A substituted β-carboline, also known as a substituted 9H-pyrido[3,4-b]indole, is a chemical compound featuring a β-carboline moiety with one or more substitutions. β-Carbolines include more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines primarily influence brain functions but can also exhibit antioxidant effects. Synthetically designed β-carboline derivatives have recently been shown to have neuroprotective, cognitive enhancing and anti-cancer properties. β-Carbolines are indole alkaloids featuring a fused pyridine and indole ring structure similar to tryptamine, forming a three-ringed system with variable saturation in the third ring. β-Carboline alkaloids naturally occur widely in prokaryotes, plants, animals, certain marine tunicates, and foods like coffee and smoked meats, and are also responsible for the fluorescence of scorpion cuticles under ultraviolet light. β-Carbolines occurring naturally in Peganum harmala (Syrian rue) are known as harmala alkaloids. Some β-carbolines, like harmaline, are hallucinogenic. According to Alexander Shulgin, harmaline is the only β-carboline that has been extensively studied and well-established as a hallucinogen. β-Carbolines are known to act as monoamine oxidase inhibitors (MAOIs), among possessing other activities. They are an essential component of ayahuasca, by inhibiting the metabolism of the psychedelic dimethyltryptamine (DMT).
Use and effects
As hallucinogens β-Carbolines are cyclized tryptamines related to serotonergic psychedelics like dimethyltryptamine (DMT) and 5-MeO-DMT. Some simple β-carbolines have been reported to be hallucinogenic and have been referred to as oneirogens. These include harmine, harmaline, tetrahydroharmine, 6-methoxyharmalan, and 6-methoxytetrahydroharman (6-MeO-THH). According to Alexander Shulgin however, harmaline is the only β-carboline that has been extensively studied and well-established as a hallucinogen. β-Carbolines are active both orally and parenterally, with doses, depending on the compound, in the area of 100 to 300 mg or more orally and 1 to 1.5 mg/kg (~70–100 mg for a 70-kg person) intravenously. Although structurally related to psychedelic tryptamines, the hallucinogenic effects of β-carbolines are said to be qualitatively distinct from those of serotonergic psychedelics. Instead, they are described as being similar to those of ibogaine, which is also a cyclized tryptamine and structurally related atypical hallucinogen.
As monoamine oxidase inhibitors Various β-carbolines are potent monoamine oxidase inhibitors (MAOIs), more specifically reversible inhibitors of MAO-A (RIMAs). They are used in ayahuasca to inhibit the monoamine oxidase (MAO)-mediated metabolism of the serotonergic psychedelic dimethyltryptamine (DMT) to allow it to be orally active and to have a much longer duration than it would otherwise. They can also used in a similar fashion with 5-MeO-DMT.
Doses and durations
Pharmacology The pharmacological effects of specific β-carbolines are dependent on their substituents. For example, the natural β-carboline harmine has substituents on position 7 and 1. Thereby, it acts as a selective inhibitor of the DYRK1A protein kinase, a protein necessary for neurodevelopment. It also exhibits various antidepressant-like effects in rats by interacting with serotonin receptor 2A. Furthermore, it increases levels of the brain-derived neurotrophic factor (BDNF) in rat hippocampus. A decreased BDNF level has been associated with major depression in humans. The antidepressant effect of harmine might also be due to its function as a MAO-A inhibitor by reducing the breakdown of serotonin and noradrenaline. A synthetic derivative, 9-methyl-β-carboline, has shown neuroprotective effects including increased expression of neurotrophic factors and enhanced respiratory chain activity. This derivative has also been shown to enhance cognitive function, increase dopaminergic neuron count and facilitate synaptic and dendritic proliferation. It also exhibited therapeutic effects in animal models for Parkinson's disease and other neurodegenerative processes. However, β-carbolines with substituents in position 3 reduce the effect of benzodiazepine on GABA-A receptors and can therefore have convulsive, anxiogenic and memory enhancing effects. Moreover, 3-hydroxymethyl-beta-carboline blocks the sleep-promoting effect of flurazepam in rodents and – by itself – can decrease sleep in a dose-dependent manner. Another derivative, methyl-β-carboline-3-carboxylate, stimulates learning and memory at low doses but can promote anxiety and convulsions at high doses. With modification in position 9 similar positive effects have been observed for learning and memory without promotion of anxiety or convulsion. β-carboline derivatives also enhance the production of the antibiotic reveromycin A in soil-dwelling Streptomyces species. Specifically, expression of biosynthetic genes is facilitated by binding of the β-carboline to a large ATP-binding regulator of the LuxR family. Also Lactobacillus spp. secretes a β-carboline (1-acetyl-β-carboline) preventing the pathogenic fungus Candida albicans to change to a more virulent growth form (yeast-to-filament transition). Thereby, β-carboline reverses imbalances in the microbiome composition causing pathologies ranging from vaginal candidiasis to fungal sepsis. Since β-carbolines also interact with various cancer-related molecules such as DNA, enzymes (GPX4, kinases, etc.) and proteins (ABCG2/BRCP1, etc.), they are also discussed as potential anticancer agents.
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