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Grayanotoxin: Difference between revisions

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{{SummarySheet}}
{{SummarySheet}}
{{talk:SubstanceBox/Grayanotoxin}}
{{talk:SubstanceBox/Grayanotoxin}}
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==History and culture==
==History and culture==
{{historyStub}}
{{historyStub}}
Grayanotoxins are an active constituent of a variety of plants with a history of medicinal and recreational use, including species of [[rhododendron]] and [[Monotropa uniflora|monotropa uniflora]] <ref>"Monotropa uniflora Indian Pipe". ''Plants for a Future''. Retrieved 2022-08-13.</ref>. Most commonly, grayanotoxins are consumed in the form of mad honey, which is contaminated with grayanotoxins from bees that pollinate rhododendron flowers <ref name=":2">Ullah S, Khan SU, Saleh TA, Fahad S. Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv. 2018 May 22;8(33):18635-18646. doi: 10.1039/c8ra01924j. PMID: 35541133; PMCID: PMC9080652</ref>. Mad honey is reportedly used as an aphrodisiac, painkiller, treatment for hypertension, and as a recreational drug, particularly in Nepal and the Black Sea region of Turkey <ref name=":2" />. Historically, mad honey has been added to [[Alcohol|alcoholic drinks]] to increase their potency <ref>"Grayanotoxins". ''Foodborne Pathogenic Microorganisms and Natural Toxins Handbook''. US FDA. 2012. Retrieved August 7, 2015.</ref>.
The Gurung people of Nepal are especially known to harvest mad honey for its supposed hallucinogenic properties <ref>Shrestha TM, Nepal G, Shing YK, Shrestha L. Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: A clinical case report. Clin Case Rep. 2018 Oct 22;6(12):2355-2357. doi: 10.1002/ccr3.1889. PMID: 30564328; PMCID: PMC6293183.</ref>.


==Chemistry==
==Chemistry==
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==Pharmacology==
==Pharmacology==
{{pharmacology}}
{{pharmacology}}
Grayanotoxins are a group of toxic [[Diterpene|diterpenes]] found in the ericacaeae family of plants <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref>. More than 25 grayanotoxin isoforms have been isolated from [[rhododendron]], though grayanotoxin I and grayanotoxin III are considered to be the most responsible for the toxic pharmacological effects of grayanotoxin-containing plants.<ref>Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA. Grayanotoxin poisoning: 'mad honey disease' and beyond. Cardiovasc Toxicol. 2012 Sep;12(3):208-15. doi: 10.1007/s12012-012-9162-2. PMID: 22528814; PMCID: PMC3404272.</ref> Grayanotoxin I, as well as grayanotoxin III, act as [[Agonist|agonists]] of [[Neuron|voltage-gated sodium channels.]]<ref>Yuki T, Yamaoka K, Yakehiro M, Seyama I. State-dependent action of grayanotoxin I on Na(+) channels in frog ventricular myocytes. J Physiol. 2001 Aug 1;534(Pt 3):777-90. doi: 10.1111/j.1469-7793.2001.00777.x. PMID: 11483708; PMCID: PMC2278746.</ref><ref name=":1">Kim SE, Shin MC, Akaike N, Kim CJ. Presynaptic effects of grayanotoxin III on excitatory and inhibitory nerve terminals in rat ventromedial hypothalamic neurons. Neurotoxicology. 2010 Mar;31(2):230-8. doi: 10.1016/j.neuro.2009.12.006. Epub 2009 Dec 28. PMID: 20038438.</ref> Through this mechanism, grayanotoxins increase the release of [[Neurotransmitter|neurotransmitters]] in the central nervous system such as [[GABA]] <ref name=":1" />, [[glutamate]] <ref name=":1" />, and [[acetylcholine]] <ref>Pischon H, Petrick A, Müller M, Köster N, Pietsch J, Mundhenk L. Grayanotoxin I Intoxication in Pet Pigs. ''Veterinary Pathology''. 2018;55(6):896-899. doi:10.1177/0300985818789482</ref>.
Additionally, grayanotoxin III may act as an [[antagonist]] of [[Glutamate|central glutamate receptors]], further contributing to [[Depressant|CNS depressant]] effects <ref>Ohgaki T, Uchida S, Meguri H, Ogita K, Yoneda Y. Preventive action of quisqualic acid against grayanotoxin-induced suppression of locomotor activity in mice. Neuropharmacology. 1988 Oct;27(10):1045-53. doi: 10.1016/0028-3908(88)90066-4. PMID: 3070432.</ref>. Reports of grayanotoxin intoxication include symptoms of the [[Cholinergics|cholinergic]] toxidrome such as [[Decreased heart rate|decreased heart rate]], [[Decreased blood pressure|hypotension]], and an [[Cognitive effects|altered mental status]] <ref name=":0" />.


==Subjective effects==
==Subjective effects==
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|{{effects/physical|
|{{effects/physical|
If applicable, a brief paragraph summary of the substance's physical effects may be included here.


You may select physical effects to add below [[Subjective effect index#Physical effects|here]].
*'''[[Effect::[[Sedation]]]]'''
 
*'''[[Effect::[[Muscle relaxation]]]] <ref>Ohgaki T, Meguri H, Ogita K, Yoneda Y. Tetrodotoxin-insensitive central depression by grayanotoxin-III in mice. Brain Res. 1987 Nov 10;425(2):364-8. doi: 10.1016/0006-8993(87)90521-x. PMID: 2448007.</ref>'''
*'''[[Effect::Physical effect]]'''  
*'''[[Effect::[[Mouth numbing]]]] <ref>Shrestha TM, Nepal G, Shing YK, Shrestha L. Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: A clinical case report. Clin Case Rep. 2018 Oct 22;6(12):2355-
*'''[[Effect::Physical effect2]]'''
2357. doi: 10.1002/ccr3.1889. PMID: 30564328; PMCID: PMC6293183.</ref>'''  - This effect occurs along with paresthesia, or a tingling sensation, especially in the extremities.
*'''[[Effect::Physical effect3]]'''
*'''[[Effect::[[Physical euphoria]]]]''' - This effect manifests as a warm tingling sensation, particularly in the face and extremities, along with a sense of bodily numbness.
*'''[[Effect::[[Physical fatigue]]]]
*'''[[Effect::[[Decreased heart rate]]]]''' - This effect is dose-dependent, potentially fatal, and occurs along with decreased blood pressure <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref>.
*'''[[Effect::[[Decreased blood pressure]]]]'''
*'''[[Effect::[[Pain relief]]]] <ref>Gunduz A, Eraydin I, Turkmen S, Kalkan OF, Turedi S, Eryigit U, Ayar A. Analgesic effects of mad honey (grayanotoxin) in mice models of acute pain and painful diabetic neuropathy. Hum Exp Toxicol. 2014 Feb;33(2):130-5. doi: 10.1177/0960327113482693. Epub 2013 Apr 12. PMID: 23584354.</ref>'''
*'''[[Effect::[[Nausea]]]]''' - This effect may occur as a result of both decreased blood pressure and the local irritant effect of grayanotoxins. In higher doses, grayanotoxins may cause vomiting <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref>.
*'''[[Effect::[[Increased perspiration]]]]'''
*'''[[Effect::[[Headache]]]]''' <ref>Ullah S, Khan SU, Saleh TA, Fahad S. Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv. 2018 May 22;8(33):18635-18646. doi: 10.1039/c8ra01924j. PMID: 35541133; PMCID: PMC9080652.</ref> 
*'''[[Effect::[[Increased salivation]]]]'''
*'''[[Effect::[[Diarrhea]]]]''' <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref> - Grayanotoxin-containing plants have been historically used as laxatives.
*'''[[Effect::[[Motor control loss]]]]''' <ref>Ohgaki T, Uchida S, Meguri H, Ogita K, Yoneda Y. Preventive action of quisqualic acid against grayanotoxin-induced suppression of locomotor activity in mice. Neuropharmacology. 1988 Oct;27(10):1045-53. doi: 10.1016/0028-3908(88)90066-4. PMID: 3070432.</ref>
*'''[[Effect::[[Temperature regulation suppression]]]]''' - This may manifest as [[Temperature regulation suppression|hypothermia]].
*'''[[Effect::[[Dizziness]]]]''' - This effect may occur along with vertigo <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref>.
*'''[[Effect::[[Appetite suppression]]]]''' <ref>Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA. Grayanotoxin poisoning: 'mad honey disease' and beyond. Cardiovasc Toxicol. 2012 Sep;12(3):208-15. doi: 10.1007/s12012-012-9162-2. PMID: 22528814; PMCID: PMC3404272.</ref>
*'''[[Effect::[[Increased libido]]]]''' - Mad honey is sometimes used as an alternative treatment for sexual dysfunction <ref name=":0">Gunduz A, Turedi S, Russell RM, Ayaz FA. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin Toxicol (Phila). 2008 Jun;46(5):437-42. doi: 10.1080/15563650701666306. PMID: 18568799.</ref>.


}}
}}
{{effects/visual|
{{effects/visual|
If applicable, a brief paragraph summary of the substance's visual effects may be included here.


You may select visual effects to add below [[Subjective effect index#Visual effects|here]].
====Suppressions====
*'''[[Effect::[[Visual acuity suppression]]]]'''
*'''[[Effect::[[Double vision]]]]''' <ref>Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA. Grayanotoxin poisoning: 'mad honey disease' and beyond. Cardiovasc Toxicol. 2012 Sep;12(3):208-15. doi: 10.1007/s12012-012-9162-2. PMID: 22528814; PMCID: PMC3404272.</ref> 
*'''[[Effect::[[Color depression]]]]''' <ref>Setareh-Shenas S, Kaplin S, Bania TC, Kornberg R. A Rare Case of Mad Honey Disease: A Reversible Cause of Complete Heart Block. JACC Case Rep. 2019 Nov 13;1(4):579-582. doi: 10.1016/j.jaccas.2019.09.015. PMID: 34316883; PMCID: PMC8288791.</ref>


====Enhancements====
*'''[[Effect::Visual acuity effect1]]'''


====Distortions====
====Distortions====
*'''[[Effect::Visual distortion effect1]]'''
*'''[[Effect::[[Drifting]]]]''' - This effect is qualitatively similar to that of other [[Cholinergics|cholinergic substances]], and is likely a result of the effects of grayanotoxins on sodium channels.
*'''[[Effect::[[Visual haze]]]]''' <ref>Roy, Saurav & Biswas, Soumya & Ghosh, Saikat & Roy, Pragyan. (2019). The Himalayan hallucinogenic honey and its future prospects and proposed uses. 10.13140/RG.2.2.29254.63041.</ref>
*'''[[Effect::[[Brightness alteration]]]]''' <ref>Setareh-Shenas S, Kaplin S, Bania TC, Kornberg R. A Rare Case of Mad Honey Disease: A Reversible Cause of Complete Heart Block. JACC Case Rep. 2019 Nov 13;1(4):579-582. doi: 10.1016/j.jaccas.2019.09.015. PMID: 34316883; PMCID: PMC8288791.</ref> - Grayanotoxin may make colors appear darker.
 


====[[Effect::Geometry]]====
If applicable, a brief paragraph summary describing the visual geometry produced by the substance may be included here.
====Hallucinatory states====
====Hallucinatory states====
If applicable, a brief summary of the substance's visual effects profile may be written here.


*'''[[Effect::Hallucinatory states1]]'''
*'''[[Effect::[[External hallucination]]]]''' - [[Deliriant]]-like hallucinations have been reported after high-dose ingestion of grayanotoxins, this is rarely reported and is unlikely to occur at common doses. <ref>Shrestha TM, Nepal G, Shing YK, Shrestha L. Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: A clinical case report. Clin Case Rep. 2018 Oct 22;6(12):2355-2357. doi: 10.1002/ccr3.1889. PMID: 30564328; PMCID: PMC6293183.</ref>
*'''[[Effect::[[Internal hallucination]]]]'''  


}}
}}


|{{effects/cognitive|
|{{effects/cognitive|
If applicable, a brief paragraph summary of the substance's cognitive effects may be included here.
You may select from a list of cognitive effects to add below [[Subjective effect index#Cognitive effects|here]].


*'''[[Effect::Cognitive effect1]]'''  
*'''[[Effect::[[Cognitive fatigue]]]]''' <ref>Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA. Grayanotoxin poisoning: 'mad honey disease' and beyond. Cardiovasc Toxicol. 2012 Sep;12(3):208-15. doi: 10.1007/s12012-012-9162-2. PMID: 22528814; PMCID: PMC3404272.</ref> 
*'''[[Effect::Cognitive effect2]]'''  
*'''[[Effect::[[Confusion]]]]'''
*'''[[Effect::Cognitive effect3]]'''  
*'''[[Effect::[[Irritability]]]]''' <ref>Ullah S, Khan SU, Saleh TA, Fahad S. Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv. 2018 May 22;8(33):18635-18646. doi: 10.1039/c8ra01924j. PMID: 35541133; PMCID: PMC9080652.</ref>
*'''[[Effect::[[Sleepiness]]]]''' - At sufficient doses, grayanotoxins may cause [[sedation]] and even a sudden loss of consciousness <ref>Jansen SA, Kleerekooper I, Hofman ZL, Kappen IF, Stary-Weinzinger A, van der Heyden MA. Grayanotoxin poisoning: 'mad honey disease' and beyond. Cardiovasc Toxicol. 2012 Sep;12(3):208-15. doi: 10.1007/s12012-012-9162-2. PMID: 22528814; PMCID: PMC3404272.</ref>.
*'''[[Effect::[[Cognitive euphoria]]]]''' - This effect manifests as a sense of relaxation <ref>Shrestha TM, Nepal G, Shing YK, Shrestha L. Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: A clinical case report. Clin Case Rep. 2018 Oct 22;6(12):2355-2357. doi: 10.1002/ccr3.1889. PMID: 30564328; PMCID: PMC6293183.</ref>
*'''[[Effect::[[Cognitive dysphoria]]]]''' <ref>Ullah S, Khan SU, Saleh TA, Fahad S. Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv. 2018 May 22;8(33):18635-18646. doi: 10.1039/c8ra01924j. PMID: 35541133; PMCID: PMC9080652.</ref> 
*'''[[Effect::[[Anxiety suppression]]]]''' - Grayanotoxin-containing plants, such as monotropa uniflora, have been historically used for their anxiolytic effects <ref>Wickes Felter, Harvey; Uri Lloyd, John (1898). King's American dispensatory (19th 3rd rev ed.). Ohio Valley Co. p. 1277.</ref>.


}}
}}
{{effects/auditory|
{{effects/auditory|
If applicable, a brief paragraph summary of the substance's auditory effects may be included here.


You may select from a list of auditory effects to add below [[Subjective effect index#Auditory effects|here]].
*'''[[Effect::[[Auditory acuity suppression]]]]''' <ref>Demircan A, Keles A, Bildik F, Aygelcel G, Dogan NO, Gomez HF. Mad honey sex: Therapeutic misadventures from an ancient biological weapon. An Emerg Med 2009; 54: 824-9</ref>


*'''[[Effect::Auditory effect1]]'''
*'''[[Effect::Auditory effect2]]'''


}}
}}
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{{#ask: [[Category:SUBSTANCE]][[Category:Experience]]|format=ul|Columns=1}}
{{#ask: [[Category:SUBSTANCE]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:
Additional experience reports can be found here:
* [https://www.erowid.org/experiences/subs/exp_SUBSTANCE.shtml Erowid Experience Vaults: SUBSTANCE] <!-- Check the link to see if it exists -->
* [https://erowid.org/experiences/subs/exp_Honey_Mad_Nepalese_Rhododendron_Flower.shtml Erowid Experience Vaults: Mad Honey]
* [https://erowid.org/experiences/subs/exp_Monotropa_uniflora.shtml Erowid Experience Vaults: Monotropa uniflora]


==Toxicity and harm potential==
==Toxicity and harm potential==
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===Lethal dosage===
===Lethal dosage===
===Tolerance and addiction potential===
===Tolerance and addiction potential===
===Dangerous interactions===
===Dangerous interactions===
{{DangerousInteractions}}
{{DangerousInteractions}}
{{DangerousInteractions/Intro}}
{{DangerousInteractions/Intro}}
*'''[[UnsafeInteraction::Cholinergics]]''' - Because grayanotoxins potentiate the effects of [[acetylcholine]], cholinergic substances such as [[nicotine]], [[caffeine]], and [[galantamine]] may carry an increased risk of [[cholinergic crisis]].
*'''[[UnsafeInteraction::Depressants]]''' - Combining grayanotoxins with other [[depressants]] increase the risk of a sudden loss of consciousness.
*'''[[DangerousInteraction::Opioids]]'''  - Grayanotoxins and opioids potentiate the [[sedation]], [[hypotension]], and [[decreased heart rate]] caused by each other, increasing the risk of sudden loss of consciousness or [[respiratory depression]].


==Legal status==
==Legal status==
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==External links==
==External links==
(List along order below)
(List along order below)
* [https://en.wikipedia.org/wiki/Grayanotoxin (Wikipedia)]
* [https://en.wikipedia.org/wiki/Grayanotoxin Grayanotoxin (Wikipedia)]
* Grayanotoxin (Erowid Vault)
* [https://erowid.org/experiences/subs/exp_Honey_Mad_Nepalese_Rhododendron_Flower.shtml Grayanotoxin (Erowid Vault)]


==Literature==
==Literature==
Retrieved from "https://psy.st/wiki/Grayanotoxin"