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Psychiatry & Medicine

Indolethylamine-N-methyltransferase Polymorphisms: Genetic and Biochemical Approaches for Study of Endogenous N,N,-dimethyltryptamine

April 23, 2018 / DMT, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Psychotic Disorders, Publications / By /

Abstract

N,N-dimethyltryptamine (DMT) is a powerful serotonergic psychedelic whose exogenous administration elicits striking psychedelic effects in humans. Studies have identified DMT and analogous compounds (e.g., 5-hydroxy-DMT, 5-methoxy-DMT) alongside of an enzyme capable of synthesizing DMT endogenously from tryptamine, indolethylamine-N-methyltransferase (INMT), in human and several other mammalian tissues. Subsequently, multiple hypotheses for the physiological role of endogenous DMT have emerged, from proposed immunomodulatory functions to an emphasis on the overlap between the mental states generated by exogenous DMT and naturally occurring altered states of consciousness; e.g., schizophrenia. However, no clear relationship between endogenous DMT and naturally occurring altered states of consciousness has yet been established from in vivo assays of DMT in bodily fluids. The advent of genetic screening has afforded the capability to link alterations in the sequence of specific genes to behavioral and molecular phenotypes via expression of identified single nucleotide polymorphisms (SNPs) in cell and animal models. As SNPs in INMT may impact endogenous DMT synthesis and levels via changes in INMT expression and/or INMT structure and function, these combined genetic and biochemical approaches circumvent the limitations of assaying DMT in bodily fluids and may augment data from prior in vitro and in vivo work. Therefore, all reported SNPs in INMTwere amassed from genetic and biochemical literature and genomic databases to consolidate a blueprint for future studies aimed at elucidating whether DMT plays a physiological role.

Dean, J. G. (2018). Indolethylamine-N-methyltransferase polymorphisms: genetic and biochemical approaches for study of endogenous N, N,-dimethyltryptamine. Frontiers in neuroscience, 12.,  10.3389/fnins.2018.00232
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Out of the box: A psychedelic model to study the creative mind

March 23, 2018 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Publications / By /

Abstract

Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multicomponent construct includes flexible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin can enhance creativity and affect state of mind (mood, empathy, openness). Of note, flexible thinking is disturbed in psychopathological conditions like anxiety disorders and depression and preliminary findings have shown psychedelics to be efficacious in the treatment of those conditions. The question how psychedelics induce this state of enhanced flexible thinking remains to be answered and investigating the neurobiology underlying this phenomenon will not only help in understanding why psychedelics are of use in the therapeutic setting but also in other settings where flexible thinking is challenged. A model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy volunteers.

Kuypers, K. P. C. (2018). Out of the box: A psychedelic model to study the creative mind. Medical hypotheses, 115, 13-16.,  10.1016/j.mehy.2018.03.010

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Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy

March 1, 2018 / Ayahuasca, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Harmine and its analogs have long been considered as anticancer agents. In vitro analyses suggested that intercalating DNA or inhibiting topoisomerase might contribute to the cytotoxic effect of this class of compound. However, this idea has not been rigorously tested in intact cells. By synthesizing novel derivatives, here we demonstrate that harmines did not activate the DNA damage response, a cellular signaling commonly induced by agents that intercalate DNA or inhibit topoisomerase. These findings suggest that mechanisms other than DNA intercalating or topoisomerase inhibiting contribute to the toxicity of harmines in vivo. Using a novel N2-benzyl and N9-arylated alkyl compound 10f that has good solubility and stability as the model, we show that harmines strongly inhibited the growth of cancer cells originated from breast, lung, bone and pancreas, but not that of normal fibroblasts. We further show that 10f induced apoptosis and inhibited autophagy in a dose and time-dependent manner. An apoptosis inhibitor suppressed 10f-induced cell death. Together, our results reveal previously unidentified insights into the anticancer mechanism of harmines, supporting future development of this compound class in the treatment of human cancers.
Geng, X., Ren, Y., Wang, F., Tian, D., Yao, X., Zhang, Y., & Tang, J. (2018). Harmines inhibit cancer cell growth through coordinated activation of apoptosis and inhibition of autophagy. Biochemical and biophysical research communications, 498(1), 99-104. 10.1016/j.bbrc.2018.02.205
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The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes

February 11, 2018 / Iboga / Ibogaine, Neuroscience, Papers, Psychiatry & Medicine, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is an indole alkaloid originally extracted from the root bark of the African rainforest shrub Tabernanthe iboga. It has been explored as a treatment for substance abuse because it interrupts drug addiction and relieves withdrawal symptoms. However, it has been shown that ibogaine treatment leads to a sharp and transient fall in cellular ATP level followed by an increase of cellular respiration and ROS production. Since contractile tissues are sensitive to changes in the levels of ATP and ROS, here we investigated an ibogaine-mediated link between altered redox homeostasis and uterine contractile activity. We found that low concentrations of ibogaine stimulated contractile activity in spontaneously active uteri, but incremental increase of doses inhibited it. Inhibitory concentrations of ibogaine led to decreased SOD1 and elevated GSH-Px activity, but doses that completely inhibited contractions increased CAT activity. Western blot analyses showed that changes in enzyme activities were not due to elevated enzyme protein concentrations but posttranslational modifications. Changes in antioxidant enzyme activities point to a vast concentration-dependent increase in H2O2 level. Knowing that extracellular ATP stimulates isolated uterus contractility, while H2O2 has an inhibitory effect, this concentration-dependent stimulation/inhibition could be linked to ibogaine-related alterations in ATP level and redox homeostasis.
Oreščanin-Dušić, Z., Tatalović, N., Vidonja-Uzelac, T., Nestorov, J., Nikolić-Kokić, A., Mijušković, A., … & Blagojević, D. (2018). The Effects of Ibogaine on Uterine Smooth Muscle Contractions: Relation to the Activity of Antioxidant Enzymes. Oxidative medicine and cellular longevity, 2018. 10.1155/2018/5969486
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Evaluating the abuse potential of psychedelic drugs for medical use in humans

February 7, 2018 / LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Psychology, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , ,

Abstract

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g. MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e. no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e. schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e. drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates [59]. We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence.
Heal, D. J., Gosden, J., & Smith, S. L. (2018). Evaluating the abuse potential of psychedelic drugs for medical use in humans. Neuropharmacology. 10.1016/j.neuropharm.2018.01.049
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The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP-treated common marmoset model of Parkinson’s disease

January 24, 2018 / Ayahuasca, Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4–113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4–7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
Fisher, R., Lincoln, L., Jackson, M. J., Abbate, V., Jenner, P., Hider, R., … & Rose, S. (2018). The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP‐treated common marmoset model of Parkinson’s disease. Phytotherapy Research. 10.1002/ptr.6017
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The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP-treated common marmoset model of Parkinson's disease

January 24, 2018 / Ayahuasca, Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4–113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4–7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
Fisher, R., Lincoln, L., Jackson, M. J., Abbate, V., Jenner, P., Hider, R., … & Rose, S. (2018). The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP‐treated common marmoset model of Parkinson’s disease. Phytotherapy Research. 10.1002/ptr.6017
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Key interindividual determinants in MDMA pharmacodynamics.

January 16, 2018 / MDMA, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , , ,

Abstract

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.
Papaseit, E., Torrens, M., Pérez-Mañá, C., Muga, R., & Farré, M. (2018). Key interindividual determinants in MDMA pharmacodynamics. Expert opinion on drug metabolism & toxicology, (just-accepted). 10.1080/17425255.2018.1424832
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Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways

November 28, 2017 / Ayahuasca, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

The effects of harmaline on the viability and apoptosis of human liver carcinoma were investigated in vitro. HepG2 cells were treated with harmaline (0‑10 µM), and the proliferation and apoptosis of HepG2 cells were investigated using an MTT assay and flow cytometry, respectively. The protein expression of cellular tumor antigen p53 (p53), cyclin‑dependent kinase inhibitor 1 (p21), tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand (FasL) and caspase‑8 was subsequently measured using western blotting. In addition, an ELISA was used to analyze caspase‑8/3 activity. Harmaline significantly increased p53, p21, Fas and FasL protein expression in HepG2 cells. Additionally, treatment with harmaline significantly increased the expression of caspase‑8 and caspase‑8/3 activity. The results from the present study suggest that harmaline suppresses the viability, but induces the apoptosis, of human liver carcinoma cells through upregulation of the p53/p21 and Fas/FasL signaling pathways.
Xu, B., Li, M., Yu, Y., He, J., Hu, S., Pan, M., … & Zhu, J. (2018). Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways. Oncology Letters, 15(2), 1931-1936. 10.3892/ol.2017.7495
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Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT

October 9, 2017 / DMT, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Dimethyltryptamines are entheogenic serotonin-like molecules present in traditional Amerindian medicine recently associated with cognitive gains, antidepressant effects, and changes in brain areas related to attention. Legal restrictions and the lack of adequate experimental models have limited the understanding of how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico analysis reinforced previously reported anti-inflammatory actions of 5-MeO-DMT and revealed modulatory effects on proteins associated with long-term potentiation, the formation of dendritic spines, including those involved in cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization. Our data offer the first insight about molecular alterations caused by 5-MeO-DMT in human cerebral organoids.
Dakic, V., Nascimento, J. M., Sartore, R. C., de Moraes Maciel, R., Araujo, D. B., Ribeiro, S., … & Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific Reports, 7(1), 12863. 10.1038/s41598-017-12779-5
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