Grayanotoxin

The experience of grayanotoxin, historically encountered through "mad honey" harvested from rhododendron-feeding bees, is unlike any other depressant. The onset takes thirty minutes to two hours and begins with a sensation that something is subtly wrong with the body's calibration. A dizziness appears, not the spinning vertigo of alcohol but a lighter, more floating variety, as though the inner ear has been gently confused about which way is up. There is a tingling in the lips and mouth that spreads to the face and extremities, a characteristic pins-and-needles sensation that announces the toxin's interaction with sodium channels throughout the nervous system.

As the effects develop, the dizziness intensifies and is joined by a noticeable drop in blood pressure and heart rate. The body feels strange -- simultaneously light-headed and heavy-limbed, as though the upper and lower halves were subject to different gravitational rules. There is a warmth that spreads from the stomach, and many users report a mild euphoria, a dreamy sense of contentment that sits oddly alongside the physical discomfort. Vision may blur slightly, and there is a sense of the world being viewed through a gentle haze. Nausea is common, a queasy reminder that this is a toxin the body is working to process, and sweating may occur despite a subjective feeling of coldness.

At what might be called the peak, the experience is a strange mixture of euphoria and malaise. The dizziness is pronounced, and coordination is significantly impaired. There is a perceptual quality that is genuinely unique -- a dreamy, slightly hallucinatory softness to the world, as though reality were being experienced through a thin membrane. The body feels weak, and exertion becomes difficult; the heart beats slowly, and the blood pressure remains low, producing lightheadedness with any change in position. Despite these uncomfortable physical effects, there is often a persistent sense of peace, a calm that seems to belong to a different substance entirely.

The offset is gradual, the dizziness and weakness slowly receding over several hours. The nausea typically resolves before the cardiovascular effects normalize, and a lingering lightheadedness may persist for half a day. The overall experience is more curiosity than pleasure -- a strange, ancient intoxication that feels like it belongs to a different era of human drug use.

The toxicity of grayanotoxin is derived from its ability to interfere with voltage-gated sodium channels located in the cell membrane of neurons. The Nav1.x channels consist of four homologous domains (I-IV), each containing six transmembrane alpha-helical segments (S1-S6). Grayanotoxin has a binding affinity (IC50) of approximately 10 μM and binds the group II receptor site located on segment 6 of domains I and IV (IS6 and IVS6). Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine.

Experiments using squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron. Additionally, grayanotoxin only binds to the activated conformation of sodium channels. Normally, voltage gated sodium channels are activated (opened) only when the cell membrane potential reaches a specific threshold voltage. This activated conformation allows for an influx of sodium ions resulting in cell depolarization, followed by the firing of an action potential. At the peak of the action potential, voltage-gated sodium channels are quickly inactivated and are only reset once the cell has repolarized to resting potential. When grayanotoxin is present, binding induces further conformational changes that prevent sodium channel inactivation and lead to a prolonged depolarization. Owing to its transient ability to activate channels and increase membrane permeability to sodium ions, grayanotoxin is classified as a reversible Nav1.x agonist.

There are currently experience reports which describe the effects of this substance in our experience index.

It is strongly recommended that one use harm reduction practices when using this substance. -Cholinergics** - Because grayanotoxins potentiate the effects of acetylcholine, cholinergic substances such as nicotine, caffeine, and galantamine may carry an increased risk of cholinergic crisis. -Depressants** - Combining grayanotoxins with other depressants increase the risk of a sudden loss of consciousness. -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.

• Responsible use

(List along order below)

• Grayanotoxin (Wikipedia)

• Grayanotoxin (Erowid Vault)

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