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Harmala alkaloid: Difference between revisions
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'''Harmala alkaloids''' are a group of psychoactive alkaloids found primarily within the seeds of [[Harmala_alkaloid#Peganum_harmala_.28syrian_rue.29|'' | '''Harmala alkaloids''' are a group of psychoactive alkaloids found primarily within the seeds of [[Harmala_alkaloid#Peganum_harmala_.28syrian_rue.29|''Peganum harmala'']], also known as syrian rue. These alkaloids are of interest for their use in Amazonian shamanism, where they are derived from plants. Harmala alkaloids are naturally occurring beta-carboline alkaloids that are structurally related to harmaline, and also found in the vine [[Banisteriopsis caapi]]. They also occur in [[tobacco]], and contribute to its subjective effects, but not to its addictiveness (which is instead caused by the presence of nicotine), and in more negligible amounts than in Peganum Harmala and Banisteriopsis cappi. | ||
==Chemistry== | ==Chemistry== | ||
Harmala alkaloids are substituted derivatives of the molecule [[beta-Carbolines|''beta''-carboline]]. The structure of''beta''-carboline is comprised of an indole skeleton fused to a pyridine ring. Harmine, harmaline, and tetrahydroharmine share structural substitutions and they all contain a methoxy group at R<sub>7</sub> and a methyl group at R<sub>1</sub>. They differ in the saturation of their six-member nitrogenous ring. Harmine contains an unsaturated pyridine ring while harmaline contains a dihydrogenated pyridine ring. Tetrahydroharmine is saturated with four additional hydrogen bonds than harmine. | Harmala alkaloids are substituted derivatives of the molecule [[beta-Carbolines|''beta''-carboline]]. The structure of ''beta''-carboline is comprised of an indole skeleton fused to a pyridine ring. Harmine, harmaline, and tetrahydroharmine share structural substitutions and they all contain a methoxy group at R<sub>7</sub> and a methyl group at R<sub>1</sub>. They differ in the saturation of their six-member nitrogenous ring. Harmine contains an unsaturated pyridine ring while harmaline contains a dihydrogenated pyridine ring. Tetrahydroharmine is saturated with four additional hydrogen bonds than harmine. | ||
==Pharmacology== | ==Pharmacology== | ||
Harmala alkaloids are classed as [[MAOIs]]. This means that they inhibit the activity of monoamine oxidase metabolic enzymes of which two varieties exist: MAO-A and MAO-B. The [[alkaloids]] bind reversibly to the active site of the enzyme, inhibiting its endogenous function of destroying amine functions of [[neurotransmitters]] and externally administered centrally active drugs. This has the effect of potentiating and prolonging the central and peripheral activity of both neurotransmitters and a variety of drugs. They are reversible [[MAOIs]] of the MAO-A isoform of the enzyme, and can stimulate the central nervous system by inhibiting the metabolism of monoamine compounds such as serotonin and norepinephrine. | Harmala alkaloids are classed as [[MAOIs]]. This means that they inhibit the activity of monoamine oxidase metabolic enzymes, of which two varieties exist: MAO-A and MAO-B. The [[alkaloids]] bind reversibly to the active site of the enzyme, inhibiting its endogenous function of destroying amine functions of [[neurotransmitters]] and externally administered centrally active drugs. This has the effect of potentiating and prolonging the central and peripheral activity of both neurotransmitters and a variety of drugs. They are reversible [[MAOIs]] of the MAO-A isoform of the enzyme, and can stimulate the central nervous system by inhibiting the metabolism of monoamine compounds such as serotonin and norepinephrine. | ||
Harmala alkaloids are selective for MAO-A at reasonable doses and bind to the enzyme temporarily, so they are classed as a [[RIMA|reversible inhibitor of monoamine-A]] ([[RIMA]]). At higher doses, they also | Harmala alkaloids are selective for MAO-A at reasonable doses and bind to the enzyme temporarily, so they are classed as a [[RIMA|reversible inhibitor of monoamine-A]] ([[RIMA]]). At higher doses, they also affect the MAO-B enzyme. Because of the reversible selectivity for MAO-A, harmala alkaloids are considered to be less dangerous when combined with food containing [[tyramine]] and other substances with monoamine moieties which are reliant on monoamine oxidase for decomposition. | ||
However, it is important to understand that this does not imply that harmala alkaloids will not cause neurotoxicity. Harmala alkaloids temporarily disable the brain's primary mechanism for breaking down [[neurotransmitters]] and drugs which can have negative consequences as material builds up in the [[synapses]], leading to a huge range of downstream central and peripheral effects including [[sedation]], [[stimulation]], [[anxiety]], [[cognitive dysphoria]], [[Physical euphoria|euphoria]], [[headaches]], [[eye strain]], and [[muscle convulsions]]. The harmala alkaloids are not especially [[Psychedelics|psychedelic]], even at higher dosages, when hypnagogic visions, alongside [[vomiting]] and [[diarrhea]], become the main effect. | However, it is important to understand that this does not imply that harmala alkaloids will not cause neurotoxicity. Harmala alkaloids temporarily disable the brain's primary mechanism for breaking down [[neurotransmitters]] and drugs which can have negative consequences as material builds up in the [[synapses]], leading to a huge range of downstream central and peripheral effects including [[sedation]], [[stimulation]], [[anxiety]], [[cognitive dysphoria]], [[Physical euphoria|euphoria]], [[headaches]], [[eye strain]], and [[muscle convulsions]]. The harmala alkaloids are not especially [[Psychedelics|psychedelic]], even at higher dosages, when hypnagogic visions, alongside [[vomiting]] and [[diarrhea]], become the main effect. | ||
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Since [[DMT]] is broken down by monoamine oxidase A, inhibition of this enzyme allows for the oral activation of DMT and prolongs the experience for the duration of the harmala alkaloid effects. In combination, harmala alkaloids and DMT are known as [[ayahuasca]]. | Since [[DMT]] is broken down by monoamine oxidase A, inhibition of this enzyme allows for the oral activation of DMT and prolongs the experience for the duration of the harmala alkaloid effects. In combination, harmala alkaloids and DMT are known as [[ayahuasca]]. | ||
Harmala alkaloids, along with other [[beta-carbolines]], also function as [[GABA-A]] [[receptor]] (benzodiazepine site) inverse [[agonists]], likely contributing to their [[anxiety|anxiogenic]] and convulsant effects.<ref>From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory. | Harmala alkaloids, along with other [[beta-carbolines]], also function as [[GABA-A]] [[receptor]] (benzodiazepine site) inverse [[agonists]], likely contributing to their [[anxiety|anxiogenic]] and convulsant effects.<ref>{{cite journal | vauthors=((Venault, P.)), ((Chapouthier, G.)) | journal=TheScientificWorldJournal | title=From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory | volume=7 | pages=204–223 | date=19 February 2007 | issn=1537-744X | doi=10.1100/tsw.2007.48}}</ref> | ||
==Examples== | ==Examples== | ||
Common harmala alkaloids include: | Common harmala alkaloids include: | ||
====Harmane==== | |||
[[File:Harmane_structure.svg|278px]] | |||
'''Harmane''' ('''harman''') is a MAO-A inhibitor.<ref name="pmid35832393">https://www.frontiersin.org/articles/10.3389/fnmol.2022.925272/full</ref><ref name="harman">{{cite journal |last1=Herraiz |first1=T |last2=Chaparro |first2=C |title=Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harman isolated from coffee. |journal=Life sciences |date=18 January 2006 |volume=78 |issue=8 |pages=795-802 |doi=10.1016/j.lfs.2005.05.074 |pmid=16139309}}</ref><!-- Added to: MAOI, Harmala alkaloid --> | |||
====Harmine==== | ====Harmine==== | ||
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'''L-Tetrahydroharmine''' does not inhibit monoamine oxidase A. Instead, it weakly [[Reuptake inhibitor|inhibits reuptake]] of [[serotonin]]. | '''L-Tetrahydroharmine''' does not inhibit monoamine oxidase A. Instead, it weakly [[Reuptake inhibitor|inhibits reuptake]] of [[serotonin]]. | ||
'''D-THH''', on the other hand, has similar potency in terms of inhibiting MAO as harmine. | '''D-THH''', on the other hand, has similar potency in terms of inhibiting MAO as harmine. | ||
==Subjective effects== | ==Subjective effects== | ||
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*'''[[Effect::Dream potentiation]]''' | *'''[[Effect::Dream potentiation]]''' | ||
*'''[[Effect::Time distortion]]''' | *'''[[Effect::Time distortion]]''' | ||
*'''[[Effect::Creativity]]''' | *'''[[Effect::Creativity enhancement]]''' | ||
*'''[[Effect::Conceptual thinking]]''' | *'''[[Effect::Conceptual thinking]]''' | ||
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Syrian rue seeds contain several different harmala alkaloids at slightly varying percentages. Only some are monoamine oxidase A inhibitors. In one study, total harmala alkaloids were at least 5.9% of dried weight. | Syrian rue seeds contain several different harmala alkaloids at slightly varying percentages. Only some are monoamine oxidase A inhibitors. In one study, total harmala alkaloids were at least 5.9% of dried weight. | ||
{{Peganum harmala alkaloids}} | |||
==Extraction== | ==Extraction== | ||
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[[Acetylcholinesterase inhibitor]]s (AChEIs) combined with [[cholinergic]] substances can result in a [https://en.wikipedia.org/wiki/Cholinergic_crisis cholinergic crisis]. | [[Acetylcholinesterase inhibitor]]s (AChEIs) combined with [[cholinergic]] substances can result in a [https://en.wikipedia.org/wiki/Cholinergic_crisis cholinergic crisis]. | ||
Banisteriopsis caapi and ''[[Peganum harmala]]'' contain harmaline and harmine. Both alkaloids are acetylcholinesterase inhibitors (AChEIs).<ref name="Pubmed-19784581"> | Banisteriopsis caapi and ''[[Peganum harmala]]'' contain harmaline and harmine. Both alkaloids are acetylcholinesterase inhibitors (AChEIs).<ref name="Pubmed-19784581">{{cite journal | vauthors=((Zheng, X.)), ((Zhang, Z.)), ((Chou, G.)), ((Wu, T.)), ((Cheng, X.)), ((Wang, C.)), ((Wang, Z.)) | journal=Archives of Pharmacal Research | title=Acetylcholinesterase inhibitive activity-guided isolation of two new alkaloids from seeds of Peganum nigellastrum Bunge by an in vitro TLC- bioautographic assay | volume=32 | issue=9 | pages=1245–1251 | date= September 2009 | issn=0253-6269 | doi=10.1007/s12272-009-1910-x}}</ref> | ||
===Lethal dosage=== | ===Lethal dosage=== | ||