Etifoxine for benzodiazepine recovery, impairment prevention, and replacement

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Benzodiazepines have long been the staple of anxiety treatment, and for good reason. Compared to their predecessors, barbiturates, they have a far greater safety profile. Compared to the current first line treatment of anxiety disorders, SSRI’s, it’s like a civil war musket to a nuclear warhead. These drugs do work, and no one is questioning that. Their side effects, however, prevent them from being a viable option for long term treatment of anxiety disorders. They’re cognitively impairing and develop more sever dependency than opioids, not exactly an ideal medicine for people who just get a little anxious sometimes. However, there are some promising alternatives that could have similar efficacy with much more limited adverse effects.

For the purpose of this write-up, I’ll primarily be discussing diazepam, as it has the widest collection of relevant literature surrounding it of any benzodiazepine. One note of relevance is that while diazepam itself is an active compound, some of its metabolites are also pharmacologically active, which can interfere with discussion of its properties. In the case of this review, that doesn’t really matter, because all other benzodiazepines share the same mechanism of action for cognitive impairment.

Chronic benzodiazepines have been associated with the development of Alzheimer’s, Dementia, and other deleterious cognitive disorders, although it appears to be a noncausal relationship, benzodiazepines do not seem to cause or worsen such conditions [1]. Still, benzodiazepines are known to cause amnesia, particularly in recreational settings, and long lasting reductions in learning capacity. The reduction in learning and memory retrieval is particularly evident in middle age and elderly populations, however even in younger populations, a reduction of spine density in hippocampal neurons is observed [2].

At first glance, the obvious culprit of this GABA-A activation. GABA is the main inhibitory neurotransmitter, why wouldn’t it cause learning deficits and cognitive decline? The problem with this is that not all GABA-A PAM’s and agonists share the same detrimental effect on cognition as benzodiazepines. Allopregnanolone, a progesterone derived neurosteroid and GABA-A PAM, can restore hippocampal neurogenesis in social isolation, not exactly a negative effect in terms of cognition [3]. Gaboxadol is a GABA-A agonist that is devoid of the persisting deleterious effects on memory and attention seen in benzodiazepine use [4].

Finding the cause of lasting deficits in memory and cognition following chronic benzodiazepine usage is much more difficult when it can’t be directly attributed to their main mechanism of action. A relatively recent paper revealed that the reduction in dendritic spine structural plasticity and microglial removal of synapses, and the subsequent cognitive impairment, is due to modulation of TSPO rather than modulation of the GABA-A recptor [5]. Now because scientists are fucking whores who care about nothing but money, and the paper can’t be found on sci-hub or libgen, the exact method of modulation, or even what kind of modulation is happening is unclear. Fortunately, because of the substance used to reverse this impairment, we can assume that some kind of negative modulation of, or reduction in, TSPO is occurring.

The drug that I’m talking about is one that I’m sure many in the NooTopics community are familiar with, etifoxine. As both a GABA-A PAM and TSPO ligand, it’s the perfect agent for recovering from benzodiazepine abuse, preventing the cognitive impairment caused by benzodiazepines, and as a replacement for clinical use of benzodiazepines.

Since benzodiazepines cause cognitive impairment via TSPO, a TSPO ligand is an easy first step in recovering cognitive abilities [5]. Although not of particular relevance, etifoxine has been used in cases of traumatic brain injury with a high degree of success. While benzodiazepine withdrawal and TBI damage aren’t directly comparable, it’s good to know that it has some neurorestoritive and protective effects [6]. It also seems to enhance peripheral nerve regeneration and increase GDNF, although, again, not entirely relevant [7]. Etifoxine’s gabaergic properties are the most important thing for the initial withdraw and the lasting GABA-A downregulation caused by chronic benzodiazepine use, but I’ll get into that more once I start onto the use of etifoxine as a replacement anxiolytic.

One of the more interesting effect of etifoxine that is seldomly discussed is it’s ability to counteract the cognitively impairing effects of benzodiazepines. Very little research has been done on this, and I don’t think I’ve seen any anecdotes reporting on this. The study just came out this year, so that is to be expected. The study showed that when rats were treated with both diazepam and etifoxine, diazepam’s amnesiac effects were almost entirely ameliorated. Etifoxine was also able to heavily improve locomotor activity, suggesting a significant mitigation of diazepam’s anti-cognitive effects [8]. While the use of benzodiazepines should be avoid in almost all situations, if their use is required, supplementing with etifoxine during use may be able to severely dampen the damage done by them.

Etifoxine’s anxiolytic effect is, of course, its most notable effect. It’s the reason it was produced and marketed in the first place. The dual action of being a GABA-A PAM and stimulation of the production of inhibitory neurosteroids makes for quite the potent anxiolytic. In fact, 150mg of etifoxine is comparable to 1mg of clonazepam, both divided into three daily doses [9]. This is particularly important because clonazepam, or Klonipin, is particularly strong benzodiazepine and is among the strongest anxiolytics available. What’s even more impressive than having similar efficacy to benzodiazepines without cognitive impairment, is being able to have it without dependency. In a comparison between 150mg etifoxine and 1.5mg alprazolam, the alprazolam outperformed. This shouldn’t be a surprise, alprazolam, or Xanax, is the gold standard for eradicating anxiety. The interesting part of this study comes after discontinuation. While alprazolam group saw a rebound of anxiety symptoms, the etifoxine group showed continued improvement [10]. This suggests that not only does etifoxine lack dependency, its effects may actually last well beyond the treatment period, possibly due to alterations in neurosteroid expression.

Final Thoughts

None of this is medical advice. In fact, you probably shouldn’t be listening to anything I say. I’m just some random 18 year old rambling about lesser known pharmaceuticals that aren’t even available in most first world countries. Please due your own research. While etifoxine may be a life changing drug for some, it does carry some risks, particularly potential dermal toxicity and hepatoxicity. Always use caution when experimenting with substances like these. Thanks for reading :)

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Sources and their Relevance

[1] While there is an association low cognition/cognitive disorders and chronic use of benzodiazepines, benzodiazepines do not appear to be the causal factor. https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.jalz.2011.05.1999

[2] Diazepam impairs learning and memory retrieval in middle aged rats, possibly by reduction decreased LTP, and decreases spine density of hippocampal neurons in both young and middle aged rats.
https://www.frontiersin.org/articles/10.3389/fnagi.2021.777404/full

[3] Allopregnanolone treatment attenuates anxiety and depression like behavior following social isolation. It also restores hippocampal neurogenesis
https://www.sciencedirect.com/science/article/abs/pii/S0028390812004480?dgcid=api_sd_search-api-endpoint

[4] Repeated administration of Gaboxadol as a sleep aid has no effect on next-day attention or memory abilities.
https://www.nature.com/articles/1300641

[5] Diazepam’s cognitive deficits are caused by TSPO, potentially by reduced synaptic plasticity https://www.nature.com/articles/s41593-022-01013-9

[6] Etifoxine is neuroprotective in cases of traumatic brain injury and improves cognitive and behavioral outcomes
https://pubmed.ncbi.nlm.nih.gov/34884686/

[7] Etifoxine promotes peripheral nerve cell regeneration/GDNF
https://www.pnas.org/doi/full/10.1073/pnas.0811201106

[8] Etifoxine ameliorates the cognitive deficits induced by diazepam, as well as alleviating the amnesiac and locomotor reducing effects of diazepam.
https://www.mdpi.com/2218-0532/91/2/25#:~:text=Etifoxine%20increased%20the%20number%20of,memory%20in%20passive%20learning%20tests

[9] Etifoxine is non-inferior to clonazepam in anxiety treatment
https://link.springer.com/article/10.1007/s00213-020-05617-6

[10] Alprazolam outperforms etifoxine, but etifoxine continues to improve anxiety related symptoms after withdrawal, whereas alprazolam increases them.
https://link.springer.com/article/10.1007/s12325-015-0176-6

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Pub: 28 Jul 2023 15:31 UTC
Edit: 30 Jul 2023 03:03 UTC
Views: 234