algekalipso's Quick takes

[Related to:  Logarithmic Scales of Pleasure and Pain; Anti-Tolerance Drugs]

Millions of people suffering from benzo/gabapentin/phenibut/alcohol withdrawal across the world thinking that tapering is the only solution, while it seems like people in Italy and Japan already figured out how to reverse tolerance without side-effects within a week? It's called Flumazenil and it's a GABAa  antagonist, which when taken in microdoses can up-regulate GABA receptors (hear me out: up-regulation and other tolerance mechanisms are *not* proportional to subjective effect size - this insight makes all the difference).

See the wikipedia entry on it:

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.[12] One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic's most common patients.[13]

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil.[14] Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.[15]

Flumazenil has been tested against placebo in benzo-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.[16] Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.[17]

In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed.[18][19][20] After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[21]

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[22] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

 Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency.[23] It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.[24]

See also a video I made about why our common-sense view of how drug tolerance works gets in the way of actually solving this crisis.