To write about the theory of etizolam reverse tolerance and eventually compare it with traditional benzodiazepines, a brief on the differences in the component between the two is necessary. Benzodiazepines are essentially a class of psychoactive medicines which are composed of a mixture of the benzene ring and a diazepine ring. Etizolam, whereas is an analog of benzodiazepines in which the benzene ring is replaced by a fusion of thiophene ring and a triazole ring. Hence etizolam is a thienotriazolodiazepine drug. Both these drugs have the same hypnotic, sedative, amnesic, anxiolytic and muscle relaxant effect despite their composition difference.
Apart from this similarity, both are, in fact, used for the treatment of panic disorder, anxiety and insomnia. This arises in mind the question of the existence of two forms of drugs for the same effect and treatment. Etizolam has been developed from traditional benzodiazepines (also called as ‘benzos’) as a solution to the potent adversities of dependence and withdrawal symptoms seen in people consuming benzos for a longer period.
The reverse tolerance of etizolam
For the general treatment of anxiety disorder, it has been found out that the effectiveness of etizolam is of the same level as of other drugs having same effects and uses. It is after 2 weeks when etizolam portrays reverse tolerance. The effectiveness increases and becomes more potent after 2 weeks and often lasts for more than 4 weeks. People consuming for a long time has experienced that the amount of etizolam needed to get the same level of sedative effect gradually decreases (less than half the initial dose even) in four to five weeks. These are clear signs of reverse tolerance associated with etizolam.
This progressive increase of sedative and anxiolytic effect over prolonged use of etizolam for more than four weeks is why people consuming it regularly are reported to have decreased their dosage to half (2mg to 1mg) over the course of time. All these facts and reports affirm the reverse tolerance of etizolam upon prolonged use.
Etizolam vs. Traditional Benzodiazepines
The level of tolerance and dependence is lower in the case of etizolam as compared to traditional benzodiazepines. The reason behind this is the allosteric potentiation of GABA (gamma-Aminobutyric Acid, an inhibitory neurotransmitter in the central nervous system) by both these drugs.
In the case of etizolam, the Cl- current brought about by α1-β2-γ2S receptors are lesser as compared to benzos. GABA basically evokes this Cl- current, and the quantity is decided by the strength and competence of each of the drug in stimulating the GABA. This is where traditional benzos stand winner and hence higher level of tolerance and dependence in comparison to etizolam.
It has been seen that rapid withdrawal from benzos does not give rise to neuroleptic malignant syndrome whereas it is a normal case for etizolam. Studies on rats showed that upon multiple consumptions of etizolam, rat neurons showed the downfall of the α1-benzodiazepine binding site (the basic cause of tolerance) whereas an increase in the α2-benzodiazepine binding site (the cause for reverse tolerance) which is not the case for traditional benzos. In comparison to the lorazepam (typical traditional benzos), etizolam is associated with significantly lower tolerance to anticonvulsant effect which is a validated proof of the superiority of reverse tolerance of etizolam over traditional benzodiazepines.
