Metizolam

Metizolam, or desmethyletizolam, is the demethylated analogue of the closely related etizolam. It is a structural relative of benzodiazepines whereby the benzene ring has been replaced by a thiophene ring, classifying it as a thienodiazepine. It differs structurally from its parent compound etizolam through the removal of the methyl group on the triazole ring.

Metizolam contains a thiophene ring fused to a diazepine ring, which is a seven member ring with the two nitrogen constituents located at R₁ and R₄. Thiophene is a five member aromatic ring with one sulfur atom. This forms the thienodiazepine core of metizolam. An ethyl chain is bound to this bicyclic structure at R₇.

Additionally, an R₂ chlorine-substituted phenyl ring is bound to this structure at R₅. Metizolam also contains a triazole ring fused to and incorporating R₁ and R₂ of its diazepine ring, classifying it as a thienotriazolodiazepine. Deschloroetizolam shares this fused triazole ring substitution with certain benzodiazepine substances, called triazolobenzodiazepines (distinguished by the suffix "-zolam").

Thienzodiazepines produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the neurotransmitter gamma aminobutyric acid (GABA) by acting on its receptors.^[6] As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of metizolam on the nervous system.

Metizolam is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.4 hours. Metizolam acts as a full agonist at the benzodiazepine/GABAa receptor to produce its range of therapeutic and adverse effects.

Thienotriazolodiazepines are easily oxidized, rapidly metabolized, and have a lower risk of accumulation, even after prolonged treatment. Metizolam has a powerful anxiolytic action that is about 6 times greater than that of diazepam. At higher dosages, metizolam allows for a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. Metzolam has also shown some similar characteristics to tricyclic antidepressants.

Although Metizolam has certain potential benefits such as anxiety suppression and muscle rest, it should be administered with caution and in small doses because of its harm and abuse potential. Metizolam can be life-threatening if administered with other depressants, including alcohol and opiates.

The harm potential due to long-term usage and toxicity dosage levels of Metizolam are not yet clear since the substance has not been adequately studied and analyzed in a scientific context. This is simply because of the lack of a known history of human usage.

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.

• Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Stimulants - It is dangerous to combine thienzodiazepines with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of benzodiazepines, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of thienzodiazepines will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of thienzodiazepines per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.

The toxicity and long-term health effects of recreational metizolam use have not been studied in any scientific context and the exact toxic dosage is unknown. This is because metizolam is a research chemical with very little history of human usage. Anecdotal evidence from people within the psychonaut community who have tried metizolam suggests that there are no negative health effects attributed to simply trying the substance by itself at low to moderate doses and using it very sparingly (but nothing can be completely guaranteed). Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.

It is strongly recommended that one use harm reduction practices, such as volumetric dosing, when using this substance to ensure the accurate administration of the intended dose.

Lethal dosage

The lethal dosage of metizolam has not been established; however, (like many benzodiazepines) it has a large therapeutic index and margin of safety. Complications may arise when administered in excess as this compound has not been formally studied and has little to no history of human usage.

As with all GABAergic drugs, overdose can be lethal when mixed with other depressants including alcohol or opioids.

It is strongly recommended that one use harm reduction practices when using this substance.

Tolerance and addiction potential

Thienzodiazepines are extremely addictive. Tolerance to the sedative-hypnotic effects develops within a couple of days of repeated administration. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Metizolam presents cross-tolerance with all thienzodiazepines and benzodiazepines, meaning that after the consumption of metizolam all compounds of the same class will have a reduced effect.

Abrupt discontinuation of metizolam following regular dosing over several days can result in a withdrawal phase which includes rebound symptoms such as increased anxiety and insomnia. It is possible to gradually reduce the dose over the course of several days, which will lengthen the duration of the withdrawal period, but reduce the perceived intensity.

Thienzodiazepine discontinuation is notoriously difficult; it is potentially life-threatening for individuals using regularly to discontinue use without tapering their dose over a period of weeks. There is an increased risk of seizure following discontinuation. Drugs which lower the seizure threshold such as tramadol should be avoided during withdrawal.

Overdose

Thienodiazepine overdose may occur when a thienodiazepine is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as barbiturates and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABA_A receptor. Thus their effects potentiate one another. Thienodiazepines increase the frequency in which the chlorine ion pore opens on the GABA_A receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer.^[7] Thienodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly.

Symptoms of a thienodiazepine overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death. Thienodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Thienodiazepine overdoses are sometimes treated with flumazenil, a GABA_A antagonist,^[8] however care is primarily supportive in nature.

Paradoxical effects

Paradoxical reactions to benzodiazepines such as increased seizures (in epileptics), aggression, increased anxiety, violent behavior, loss of impulse control, irritability and suicidal behavior sometimes occur (although they are rare in the general population, with an incidence rate below 1%).^[9][10]

These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.^[11][12] Due to the close structural and pharmacological similarities they share, it is likely that these same risks apply to thienodiazepines as well.

• Volumetric liquid dosing - If one's thienodiazepines are in powder form, they are unlikely to weigh out accurately without the most expensive of scales due to their extreme potency. To avoid this, one can dissolve the thienodiazepine volumetrically into a solution and dose it accurately based upon the methodological instructions linked within this tutorial here.

Metizolam is currently a grey area compound within most parts of the world. This means that it is not known to be specifically illegal within any country, but people may still be charged for its possession under certain circumstances such as under analogue laws and with intent to sell or consume.

• Canada: All benzodiazepines are Schedule IV controlled substances in Canada.^[13]
• Germany: Metizolam is controlled under the NpSG (New Psychoactive Substances Act)^[14] as of July 18, 2019.^[15] Production and import with the aim to place it on the market, administration to another person and trading is punishable. Possession is illegal but not penalized.^[16]
• Sweden: Following its sale as a designer drug, metizolam was made illegal in Sweden on January 26, 2016.^[17]
• Switzerland: Metizolam is a controlled substance specifically named under Verzeichnis E.^[18]
• Turkey: Metizolam is a classed as drug and is illegal to possess, produce, supply, or import.^[19]
• United Kingdom: It is illegal to produce, supply, or import this drug under the Psychoactive Substance Act, which came into effect on May 26, 2016.^[20]

• Responsible use
  • Volumetric liquid dosing
• Etizolam
• Thienodiazepine
• Benzodiazepine

• Metizolam (Wikipedia)
• Metizolam (Isomer Design)
• Metizolam (Bluelight)
• Metizolam (UK Chemical Research)