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Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review

February 28, 2017 / Ayahuasca, Biology & Ethnobotany, Depressive Disorders, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

Depression is the most common illness observed in the elderly, adults, and children. Antidepressants prescribed are usually synthetic drugs and these can sometimes cause a wide range of unpleasant side effects. Current research is focussed on natural products from plants as they are a rich source of potent new drug leads. Besides Hypericum perforatum (St. John’s wort), the plants studied include Passiflora incarnata L. (passion flower), Mitragyna speciosa (kratom), Piper methysticum G. Forst (kava) and Valeriana officinalis L. Harman, harmol, harmine, harmalol and harmaline are indole alkaloids isolated from P. incarnata, while mitragynine is isolated from M. speciosa. The structure of isolated compounds from P. methysticum G. Forst and V. officinalis L. contains an indole moiety. The indole moiety is related to the neurotransmitter serotonin which is widely implicated for brain function and cognition as the endogenous receptor agonist. An imbalance in serotonin levels may influence mood in a way that leads to depression. The moiety is present in a number of antidepressants already on the market. Hence, the objective of this review is to discuss bioactive compounds containing the indole moiety from plants that can serve as potent antidepressants.

Hamid, H. A., Ramli, A. N., & Yusoff, M. M. (2017). Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review. Frontiers in Pharmacology, 8, 96. 10.3389/fphar.2017.00096
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Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells

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

Abstract

BACKGROUND:
Harmine, a β-carboline alkaloid from Peganum harmala, has multiple anti-tumor activities, especially for its folk therapy for digestive system neoplasm. However, the underlying mechanism of harmine on gastric cancer remains unclear.
PURPOSE:
To illuminate the potential anti-tumor activity and mechanism of harmine against gastric cancer cells.
METHODS/STUDY DESIGNS:
The anti-proliferative activity of harmine in vitro was evaluated by MTT assay. The autophagic activity induced by harmine was assessed using GFP-LC3 transfection. FITC/PI double staining was applied for the apoptosis inspection. The mitochondrial membrane potential was detected by JC-1 fluorescence probe. The potential mechanisms for proteins level in autophagy and apoptosis were analyzed by Western blot.
RESULTS:
Harmine exhibited potent effects on both autophagy and apoptosis. Treatment with harmine could enhance dots of GFP-LC3 in cells. Meanwhile, the process had connection with Beclin-1, LC3-II, and p62 by the inhibition of Akt/mTOR/p70S6K signaling. However, high concentration of harmine led to apoptosis characterized by the propidium/Annexin V-positive cell pollution, cell shrunk and the collapse of mitochondrial membrane potential. The regulation of Bcl-2, Bax and the gathering of cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 contributed to the induction of apoptosis. In addition, 10μM LY294002 (a specific inhibitor of PI3K/Akt) combination with 40μM harmine significantly increased the cytotoxicity to the gastric cancer cells and up-regulated both the apoptosis-related protein (cleaved-PARP, cleaved-caspase-3) and autophagy-related protein (Beclin-1, LC3-II, and p62). Adding the inhibitor of autophagy, 3-MA or BafA1, increased the viability of harmine-exposured gastric cancer cells, which confirmed the role of autophagy played in the gastric cancer cell death induced by harmine.
CONCLUSION:
Harmine might be a potent inducer of apoptosis and autophagy, which offered evidences to therapy of harmine in gastric carcinoma in the folk medicine.
Li, C., Wang, Y., Wang, C., Yi, X., Li, M., & He, X. (2017). Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. Phytomedicine, 28, 10-18. 10.1016/j.phymed.2017.02.008
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LSD instead of 25I-NBOMe: The revival of LSD? A case report

February 27, 2017 / LSD, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Observation: We report a case of a 25-year-old man crushed by a train while he was returning from a rave party. The consumption of 25I-NBOMe was rapidly evoked by people who had participated at the party.

Materials and methods: In this context, the post-mortem toxicological expertise was completed by a broad screening using high-resolution mass spectrometry detection (LC-HRMS). Three hundred NPS and metabolites (including 25B, 25C and 25I-NBOMes) can be found with this method. A targeted screening in MRM mode was also performed on a smaller number of hallucinogens.

Results: The toxicological analyses were performed on blood and urine samples. Amphetamines, cocaine, cannabinoids and opiates were not detected. Ethanol was measured at 0.71 g/L and 1.59 g/L in blood and urine samples, respectively. The screening by LC-HRMS did not reveal the presence of NPS, including NBOMes. The targeted screening in MRM mode revealed the presence of LSD and its metabolite, the 2-oxo-3-hydroxy-LSD. LSD was quantified at 0.2 ng/mL in blood.

Conclusion: This case alerts on the frequent confusion between NBOMes and LSD and on the renewed interest for LSD due to the popularity of NBOMes. This case therefore encourages the prudence and research of all hallucinogenic substances, even when the context is evocative.

Bodeau, S., Bennis, Y., Régnaut, O., Fabresse, N., Richeval, C., Humbert, L., … & Lemaire-Hurtel, A. S. (2017). LSD instead of 25I-NBOMe: The revival of LSD? A case report. Toxicologie Analytique et Clinique, 29(1), 139-143. 10.1016/j.toxac.2016.12.007
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Effects of Hallucinogens on Neuronal Activity

February 26, 2017 / Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , ,

Abstract

Hallucinogens evoke sensory, perceptual, affective, and cognitive effects that may be useful to understand the neurobiological basis of mood and psychotic disorders. The present chapter reviews preclinical research carried out in recent years in order to better understand the action of psychotomimetic agents such as the noncompetitive NMDA receptor (NMDA-R) antagonists and serotonergic hallucinogens. Our studies have focused on the mechanisms through which these agents alter cortical activity. Noncompetitive NMDA-R antagonists, such as phencyclidine (PCP) and MK-801 (dizocilpine), as well as the serotonergic hallucinogens DOI and 5-MeO-DMT, produce similar effects on cellular and population activity in prefrontal cortex (PFC); these effects include alterations of pyramidal neuron discharge (with an overall increase in firing), as well as a marked attenuation of the low frequency oscillations (0.2–4 Hz) to which neuronal discharge is coupled in anesthetized rodents. PCP increases c–fos expression in excitatory neurons from various cortical and subcortical areas, particularly the thalamus. This effect of PCP involves the preferential blockade of NMDA-R on GABAergic neurons of the reticular nucleus of the thalamus, which provides feedforward inhibition to the rest of thalamic nuclei. It is still unknown whether serotonergic hallucinogens also affect thalamocortical networks. However, when examined, similar alterations in other cortical areas, such as the primary visual cortex (V1), have been observed, suggesting that these agents affect cortical activity in sensory and associative areas. Interestingly, the disruption of PFC activity induced by PCP, DOI and 5-MeO-DMT is reversed by classical and atypical antipsychotic drugs. This effect suggests a possible link between the mechanisms underlying the disruption of perception by multiple classes of hallucinogenic agents and the therapeutic efficacy of antipsychotic agents.

Lladó-Pelfort, L., Celada, P., Riga, M. S., Troyano-Rodríguez, E., Santana, N., & Artigas, F. (2017). Effects of Hallucinogens on Neuronal Activity. 10.1007/7854_2017_473

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Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies

February 23, 2017 / Ayahuasca, DMT, Papers, Psychology, Publications / By / , ,

Abstract

Ayahuasca is a hallucinogen brew traditionally used for ritual and therapeutic purposes in Northwestern Amazon. It is rich in the tryptamine hallucinogens dimethyltryptamine (DMT), which acts as a serotonin 5-HT2A agonist. This mechanism of action is similar to other compounds such as lysergic acid diethylamide (LSD) and psilocybin. The controlled use of LSD and psilocybin in experimental settings is associated with a low incidence of psychotic episodes, and population studies corroborate these findings. Both the controlled use of DMT in experimental settings and the use of ayahuasca in experimental and ritual settings are not usually associated with psychotic episodes, but little is known regarding ayahuasca or DMT use outside these controlled contexts. Thus, we performed a systematic review of the published case reports describing psychotic episodes associated with ayahuasca and DMT intake. We found three case series and two case reports describing psychotic episodes associated with ayahuasca intake, and three case reports describing psychotic episodes associated with DMT. Several reports describe subjects with a personal and possibly a family history of psychosis (including schizophrenia, schizophreniform disorders, psychotic mania, psychotic depression), nonpsychotic mania, or concomitant use of other drugs. However, some cases also described psychotic episodes in subjects without these previous characteristics. Overall, the incidence of such episodes appears to be rare in both the ritual and the recreational/noncontrolled settings. Performance of a psychiatric screening before administration of these drugs, and other hallucinogens, in controlled settings seems to significantly reduce the possibility of adverse reactions with psychotic symptomatology. Individuals with a personal or family history of any psychotic illness or nonpsychotic mania should avoid hallucinogen intake.

dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2017). Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies. Therapeutic Advances in Psychopharmacology, 2045125316689030. 10.1177/2045125316689030
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Safety pharmacology of acute MDMA administration in healthy subjects

February 21, 2017 / MDMA, Papers, Psychology, Publications / By / ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4–8.2 h). The 125 mg dose of MDMA produced greater ‘good drug effect’ ratings than 75 mg. MDMA produced moderate and transient ‘bad drug effect’ ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

Vizeli, P., & Liechti, M. E. (2017). Safety pharmacology of acute MDMA administration in healthy subjects. Journal of Psychopharmacology, 0269881117691569. 10.1177/0269881117691569
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Hallucinogenic Drugs: A New Study Answers Old Questions about LSD

February 20, 2017 / LSD, Papers, Psychology, Publications / By /

Abstract

LSD induces profound psychedelic effects, including changes in the meaning of percepts. The subjective effects of LSD are fully blocked by a 5-HT2A receptor antagonist. LSD may alter meaningfulness by increasing activity in cortical regions responsible for processing personal attribution.

Halberstadt, A. L. (2017). Hallucinogenic Drugs: A New Study Answers Old Questions about LSD. Current Biology, 27(4), R156-R158. 10.1016/j.cub.2016.12.058
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Hallucinogenic Drugs: A New Study Answers Old Questions about LSD.

February 20, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By /

Abstract

LSD induces profound psychedelic effects, including changes in the meaning of percepts. The subjective effects of LSD are fully blocked by a 5-HT2A receptor antagonist. LSD may alter meaningfulness by increasing activity in cortical regions responsible for processing personal attribution.

Halberstadt, A. L. (2017). Hallucinogenic drugs: A new study answers old questions about LSD. Current Biology, 27(4), R156-R158., https://doi.org/10.1016/j.cub.2016.12.058
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22-azidosalvinorin A exhibits antidepressant-like effect in mice

February 17, 2017 / Depressive Disorders, Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , , ,

Abstract

The increasing cases of depression has made the searches for new drugs and understanding of the underligning neurobiology of this psychiatric disorder a necessity. Here, we modified the structure of salvinorin A (a known halucinogen) and investigated antidepressant-like activity of its four derivatives; 22-methylsulfanylsalvinorin A(SA1), 2-O-cinnamoylsalvinorin B (CSB), 22-azidosalvinorin A (SA2), and 2-O-(4’-azidophenylsulfonyl)salvinorin B (SA3). Prior to behavioural tests (Irwin test, open field test – OFT, forced swimming test – FST and tail suspension test – TST), SA1 was prepared by reacting salvinorin B and methylthioacetic acid with 89% yield; CSB was obtained from the reaction of salvinorin B and cinnamic acid with 92% yield; SA2 was obtained from the reaction of salvinorin B and azidoacetic acid with 81% yield; and SA3 was prepared by reacting salvinorin B with 4-azidophenylsulfonyl chloride with 80% yield. Oral treatment of mice with these derivatives (1–1000 mg/kg) did not elicit toxic sign or death. Unlike SA, SA1, CSB and SA3, treatment with SA2 (5, 10 and 20 mg/kg) decreased the immobility (TST and FST) and swimming time (FST) without altering locomotor activity in OFT. A decrease in the immobility time in TST and FST confirmed antidepressant-like property of SA2. Although p-chlorophenylalanine (serotonin depletor) or WAY100635 (selective 5-HT1A receptor antagonist) did not attenuate effect of SA2, alpha-methyl-para-tyrosine (catecholamine depletor) and prazosin (selective α1-receptor antagonist) attenuated this effect. SA2 mildly inhibited monoamine oxidase and showed affinity for α1A, α1B, α1D and κ-opioid receptor subtypes. In summary, SA2 induced monoamine-mediated antidepressant-like effect.

Fajemiroye, J. O., Prabhakar, P. R., da Cunha, C. L., Costa, E. A., & Zjawiony, J. K. (2017). 22-Azidosalvinorin A exhibits antidepressant-like effect in mice. European Journal of Pharmacology. 10.1016/j.ejphar.2017.02.031
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Altered Insula Connectivity Under MDMA

February 14, 2017 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Recent work with noninvasive human brain imaging has started to investigate the effects of 3, 4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations-both of which are known to be associated with insular functioning.

Walpola, I. C., Nest, T., Roseman, L., Erritzoe, D., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2017). Altered Insula Connectivity Under MDMA. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 10.1038/npp.2017.35
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