
C.P. 04510, Ciudad Universitaria, Ciudad de México, Mexico.
(6)Laboratorio Integrativo Para el Estudio de Sustancias Inhalables Adictivas, 
Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría 
"Ramón de la Fuente Muñiz", Calz. México-Xochimilco 101, Col. San Lorenzo 
Huipulco, Ciudad de México 14370, Mexico.
(7)Instituto de Química, Universidad Nacional Autónoma de México, Ciudad 
Universitaria, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, 
C.P. 04510, Ciudad Universitaria, Ciudad de México, Mexico. Electronic address: 
chilpa@unam.mx.
(8)CONAHCyT-Instituto de Investigaciones Biomédicas, Universidad Nacional 
Autónoma de México, Av. Universidad 3000, Circuito Escolar S/N, Delegación 
Coyoacán, C.P. 04510, Ciudad Universitaria, Ciudad de México, Mexico. Electronic 
address: saguzmangu@conahcyt.mx.

Tabernaemontana arborea (Apocynaceae) is a Mexican tree species known to contain 
ibogan type alkaloids. This study aimed at determining central nervous 
system-related activities of an alkaloid extract obtained from the root bark of 
T. arborea. A gas chromatography-mass spectrometry (GC-MS) analysis was 
performed to describe the alkaloid profile of the extract. A wide dosing range 
(0.1 to 56.2 mg/kg) of this extract was evaluated in different murine models. 
Electrical brain activity was examined by electroencephalography (EEG). The 
extract's effects on motor coordination, ambulatory activity, and memory were 
analyzed based on the rotarod, open field (OFT), and object recognition tests 
(ORT), respectively. Antidepressant and antinociceptive activities were 
determined using the forced swimming test (FST) and the formalin assay, 
respectively. In order to elucidate the underlying mechanisms of action, the 
5-HT1A receptor antagonist WAY100635 (1 mg/kg) or the opioid receptor antagonist 
naloxone (1 mg/kg) was included in the latter experiments. GC-MS analysis (μg/mg 
extract) confirmed the presence of the monoterpenoid indole alkaloids (MIAs) 
voacangine (207.00), ibogaine (106.33), vobasine (72.81), coronaridine (30.72), 
and ibogamine (24.2) as principal constituents of the extract, which exhibited 
dose- and receptor-dependent antidepressant (0.1 to 1 mg/kg; 5-HT1A) and 
antinociceptive (30 and 56.2 mg/kg; opioid) effects, without altering motor 
coordination, ambulatory activity, and memory. EEG indicated CNS depressant 
activity at high doses (30 and 56.2 mg/kg). The root bark of T. arborea contains 
a mixture of alkaloids that may hold therapeutic value in pain relief and the 
treatment of psychiatric diseases without causing neurotoxic activity at 
effective doses.

Copyright © 2023 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.fitote.2023.105602
PMID: 37423501 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest The authors 
declare no conflict of interest.


3. ACS Chem Neurosci. 2023 Jul 19;14(14):2537-2547. doi: 
10.1021/acschemneuro.3c00212. Epub 2023 Jun 29.

DM506 (3-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a Novel 
Derivative of Ibogamine, Inhibits α7 and α9α10 Nicotinic Acetylcholine Receptors 
by Different Allosteric Mechanisms.

Tae HS(1), Ortells MO(2), Tekarli BJ(3), Manetti D(4), Romanelli MN(4), McIntosh 
JM(3)(5)(6), Adams DJ(1), Arias HR(7).

Author information:
(1)Illawarra Health and Medical Research Institute (IHMRI), Faculty of Science, 
Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
(2)Facultad de Medicina, Universidad de Morón, CONICET, B1708 Morón, Argentina.
(3)School of Biological Sciences University of Utah, Salt Lake City, Utah 84112, 
United States.
(4)Department of Neurosciences, Psychology, Drug Research and Child Health 
Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, 
Sesto Fiorentino 50019, Italy.
(5)Department of Psychiatry, University of Utah, Salt Lake City, Utah 84112, 
United States.
(6)George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, 
United States.
(7)Department of Pharmacology and Physiology, Oklahoma State University College 
of Osteopathic Medicine, Tahlequah, Oklahoma 74464, United States.

The main objective of this study was to determine the pharmacological activity 
and molecular mechanism of action of DM506 
(3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a novel ibogamine 
derivative, at different nicotinic acetylcholine receptor (nAChR) subtypes. The 
functional results showed that DM506 neither activates nor potentiates but 
inhibits ACh-evoked currents at each rat nAChR subtype in a non-competitive 
manner. The receptor selectivity for DM506 inhibition follows the sequence: 
α9α10 (IC50 = 5.1 ± 0.3 μM) ≅ α7β2 (5.6 ± 0.2 μM) ∼ α7 (6.4 ± 0.5 μM) > 
α6/α3β2β3 (25 ± 1 μM) > α4β2 (62 ± 4 μM) ≅ α3β4 (70 ± 5 μM). No significance 
differences in DM506 potency were observed between rat and human α7 and α9α10 
nAChRs. These results also indicated that the β2 subunit is not involved or is 
less relevant in the activity of DM506 at the α7β2 nAChR. DM506 inhibits the α7 
and α9α10 nAChRs in a voltage-dependent and voltage-independent manner, 
respectively. Molecular docking and molecular dynamics studies showed that DM506 
forms stable interactions with a putative site located in the α7 cytoplasmic 
domain and with two intersubunit sites in the extracellular-transmembrane 
junction of the α9α10 nAChR, one located in the α10(+)/α10(─) interface and 
another in the α10(+)/α9(─) interface. This study shows for the first time that 
DM506 inhibits both α9α10 and α7 nAChR subtypes by novel allosteric mechanisms 
likely involving modulation of the extracellular-transmembrane domain junction 
and cytoplasmic domain, respectively, but not by direct competitive antagonism 
or open channel block.

DOI: 10.1021/acschemneuro.3c00212
PMID: 37386821 [Indexed for MEDLINE]


4. Org Lett. 2023 Jun 23;25(24):4567-4570. doi: 10.1021/acs.orglett.3c01595. Epub
 2023 Jun 13.

Gram-Scale Total Synthesis of (±)-Ibogamine.

Hughes AJ(1), Townsend SD(1).

Author information:
(1)Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, 
United States.

We describe the gram-scale total synthesis of (±)-ibogamine in nine steps and 
24% overall yield. The approach features a Mitsunobu fragment coupling and 
macrocyclic Friedel-Crafts alkylation to establish the nitrogen-containing core 
of ibogamine. A regio- and diastereoselective hydroboration allows for 
simultaneous formation of the tetrahydroazepine and isoquinuclidine ring systems 
via sulfonamide deprotection and concomitant intramolecular cyclization.

DOI: 10.1021/acs.orglett.3c01595
PMID: 37310034


5. Forensic Sci Med Pathol. 2021 Mar;17(1):126-129. doi: 
10.1007/s12024-020-00342-0. Epub 2021 Jan 12.

Death due to consumption of ibogaine: case report.

Aćimović T(1), Atanasijević T(2), Denić K(2), Lukić V(2), Popović V(2), 
Bogdanović M(2).

Author information:
(1)Institute of Forensic Medicine "Milovan Milovanović", School of Medicine, 
University of Belgrade, Deligradska 31a, Belgrade, Serbia. 
tijana.durmic@med.bg.ac.rs.
(2)Institute of Forensic Medicine "Milovan Milovanović", School of Medicine, 
University of Belgrade, Deligradska 31a, Belgrade, Serbia.

Ibogaine is a psychotropic indole alkaloid extracted from the roots of the 
Tabernanthe iboga shrub from the Apocynaceae family. Depending on the taken 
dose, it can lead to stimulant effects, euphoria, visual and auditory 
hallucinations, along with auditory, olfactory, and gustatory synesthesia. In 
addition to its historical usage in spiritual rituals of African tribes, these 
days iboga extract presents a prohibited, alternative drug widely used as a part 
of addiction treatment. Ibogaine used in opioid withdrawal is associated with 
serious side effects and sudden deaths. Besides its main use as an 
anti-addiction medication in alternative medicine, in moderate doses (from 100mg 
to 1g) ibogaine most commonly causes a "trance-like state".In this paper, we 
report the case of a heroin addict who died suddenly 5-12 hours after oral 
ingestion of powder labeled Tabernanthe iboga which had been bought online and 
used in the process of detoxification during an addiction treatment. The man was 
found dead in a rented apartment, where he was undergoing the addiction 
treatment.External examination revealed no lesions other than nonspecific 
injuries on the legs. The autopsy showed congestion of internal organs and 
pulmonary edema. Histopathological analysis of the heart showed neither 
macroscopic nor microscopic abnormalities. The concentration of ibogaine was 
3.26mg/L. Moreover, systematic toxicological analyses of biological samples 
showed the presence of morphine and codeine. These data suggest that death, 
which occurred unnaturally after initiation of the "treatment", was probably the 
result of the cardiovascular effects caused by the ibogaine powder.The presented 
case highlights the worldwide problem of various products being widely available 
over the internet and the danger associated with consumption thereof.

DOI: 10.1007/s12024-020-00342-0
PMID: 33433774 [Indexed for MEDLINE]