Heme peroxidases are responsible for the dehydrogenation and oxidation metabolism of harmaline into harmine / 中国天然药物

Harmaline and harmine are β-carboline alkaloids with effective pharmacological effects. Harmaline can be transformed into harmine after oral administration. However, enzymes involved in the metabolic pathway remain unclear. In this study, harmaline was incubated with rat liver microsomes (RLM), rat brain microsomes (RBM), blood, plasma, broken blood cells, and heme peroxidases including horseradish peroxidase (HRP), lactoperoxidase (LPO), and myeloperoxidase (MPO). The production of harmine was determined by a validated UPLC-ESI-MS/MS method. Results showed that heme peroxidases catalyzed the oxidative dehydrogenation of harmaline. All the reactions were in accordance with the Hill equation. The reaction was inhibited by ascorbic acid and excess H2O2. The transformation of harmaline to harmine was confirmed after incubation with blood, plasma, and broken blood cells, rather than RLM and RBM. Harmaline was incubated with blood, plasma, and broken cells liquid for 3 h, and the formation of harmine became stable. Results indicated an integrated metabolic pathway of harmaline, which will lay foundation for the oxidation reaction of dihydro-β-carboline. Moreover, the metabolic stability of harmaline in blood should not be ignored when the pharmacokinetics study of harmaline is carried out.

The pharmacological interaction of compounds in ayahuasca: a systematic review

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

Progress in study on effect of harmine on bone and cartilage metabolism / 中南大学学报(医学版)

Harmine, a β-carboline alkaloid, is widely distributed in the plants, animals as well as in human tissues and body fluids. Harmine has various types of pharmacological activities including antimicrobial, antiplasmodial, antioxidative, antitumor, antimutagenic, antidiabetic, vasorelaxant and central excitation properties. Moreover, it can exert regenerative and protective effects on bone and cartilage tissues by regulating the proliferation, differentiation and metabolism of osteoclasts, osteoblasts and chondrocytes. These features make harmine a novel candidate for the prevention and treatment of bone and cartilage diseases, such as osteoporosis, bone fracture and osteoarthritis.

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Methods: Open-label trial conducted in an inpatient psychiatric unit. Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder. .

Bio-elicitation of beta-carboline alkaloids in cell suspension culture of Peganum Harmala L.

Background: Sustainable and commercial production of secondary metabolites is a critical issue when dealing with its clinical application. Efforts are still being made to look for biotic or abiotic elicitors with more efficient and universal effects on the improvement of secondary metabolites

Objective: In order to evaluate the suitability of different biotic elicitors on P. harmala L. cell suspension cultures was established to enhance the beta-carboline alkaloids [harmaline and harmine] production

Methods: The elicitation of cell suspension cultures of Peganum harmala L. was done by adding various fungal mycelium homogenates [Aspergillus flavus, Alternaria alternate, Coriolus versicolor, Fusarium oxysporum, Mucor sp, Penicillium notatum, and Rhizopus stonifer], Casein hydrolysate and Saccharomyces cerevisiae at different concentrations. The cell cultures of P. harmala L. were subcultured on MS medium with optimal treatment of biotic elicitor. CAMAG analytical HPTLC system was used for estimation of harmaline and harmine after extraction of beta-carboline alkaloids

Results: The maximum harmine production [91.2 +/- 1.8 microg g[-1] DW] was observed at 1000 mg l[-1] S. cerevisiae in cell suspension culture of P. harmala L. [1.68 fold over than the control]. Also the results showed that supplement of 75-100 mg l-1 casein hydrolysate in cell cultures media increased biomass of cell culture and harmaline and harmine production [1.61 and 1.46 times over than the control, respectively]

Conclusion: The conclusion of the research showed that by applying biotic elicitors, we can reach to higher secondary metabolites [harmaline and harmine] in cell suspension culture of P. harmala L. We suggest future investigation on using other elicitors like bacterial extract or signal transduction compounds in cell suspension culture of P. harmala L. in order to increase the production of different kind of secondary metabolites

Cytotoxicity of alkaloids isolated from peganum harmala seeds

Ethnopharmacological relevance: Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seedextract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction [TAF] in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine [vasicine] and vasicinone were isolated from the P. harmala seedextract and their activity and that of TAF were tested a] for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1] Med-mek carcinoma ; 2] UCP-med carcinoma ; 3] UCP-med sarcoma]; and 4] SP2/O-Ag14, and b] for antiproliferative effect on cells of Jurkat, E6-1 clone [inhibition of incorporation of [[3]H-thymidine] in cellular DNA]. The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC[50] values [concentration of the active substance that inhibited the growth of the tumor cells by 50%] ranging between 2.43 microg/mL and 19.20 microg/mL, while UCP-med carcinoma was the least sensitive [range of IC[50] = 13.83 microg/mL to 59.97 microg/mL]. Of the substances evaluated, harmine was the most active compound [IC[50] for the 4 tumor cell lines varying between 2.43 microg/ml and 18.39 microg/mL], followed by TAF [range of IC[50] = 7.32 microg/mL to 13.83 microg/mL]; peganine was the least active [IC[50] = 50 microg/mL to > 100 microg/ml]. In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of [[3]H-TDR] in the DNA cells of Jurkat, E6-1 clone by 50% [IC[50]] were 8.60 +/- 0.023 microg/mL and 8.94 +/- 0.017 microg/mL, respectively, while peganine was the least active [IC[50] >100 microg/mL]. The IC[50] values for harmalacidine [27.10 +/- 0.011 microg/mL] and harmine [46.57 +/- 0.011 microg/mL] were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity

[Effects of harmane, norharmane and harmine on writhing behavior induced by acetic acid in mice]

The beta-carbolines harmane, harmine and norharmane are the members of Harmala,s alkaloids group [Peganum harmala, Zygophillaceae]. The beta-carboline alkaloids adjoined to benzodiazepine site of the gamma-aminobutyric acid type A [GABA[A]]. These alkaloids also inhibited cyclooxygenase and lipoxygenase activities. These findings showed that the beta-carbolines should be able to reduce writhing nociception induced by acetic acid- in mice. To assess the effects of acute treatment with harmane, norharmane and harmine on the writhing induced by acetic acid in mice. The experiments were carried out on male BALB/C mice [20-25g]. Intraperitoneal [I.p] injection of acetic acid [0.6%] was performed in order to cause writhing behavior. This behavior was recorded by direct observation for a 30-minutes period. Decrease of writhing count is indicative of an anti-nociception. In order to avoid the possibility of a physicochemical interaction between them, Drugs were administered on opposite sides of peritoned. Intraperitoneal [I.p] injection of Harmane [5-20mg/kg] on 6-9 mice, norharmane [5-15mg/kg] on 8-9 mice and harmine [10-15mg/kg] on 8-9 mice in per group decreased the writhing behavior significantly [P<0.0001, P<0.0003 and P<0.0016, respectively]. The inhibitory effects of the mentioned drugs were antagonized by flumazenil [2 mg/kg]. Effects of harmane, norharmane and harmine on writhing response may be mediated through an inverse agonistic mechanism located in the benzodiazepine receptors

[Effects of harmane, norharmane and harmine on apomorphine-induced pecking behavior in chick]

Beta-carboline alkaloids, also known as harmala's alkaloids have a wide spectrum of pharmacological actions including a stimulatory action on release of dopamine and other catecholamines in several brain regions and an inhibitory action on monoamine oxidase [MAO]. These findings suggest that beta-carbolines should alleviate at least some of the dopaminergic stereotyped behaviors. The purpose of present study is to determine the effects of beta-carbolines harmane, norharmane and harmine on apomorphine-induced pecking behavior in chick. All experiments were carried out on male/female chicks [40-60 g]. The modulatory effects of beta-Carbolines on stereotyped behavior were assessed using the pecking behavior induced by apomorphine. Subcutaneous [s.c.] injection of apomorphaine [0.025 mg/kg, mixed agonist of dopamine D1/D2 receptors] induced pecking. The pecking response was counted by direct observation and recorded for a 40-minute period. S.C. injection of harmane [2.5-10 mg/kg] and harmine [1.25-5 mg/kg] significantly decreased the pecking behavior induced by apomorphine [0.25 mg/kg]. The norharmane [2.5-15 mg/kg, i.p.] response was biphasic. The inhibitory effects of harmane, norharmane and harmine were blocked by flumazenil [5 mg/kg, i.e., 30 minutes before the test] or reserpine [5 mg/kg, i.e., 18 hours before the test]. Results suggest that the modulatory effect of harmane, norharmane and harmine on the pecking behavior may be mediated through an inverse agonistic/monoaminergic mechanism

[Evaluation of antidepressant activities of harmane, norharman and harmine in mice]

It has been reported that, the [R]-carboline alkaloids of peganum harmala seeds have a stimulatory action on serotonin and catecholamines releases in different brain regions. In addition, one of the most important pharmacological effects demonstrated for [R]- carbolines is a revesible inhibitory action on MAO-A. These findings suggest that - carbolines, should alleviate at least some of the signs of depression. The purpose of present study is to determine the antidepressant activity of [R]-carbolines harmane, norharmane and harmine. All experiments were carried out on male Swiss-Webster mice [25-30g]. The antidepressant activities of the [R]-carbolines were assessed using the forced swim test. This test is the most widely used tool for antidepressant activity preclinically. In this test, mice were placed into a cylinderical glass [25 cm height, 12 cm in diameter] containing a column of 15 cm of water at 25 +/- 1 [o]C. After 30 min of the-carbolines injections, the mice were subjected to forced swimming test for 8 min and their immobility time was recorded. Intraperitoneal [i.p.] injections of harmane [5-15 mg/kg], norharmane [2.5-10 mg/kg] and harmine [5-15 mg/kg] significantly decreased the immobility time in the mouse forced swim test. The inhibitory effects of harmane, norharmane and harmine were antagonized by flumazenil [5 mg/kg, i.p.] but not by reserpine [5 mg/kg, i.p., 18 h before test]. The results suggest that the antidepressant activities of harmane, norharmane and harmine may be mediated through an inverse agonistic mechanism

Consideraciones acerca del brebaje ayahuasca y perspectivas terapéuticas / About considerations of the ayahuasca beverage and therapeutical perspectives

El extracto acuoso de Banisteriopsis Caapi, Psychotria Viridis y Brugmansia sp., bastante conocido en la selva como Ayahuasca por sus efectos purgativos y psicotrópicos constituye el eje central del curanderismo (shamanismo) en la hoya amazónica. Estudios antropológicos, psicológicos y fitoquímicos demuestran que pueden ser utilizados con fines beneficiosos para el tratamiento de las toxicomanías y la patología mental a condición de impartirlo adecuadamente. Asimismo se constató en el tratamiento de pacientes que las sesiones curativas no sólo se ven influenciadas por los principios activos B-carbolínicos y triptamínicos, sino que se ven modificadas por el estado psicosomático del paciente, factores ambientales naturales y otros condicionados por el terapeuta.