Etizolam and Xanax are interventions that may be utilized for the treatment of acute episodes of anxiety, panic disorder, and/or generalized anxiety disorder. Although Etizolam has no accepted medical use in the United States where it is federally considered an unregulated “research chemical,” it is regularly utilized in Japan, Italy, and India as a prescription anxiolytic.
Comparatively, Xanax is approved by the U.S. FDA for the treatment of generalized anxiety disorder and panic disorder – and is presently the most-prescribed anxiolytic in the United States. Additionally, Xanax was released as a pharmaceutical in 1981 throughout the United States whereas Etizolam was released as a pharmaceutical in 1983 throughout Japan under the trade name “Depas.”
Depas (Etizolam) vs. Xanax (Alprazolam): Comparison
Documented below is a comparative chart of general attributes associated with Etizolam and Xanax, respectively. Analysis of the chart should help underscore obvious similarities and differences between Etizolam and Xanax. In the event that you have specific questions about attributes of these substances – it is strongly advised to consult a pharmacist and/or medical doctor.
|Approved medical uses||None (U.S.)|
Generalized anxiety disorder. Panic disorder. Acute anxiety. Insomnia. (Japan, Italy, India)
|Generalized anxiety disorder. Panic disorder.|
|Off-label uses||N/A (Unknown)||Chemotherapy-induced nausea and vomiting. Insomnia. Agitation. Premenstrual dysphoric disorder.|
|Bioavailability||~93% (oral)||~90% (oral)|
|Formats||Tablet.||Tablet. Extended-release (XR or ER) pill. Oral disintegrating tablet. Oral solution.|
|Dosages||0.25 mg, 0.5 mg, 1 mg||Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg|
Oral disintegrating tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Extended-release (XR) pills: 0.5 mg, 1 mg, 2 mg, 3 mg
Oral solution: 30 ml 1 mg/ml
|Manufacturer||N/A (Unknown)||Pfizer Inc. (Upjohn)|
|Legal status||Research chemical (U.S.)|
Prescription (Rx)-only (Japan, Italy, India)
|Schedule IV (U.S.)|
|Mechanism of action||GABAA receptor positive allosteric modulator (PAM). |
Dose-dependently inhibits acetylcholine release in hippocampus and prefrontal cortex.
Exhibits lower intrinsic activity at A1 subunit-containing GABAA receptors than conventional benzodiazepines.
|GABAA receptor positive allosteric modulator (PAM). |
Suppresses activity within the HPA (hypothalamic-pituitary-adrenal) axis.
Increases extracellular D1 and D2 dopamine concentrations in the striatum.
|Generic version (?)||Yes.||Yes.|
|Half-Life||7 to 15 hours||9 to 16 hours (~12 hours)|
|Common side effects||Sedation. Muscle weakness. Ataxia.||Drowsiness. Lightheadedness. Dry mouth. Depression. Headache. Constipation. Diarrhea.|
|Duration of effect||5 to 7 hours||Standard: ~5 hours|
Extended-release: ~11 hours
|Metabolism||Hepatic: CYP3A4. CYP2C18. CYP2C19.||Hepatic: CYP3A4.|
|Onset of action||15 to 25 minutes||20 to 40 minutes|
Etizolam vs. Xanax: What are some notable differences?
Substantial differences between Etizolam and Xanax include: chemical classification; medical status in the United States; available formats; route of metabolism; and elimination half-life. There also may be modest differences between Etizolam and Xanax in other aspects such as: mechanism of action; onset of action; duration of effect; and side effects.
Chemically, Etizolam is classified as a “thienodiazepine” and is commonly referred to as a benzodiazepine analogue – whereas Xanax is classified as a “triazolobenzodiazepine.” The chemical structure of Etizolam is heterocyclic and contains a thiophene ring fused to a triazole ring – whereas the core chemical structure of Xanax contains a benzene ring fused to a triazole ring.
In the United States, Etizolam has no accepted medical uses and is solely legal to utilize as a research chemical – whereas Xanax is approved by the FDA for the treatment of anxiety disorders and as a specific treatment for panic disorder. However, if considering the medical uses for Etizolam in countries where it is approved (Japan, Italy, India) – it has similar indications as Xanax.
In terms of formatting, Etizolam is solely manufactured in an immediate-release tablet format – whereas Xanax is manufactured in a variety of formats including: immediate-release tablet; orally-disintegrating tablet (ODT); extended-release tablet (ER or XR); and oral solution. Moreover, a greater number of dosing increments are available for Xanax tablets than Etizolam tablets.
Etizolam and Xanax differ slightly in route of metabolism and elimination half-life. Evidence suggests that Etizolam is metabolized by the enzymes CYP3A4, CYP2C18, and CYP2C19 – and Xanax is metabolized by the enzyme CYP3A4. The average elimination half-life range of Etizolam is 7 to 15 hours whereas the average elimination half-life range of Xanax is 9 to 16 hours.
The respective mechanisms of action associated with Etizolam and Xanax may slightly differ. It is thought that Etizolam interacts with A1 subunits of GABAA receptors to a lesser extent than most benzodiazepines, whereas Xanax may be unique in its ability to upregulate D1 and D2 dopamine receptors in the striatum.
Etizolam and Xanax are thought to slightly differ in onset of effect (15-25 minutes for Etizolam vs. 20-40 minutes for Xanax) and duration of effect for immediate-release tablets (5-7 hours for Etizolam vs. 4-6 hours for Xanax). Finally, Etizolam may be more likely than Xanax to cause the side effects of muscle weakness and ataxia – and Xanax may be more likely than Etizolam to cause the side effects of lightheadedness, dry mouth, depression, headache, constipation, and diarrhea.
Addiction & Abuse Potential
Although Xanax is the most frequently-abused benzodiazepine in the United States and is significantly more popular than Etizolam, the respective addiction and abuse potential of these medications is analogous. Analogous addiction and abuse potential for Etizolam and Xanax stems from the fact that their mechanisms of action.
Etizolam and Xanax function by allosterically modulating GABAA receptor subunits which decreases the frequency of inhibitory interneuron firing in the ventral tegmental area (VTA) of the brain. A decrease in the frequency of inhibitory interneuron firing in the ventral tegmental area (VTA) causes (1) dopamine-secreting neurons to fire less and (2) dopamine to accumulate in extracellular spaces.
The elevation in extracellular dopamine can activate reward pathways to produce a euphoriant state of pleasurable intoxication. This pleasurable state of consciousness paired with anxiolytic and myorelaxant effects, plus a highly-reinforcing fast onset of action – can lead to addiction, abuse, and/or dependence.
In 1989, the World Health Organization (WHO) rated the abuse potential of Etizolam as “moderate.” Later in 1990, the WHO revised its original stance on the abuse potential of Etizolam from “moderate” to “low-to-moderate.” Furthermore, the WHO stated that because few public health and social problems are linked to Etizolam, international control wasn’t necessary.
Interestingly, an animal study by Sanna et al. (2005) indicated that Etizolam may be significantly less likely to cause tolerance and dependence than classical benzodiazepines (e.g. lorazepam) – following long-term exposure. It is unknown as to whether the results of the study by Sanna et al. (2005) can be extrapolated to humans – as multiple reports of Etizolam dependence have been documented in medical literature among human users.
For this reason, Gupta and Garg (2014) recommend that medical professionals exercise the same caution when prescribing Etizolam as they would when prescribing conventional benzodiazepines. Also worth mentioning is that, according to O’Connell et al. (2015), reports of Etizolam abuse and overdose are on the rise.
In the United States, Xanax is classified as a “Schedule IV” controlled-substance – suggesting that users may be prone to developing modest psychological and/or physical dependence. That said, most experts believe that using Xanax in ways that are consistent with medical instruction is unlikely to induce dependence (psychological and/or physical).
Deliberately misusing Xanax, however, increases one’s risk of developing psychological and/or physical dependence. Furthermore, it’s also necessary to mention that some researchers regard benzodiazepines as a drug classification as being among the most addictive drugs in mainstream pharmaceutical distribution.
As a benzodiazepine analogue with a mechanism of action akin to Xanax, it’s logical to surmise that Etizolam isn’t much different from Xanax in its potential for addiction and abuse. For this specific reason, various states throughout the U.S. have passed laws to regulate possession and/or use of Etizolam.
For example, Etizolam is a “Schedule I” substance in Alabama, Arkansas, Florida, Louisiana, Mississippi, Ohio; a “Schedule IV” substance in Georgia and Texas; and scheduled (scheduling unspecified) in Arizona and Indiana. Overall, there’s probably not much difference between Etizolam and Xanax in the domains of addiction and abuse potential.
- Source: Etizolam International Report (WHO)
- Source: Etizolam DEA Documentation
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16107249
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25538342
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25805032
- Source: https://www.ncbi.nlm.nih.gov/pubmed/3061941
Approved medical uses
If comparing the approved medical uses of Etizolam and Xanax within the United States – the medications differ significantly. Etizolam has zero approved medical uses in the U.S., whereas Xanax is approved by the FDA for the treatment of generalized anxiety disorder and panic disorder.
However, if comparing the medical uses of Etizolam to Xanax among countries where Etizolam has accepted medical uses – the medical uses for Etizolam and Xanax are similar. For example, in Japan, Italy, and India, Etizolam is prescribed for conditions such as: generalized anxiety disorder (with or without depressive symptoms) and panic disorder – conditions for which Xanax is regularly prescribed in the United States.
According to the World Health Organization, administration of Etizolam (0.5 mg, b.i.d.) is as efficacious as Xanax (0.5 mg, b.i.d.) in the treatment of generalized anxiety disorder. Because Etizolam and Xanax function similarly, it’s unlikely that one medication would be significantly superior over the other for any particular medical condition.
In other words, hypothetically assuming that Etizolam were approved for medical use in the United States, it would probably be considered relatively interchangeable with Xanax as a treatment option for anxiety disorders. Furthermore, it’s unlikely that Etizolam and Xanax would significantly differ in “off-label” medical uses.
Although the “off-label” medical uses for Etizolam haven’t been documented, some reports state that Etizolam is prescribed off-label as a treatment for insomnia. Similar to Etizolam, Xanax is occasionally prescribed off-label for the treatment of insomnia – but also as a treatment for chemotherapy-induced nausea and vomiting; agitation; and premenstrual dysphoric disorder.
Cost: Which is more expensive?
Both Etizolam and standard generic Xanax (alprazolam) are relatively inexpensive and retail for similar prices at most pharmacies. Etizolam can be attained for approximately $0.50 per 0.25 mg tablet, $0.80 per 0.5 mg tablet, and $1.05 per 1 mg tablet (on average). Standard generic Xanax (alprazolam) tablets can be attained within the price range of $0.11 to $0.35 per tablet (on average); higher doses tend to cost more than lower doses.
- Etizolam (0.25 mg): $0.50 per tablet (100 tablet pack)
- Etizolam (0.5 mg): $0.80 per tablet (100 tablet pack)
- Etizolam (1 mg): $1.05 per tablet (100 tablet pack)
- Xanax tablets (generic): $7 to $21 ($0.11-$0.35 per tablet) (60 tablets)
- Xanax standard (brand): $245 to $800 (60 tablets)
- Xanax ODT (orally disintegrating tablet): $29 to $183 (30 tablets)
- Xanax XR or ER (extended release): $16 to $67 (30 tablets)
- Xanax (oral solution): $47 to $103 (1 bottle – 30 ml of 1 mg/ml)
It’s worth noting that various pharmacies in India sell Etizolam at rates of approximately $0.04 per 0.25 mg tablet (10 tablet pack), $0.05 per 0.5 mg tablet (10 tablet pack), and $0.08 per 1 mg tablet (10 tablet pack). That said, pharmacies in India sell generic Xanax (alprazolam) at nearly identical prices as Etizolam.
If you live in the United States and purchase Etizolam online (for research purposes), it’ll probably be slightly more expensive than standard generic Xanax (alprazolam) unless the Etizolam is purchased in bulk. In most cases, Etizolam tablets will be $0.15 to $0.95 more expensive than standard generic Xanax (alprazolam) tablets.
Despite the fact that most consumers probably prefer using generics over “brand name” formats due to their significantly lower price – select patients may prefer utilizing the “brand name” formats over the generics due to perceived superiority in tolerability and/or efficacy. Although the price of brand name Etizolam (i.e. “Depas”) remains unclear – brand name Xanax sells from $245 to $800 for 60 tablets (on average) at most pharmacies.
Other formats of Xanax vary in price, including: orally-disintegrating tablets (ODT) for $29 to $183 (30 tablets); extended-release tablets (ER or XR) for $16 to $67; and oral solution for $47 to $103 (per 30 ml bottle). Overall, while the price of Etizolam may be more expensive than standard generic Xanax (alprazolam) per tablet – most consumers probably won’t consider the cost difference as being of major financial significance.
Note: It should be stated that the prices of Etizolam and Xanax could be subject to future fluctuations. Generally, the cost of each substance will be (1) dose-dependent (with high doses being of greater expense than low doses – irrespective of formatting) and (2) pharmacy-dependent.
Dosage & Formats
Etizolam and Xanax are similar in that both medications are sold in the format of immediate-release tablets. Immediate-release Etizolam tablets are produced in 3 dosage increments of 0.25 mg, 0.5 mg, and 1 mg – and immediate-release Xanax tablets are produced in 4 dosage increments of 0.25 mg, 0.5 mg, 1 mg, and 2 mg.
If strictly comparing the immediate-release Etizolam and Xanax dosing, one might consider Xanax as being modestly advantageous in that it provides patients with an additional dosage increment of 2 mg. The larger top dose of 2 mg tablets might lead some to regard Xanax as being more convenient to administer (relative to Etizolam) – in that one tablet of 2 mg can be administered versus two 1 mg tablets of Etizolam.
That said, there don’t appear to be any significant differences in the respective potencies of Etizolam and Xanax – the World Health Organization notes that 0.5 mg Etizolam twice daily is comparable in effect to 0.5 mg Xanax twice daily. Moreover, the respective estimated onsets of action (15-25 and 20-40 minutes) and durations of effect (5-7 hours and 20-40 minutes) do not significantly differ between Etizolam and Xanax immediate-release formats.
However, unlike Etizolam, Xanax is available in additional formats such as: orally-disintegrating tablet; extended-release tablet (ER or XR); and oral solution. The orally-disintegrating tablets are available in dosages of: 0.25 mg, 0.5 mg, 1 mg, and 2 mg; extended-release Xanax tablets are available in dosages of: 0.5 mg, 1 mg, 2 mg, and 3 mg; and Xanax oral solution is available in a 30 ml bottle with dosages of 1 mg/ml.
It’s reasonable to assume that certain individuals may prefer administering orally-disintegrating Xanax tablets (ODT) over standard tablets for the sake of convenience – they dissolve in the mouth without swallowing. Others might prefer using Xanax oral solution due to the fact that it could (1) be easier to swallow than a tablet and/or (2) make for easier dosage titration.
The extended-release Xanax tablets (ER or XR) might also be preferred by a subset of persons because their duration of effect is 11 hours (on average). Worth noting is that some Xanax users may rotate between formats on a situational basis such as by using Xanax extended-release on days requiring lasting anxiety relief and switching to immediate-release Xanax on days when only brief anxiety relief is needed.
If specifically considering the available formats and their respective dosage increments, Xanax should be considered as a favorable option over Etizolam. Xanax is available: (1) in an additional dosage increment in immediate-release format than Etizolam and (2) in three formats that Etizolam isn’t (orally-disintegrating tablet, extended-release tablet, oral solution) – some of which might be preferred by practitioners and/or patients for the sake of convenience and/or modifying duration of effect.
Efficacy: Which medication is more effective?
According to the World Health Organization, there are no significant differences in the respective efficacies of Etizolam and Xanax as treatments for generalized anxiety disorder. Both Etizolam and Xanax have undergone extensive testing in the form of large-scale randomized controlled trials – and have proven to be more efficacious than a placebo in reducing anxious symptoms.
Furthermore, multiple studies have directly compared the anxiolytic efficacy of Etizolam to that of Xanax among patients with generalized anxiety disorder. The results of all comparison studies are consistent in suggesting that Etizolam and Xanax are similar in efficacy as interventions for anxiety disorders.
1989: Etizolam in the treatment of generalized anxiety disorder associated with depressive symptoms.
A trial by Pariante, Caddeo, and Ecari (1989) compared the effectiveness of Etizolam to that of Alprazolam among 30 women with generalized anxiety disorder (and comorbid depressive symptoms). Researchers implemented a double-blind design and assigned the women at random to receive either: Etizolam (0.5 mg, b.i.d.) or Alprazolam (0.5 mg, b.i.d.) for a 5-week period.
At trial baseline, after Week 3, and after Week 5 – the Hamilton Rating Scale for Anxiety and the Hamilton Rating Scale for Depression were administered to assess the severities of participants’ symptoms. Results of the trial indicated that both Etizolam and Alprazolam significantly reduced symptoms of anxiety and depression among trial participants (as evidenced by substantial improvements on anxiety and depression rating scale scores).
Researchers further mentioned that there were no “statistically significant” differences in the therapeutic efficacies of Etizolam and Alprazolam throughout the trial. Although this was a small-scale trial, it supports the preexisting statement by the World Health Organization that Etizolam and Alprazolam are of equal clinical utility as anxiolytics among patients with generalized anxiety disorders.
Note: There was a trend for greater alleviation of “somatization” symptoms among Etizolam recipients than Xanax recipients. That said, the trend for greater alleviation of somatization symptoms with Etizolam (relative to Xanax) wasn’t of clinical significance.
1989: Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial.
A trial by Bertolino et al. (1989) sought to compare the effectiveness of Etizolam (0.5 mg, b.i.d.), Alprazolam (0.5 mg, b.i.d.), and Bromazepam (3 mg, b.i.d.) among 45 patients with generalized anxiety disorder. Researchers implemented a double-blind design and assigned participants at random to receive one of the aforementioned medications for a 4-week period.
The Hamilton Rating Scale for Anxiety and the Hamilton Rating Scale for Depression were utilized to track changes in symptom severity from pre-trial baseline through the 4-week trial duration. After the initial 2 weeks of the trial, a subset of patients who exhibited poor responses to their medications transitioned from a twice-daily (b.i.d.) schedule routine to thrice-daily (t.i.d.) dosing schedule.
Results of the trial indicated that Etizolam, Alprazolam, and Bromazepam were effective in reducing symptoms of generalized anxiety disorder over a 4-week span. No medication used in this trial significantly differed in anxiolytic efficacy – as evidenced by similar reductions in Hamilton Rating Scale for Anxiety scores.
Though this was a relatively small-scale trial, it supports the idea that Etizolam and Xanax are equally efficacious as treatments for generalized anxiety disorder. Still, it is worth noting that Etizolam exhibited a significantly greater antidepressant effect than Alprazolam and Bromazepam – indicating that it may be more useful as a treatment for anxiety with comorbid depression than conventional benzodiazepines.
Both Etizolam and Alprazolam have proven to be efficacious in large-scale, randomized controlled trials among patients with anxiety disorders. Moreover, in head-to-head (i.e. direct comparison) studies, neither intervention appears more efficacious than the other in treating anxiety.
Nevertheless, one comparison study documented a trend for greater relief of “somatization” symptoms among Etizolam users – relative to Alprazolam users. Considering this trend, some might hypothesize that Etizolam is of greater usefulness than Xanax in managing somatization symptoms among patients with anxiety disorders.
This trend warrants further investigation – as the trend was: (1) not statistically significant and (2) derived from a small-scale, short-term study. Additionally, a separate comparison study noted that Etizolam was significantly more effective than Alprazolam in reducing symptoms of depression among patients with generalized anxiety disorder.
Based on this finding, it’s fair to hypothesize that Etizolam is of greater usefulness than Xanax in treating comorbid depression among patients with anxiety disorders. Still, it’s necessary to underscore that this finding was derived from a small-scale, short-term study and may be subject to inaccuracy (such that it wouldn’t reflect legitimate differences in the antidepressant effects of Etizolam and Xanax).
Overall, there’s no strong evidence to suggest that Etizolam is superior to Xanax (or vice-versa) for the treatment of generalized anxiety disorder, panic disorder, and acute anxiety. Unless additional research suggests otherwise, Etizolam and Alprazolam should be regarded as therapeutically equivalent anxiolytics in clinical settings.
Mechanism of action
The respective primary mechanisms of action associated with Etizolam and Xanax are relatively indistinguishable in that each medication functions primarily as a GABA receptor positive allosteric modulator. More specifically, Etizolam and Xanax bind to subunits of GABAA receptors at positions distinct from orthosteric binding sites (i.e. binding sites for endogenous ligands) whereby they amplify the effect of the primary ligand GABA (gamma-aminobutyric acid) – rather than directly stimulating GABAA receptors.
In other words, the presence of Etizolam and Xanax upon GABAA subunits amplifies the efficiency by which the endogenous inhibitory neurotransmitter GABA (gamma-aminobutyric acid) binds to GABAA receptors. An amplification of GABA binding efficiency to GABA receptors enables negatively-charged chloride ions to penetrate neurons and induce a state of hyperpolarization.
The induction of neuronal hyperpolarization (internal negative charge exceeds external negative charge) causes neuronal activity to significantly decrease. Neurons become less responsive and/or remain unresponsive when stimulated by excitatory postsynaptic potentials, and central nervous system activation is depressed (or slowed).
Central nervous system depression resulting from the primary GABAergic effect of Etizolam and Xanax generally leads users to report psychological and physical relaxation that alleviates preexisting symptoms of anxiety. In any regard, while Etizolam and Xanax exhibit seemingly identical primary mechanisms of action – there are likely differences in secondary neurochemical actions.
Secondary neurochemical actions of Etizolam might include: platelet-activating-factor (PAF) receptor antagonism and dose-dependent inhibition of acetylcholine release in the hippocampus and prefrontal cortex. Secondary neurochemical actions of Xanax might include: increasing D1 and D2 dopamine receptor density within the striatum; inducing norepinephrine release (to stimulate β2 receptors); increasing serotonin release in the hippocampus; and suppressing adrenomedullary activity.
Moreover, it’s unknown as to whether there might be significant overlap in the specific secondary actions of Etizolam and Xanax. It’s possible that Xanax also antagonizes platelet-activating-factor receptors and dose-dependently inhibits acetylcholine (similar to Etizolam) – and/or that Etizolam increases D1 and D2 dopamine receptor density, induces norepinephrine release, increases hippocampal serotonin secretion, and/or suppresses adrenomedullary activity (similar to Xanax).
Some researchers also speculate that positive allosteric modulators of GABAA receptors like Etizolam and Xanax may modulate voltage-gated ion channels (e.g. sodium and/or calcium channels), however, there aren’t any strong data to substantiate this as a mechanism of action.
Research by Sanna et al. (1999) comparing the binding of Etizolam to Xanax noted that Etizolam exhibits less significant potentiation and potency at various GABA receptor subunits – as evidenced by a 73% increase in GABA currents for Etizolam and a 98% increase in GABA currents for Xanax. For this reason, researchers concluded that Etizolam exhibits reduced intrinsic activity at specific GABAA receptors containing the alpha-1 subunit.
Other research by Sanna et al. (2005) indicates that chronic Etizolam treatment decreases mRNA levels of alpha-5 and gamma-2S GABAA receptor subunits. (This differed from lorazepam which decreased mRNA levels of alpha-1 and gamma-2S GABAA receptor subunits and increased mRNA levels of alpha-3 GABAA receptor subunits).
Sanna et al. (2005) also discovered that chronic Etizolam treatment and discontinuation does not impact the modulatory actions of Etizolam and lorazepam on GABA-evoked chloride currents in cultured neurons (indicative of no GABAergic tolerance). Comparatively, chronic lorazepam treatment reversibly reduced the modulatory effects of lorazepam on GABA-evoked chloride currents (indicative of GABAergic tolerance).
In mice, chronic administration of Etizolam (1.5 mg/kg, t.i.d.) did not affect its anticonvulsant activity over a 3-week duration. (This differed from other benzodiazepines like lorazepam which diminished in anticonvulsant activity when administered chronically for 3 weeks).
Subtle discrepancies between Etizolam and Xanax in GABAA receptor subunit binding and/or potentiation and/or discrepancies in secondary neurochemical actions might account for differences in: tolerance (likelihood and/or rate of onset), alleviation of specific symptoms (e.g. somatization, depression, etc.), and/or tolerability (specific side effects and their severities).
- Source: https://www.ncbi.nlm.nih.gov/pubmed/10083975
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16107249
- Source: https://www.ncbi.nlm.nih.gov/pubmed/8944402
- Source: https://www.ncbi.nlm.nih.gov/pubmed/9600648
- Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074285/
Metabolism & Half-Life
Pharmacokinetic research indicates that Etizolam and Xanax exhibit the same primary route of metabolism within the liver via the CYP3A4 enzyme. Furthermore, the bioavailability of orally-administered Etizolam (~93%) is similar to the bioavailability of orally-administered Xanax (~90%).
However, CYP2C18 and CYP2C19 enzymes are implicated in the metabolism of Etizolam (at approximately 25% and 5% the involvement of CYP3A4) but not in the metabolism of Xanax. (Polymorphisms of CYP2C19 can significantly alter the plasma concentrations and elimination half-life of Etizolam – relative to normative CYP2C19 expression).
Metabolism of Etizolam involves extensive hydroxylation and conjugation to form alpha-hydroxyetizolam, a major bioactive metabolite. Metabolism of Xanax (alprazolam) involves microsomal oxidation to form alpha-OHALP (alpha-hydroxy alprazolam) and 4-OHALP (4-hydroxy alprazolam), major bioactive metabolites.
Research suggests that the elimination half-life of Etizolam significantly differs from the elimination half-life of Xanax (alprazolam). The elimination half-life of Etizolam is estimated to range from 7 to 15 hours and the elimination half-life of Xanax (alprazolam) is estimated to range from 9 to 16 hours.
The elimination half-life of alpha-hydroxyetizolam (the chief bioactive metabolite of Etizolam) is ~8.2 hours – which is longer than its parent compound. The elimination half-life of alpha-OHALP and 4-OHALP (chief bioactive metabolites of Xanax) do not differ from their parent compound.
Because Etizolam isn’t approved for medical use in the United States, it’s reasonable to suspect that Etizolam is of low popularity throughout the U.S. – even as a federally unregulated substance. United States citizens seeking to acquire Etizolam may resort to ordering the drug online from research chemical vendors, foreign pharmaceutical companies, or less-trustworthy entities.
Ordering Etizolam online comes with risks including: (1) receiving a fake or inert substance (rather than Etizolam); (2) receiving a tainted product (laced with toxic compounds); and/or (3) the possibility of getting arrested (as Etizolam is “scheduled” in many states). While all of the aforementioned risks associated with acquiring Etizolam may account for its lack of popularity in the U.S. – the fact that Etizolam isn’t authorized for medical use is probably the chief reason that Etizolam may remain unpopular in the United States.
Nevertheless, even in countries where Etizolam is available, the drug might remain unpopular due to perceived superior alternative medications and/or risks of long-term adverse effects (e.g. blepharospasm). For example, although approved for medical use in 2007 throughout India, research by Grover et al. (2013) suggests that Etizolam remains among the least-utilized benzodiazepines.
According to the ClinCalc DrugStats database (an organization that tracks prescribing rates for medications), generic Xanax (alprazolam) was the most-prescribed benzodiazepine in the United States in 2015. The number of prescriptions filled for generic Xanax (alprazolam) in 2015 exceeded 27 million, and overall, it was the 23rd most-prescribed medication.
The longstanding track-record of Xanax as being effective, safe, and well-tolerated – coupled with its rapid-onset of action, availability in numerous formats, FDA-approved medical uses, and discussion in mainstream media – may contribute to its popularity. In summary, Etizolam is significantly less popular in both medical and non-medical settings – relative to Xanax.
A report by the World Health Organization (WHO) suggests that the most common side effects of Etizolam are drowsiness (or sedation), ataxia, and muscle weakness. The report also notes that Etizolam frequently causes adverse effects that are similar to other benzodiazepines including: sleepiness, slurred speech, and loss of consciousness.
Although numerous reports suggest that long-term administration of Etizolam can induce blepharospasm (abnormal contraction of the eyelid muscles) as an adverse reaction – blepharospasm can result as an adverse reaction to any benzodiazepine, including Xanax. According to FDA database reports, the most common side effects of Xanax are: drowsiness, lightheadedness, dry mouth, depression, headache, constipation, and diarrhea.
Despite the fact that Etizolam and Xanax may exhibit slightly different: (1) routes of hepatic metabolism; (2) affinities for GABAA receptor subunits; (3) secondary neurochemical actions; and (4) chemical structure and composition – differences in rates and/or magnitudes of adverse reactions between these medications are unlikely to be of clinical relevance. Both medications have potential to induce CNS depression-related side effects such as: drowsiness, incoordination, muscle weakness, cognitive impairment, psychomotor dysfunction, and slurred speech.
While Xanax may be more likely than Etizolam to cause dry mouth, depression, headache, constipation, and/or diarrhea – differences in rates of these side effects remain unclear. In two studies that directly compared Etizolam to Xanax (Bertolino et al. (1989) & Pariante et al. (1989)), there were no significant differences in side effects (i.e. tolerability).
Considering the extremely similar mechanisms of action and lack of data suggesting that one medication exhibits superior tolerability relative to the other, it’s logical to assume that Etizolam and Xanax are equally tolerable medications.
Discontinuation of Etizolam or Xanax following a moderate term of regular administration can yield disconcerting withdrawal symptoms, and in a subset of users, post-acute withdrawal syndrome (PAWS). Disconcerting withdrawal symptoms in the aftermath of Etizolam or Xanax cessation are suggested to emerge as a result of neurochemistry recalibrating itself back to sober (i.e. pre-drug) homeostasis from an Etizolam-adapted or Xanax-adapted state of functioning.
More specifically, when either Etizolam or Xanax is administered regularly for a moderate term, neurochemistry adapts to the GABAergic modulation of each substance such that compensatory neurophysiologic reactions occur. Such compensatory reactions might include: altered subunit mRNA transcription; degradation of subunits in endoplasmic reticulum; decreased GABAA receptor-associated helper proteins; altered endocytosis of GABAA receptor subtypes; shifts in perisynaptic or extrasynaptic localization of GABAA receptors; changes in the glutamate system; and shifts in neurotrophic factors.
Due to the aforementioned compensatory neurophysiologic responses that’ve occurred during treatment, neurochemical activity of former users will appear grossly imbalanced after Etizolam or Xanax cessation, especially within GABA systems. Although neurochemistry will gradually recalibrate back to functioning without Etizolam or Xanax, it may take weeks or months to reestablish neurochemical homeostasis.
During the transition from a drug-adapted state to homeostasis, a variety of unpleasant discontinuation symptoms might emerge such as: shakiness, dizziness, tachycardia, heart palpitations, seizures, panic attacks, heightened anxiety, muscle tension, frequent urination, high blood pressure, etc. For this reason, anyone stopping Etizolam or Xanax treatment should be advised to only do so with professional medical instruction and/or supervision.
Are there any differences in the respective severities of withdrawal symptoms following the cessation of Etizolam and Xanax? Because discontinuation symptoms associated with Etizolam and Xanax haven’t been directly compared in a large-scale, randomized controlled trial, it remains unelucidated as to whether the difficulty of withdrawal is greater with one substance relative to the other.
There is some evidence from research by Sanna et al. (1999) indicating that Xanax may bind and potentiate the activity of GABAA receptor subunits to a greater extent than Etizolam. Specifically, the research found that Etizolam increased GABA currents by ~73% whereas Xanax increased GABA currents by ~98%; (doses were equal).
A second [non-human] study by Sanna et al. (2005) suggests that Etizolam may be less likely to cause and/or cause less significant GABAergic tolerance than conventional benzodiazepines like Xanax. If Etizolam is slightly less potent than Xanax and/or interacts with GABAA receptor subunits differently than Xanax – then it’s fair to hypothesize that Etizolam discontinuation symptoms might be less severe than Xanax discontinuation symptoms.
However, because Etizolam and Xanax exhibit similar primary mechanisms of action as GABAA positive allosteric modulators; short elimination half-lives; and potencies are nearly identical (i.e. 0.5 mg Etizolam is therapeutically equivalent to 0.5 mg Xanax), most would assume that neurochemical modulation and compensatory neurophysiologic reactions among users of each agent would be similar. Everything considered, it’s reasonable to surmise that discontinuation symptoms of Etizolam and Xanax are similar.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25538342
- Source: https://www.ncbi.nlm.nih.gov/pubmed/23789008
- Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/
Similarities (Summary): Etizolam vs. Xanax
Listed below is a summary of notable similarities between Etizolam and Xanax. Etizolam and Xanax are similar in: abuse potential; cost; duration of action; efficacy; generic availability; elimination half-life; mechanism of action; medical uses; tolerability; and discontinuation severity and/or symptoms.
- Abuse potential: The abuse potential of Etizolam and Xanax are similar. Each medication is psychologically reinforcing as a result of: (1) exerting a rapid onset of effect and (2) activating reward pathways in the brain. Reward pathways are activated as a result of extracellular dopamine accumulation as a downstream effect of GABAergic modulation (the primary action of Etizolam and Xanax). This may cause users of Etizolam or Xanax to experience a combination of relaxation and euphoria – possibly leading to abuse or addiction.
- Cost: In countries where both Etizolam and Xanax are approved for medical use, the cost of standard generic Etizolam and standard generic Xanax (alprazolam) do not significantly differ. In the United States, it costs between $0.11 and $0.35 per standard generic Xanax tablet (on average). Although Etizolam tablets may be slightly more expensive for persons in the U.S., costing between $0.50 and $1.05 per tablet (on average), neither Etizolam nor Xanax is expensive in generic immediate-release format.
- Duration of effect: The duration of effect for standard Etizolam and Xanax formats falls within a similar range. Etizolam is estimated to facilitate a neurochemical effect that persists for 5 to 7 hours, whereas standard Xanax is estimated to facilitate a neurochemical effect that persists for 4 to 6 hours.
- Effectiveness: There are no data suggesting that Etizolam is more effective than Xanax (or vice-versa) for the treatment of generalized anxiety disorder, panic disorder, or acute anxiety. In head-to-head comparison studies, Etizolam and Xanax are equally efficacious as anxiolytics. Moreover, administering two 0.5 mg Etizolam per day generates an indistinguishable therapeutic effect from taking two 0.5 mg Xanax per day.
- Generic availability: Etizolam and Xanax are each manufactured in generic formats. Etizolam is the generic chemical name for the medication “Depas” (developed in Japan). Generic Xanax is sold under the chemical name “alprazolam” in the United States.
- Half-life: There are differences in the elimination half-lives of Etizolam and Xanax following ingestion, however, it’s unclear as to whether the differences are of clinical significance. Across studies elimination half-lives of Etizolam were documented as: 3.4 hours, 3.5 hours, 12 hours, 10 hours, 11 hours, and 7 to 15 hours – plus 8.2 hours for the elimination half-life of its primary metabolite. The elimination half-life of Xanax is estimated to range from 9 to 16 hours (~12-hour average).
- Mechanism of action: The predominant general mechanism of action exerted by Etizolam and Xanax is identical. Etizolam and Xanax function by allosterically binding to GABAA receptor subunits to enhance the binding of GABA to GABAA receptors. This action allows negatively-charged chloride ions to induce neuronal hyperpolarization and CNS depression.
- Medical uses: In most medical settings, Etizolam and Xanax are utilized similarly as anxiolytics. In countries where Etizolam is medically approved, it is prescribed to treat generalized anxiety disorder, panic disorder, and acute anxiety. In the United States, Xanax is FDA approved to treat generalized anxiety disorder and panic disorder – and is regularly used to manage acute anxiety.
- Metabolism: While there are differences in the metabolism of Etizolam and Xanax, the primary route of metabolism is identical. The primary route of metabolism for Etizolam and Xanax involves hepatic microsomal oxidation via the CYP3A4 enzyme. (The only slight difference in metabolism is that enzymes CYP2C18 and CYP2C19 contribute to the breakdown of Etizolam – but not Xanax).
- Side effects: Evidence from comparison studies suggests that Etizolam and Xanax are equally tolerable anxiolytics. Given their similar mechanisms of action, Etizolam and Xanax do not differ significantly with regard to overall rates of side effects (i.e. adverse reactions). Though there may be modest differences between Etizolam and Xanax in the occurrence of specific side effects, the most common side effects of each agent are similar (e.g. drowsiness, sedation, sleepiness) and attributable to the induction of CNS depression.
- Withdrawal: Though some individuals may extrapolate data from short-term non-human studies to suggest that Etizolam withdrawal is less severe than Xanax withdrawal, there are zero credible human data to substantiate the idea that Etizolam cessation is somehow easier to manage than Xanax cessation. Because the medications are similar in aspects of: pharmacodynamics, duration of effect, elimination half-life, bioavailability, and potency – there’s little reason to assume that withdrawal is less significant with one agent relative to the other. Discontinuation of either Etizolam or Xanax [after long-term, frequent administration] could induce protracted, severe (possibly life-threatening) symptoms.
Differences (Summary): Etizolam vs. Xanax
Listed below is a summary of notable differences between Etizolam and Xanax. Etizolam and Xanax differ in: available formats; drug classification; ingredients; legal status (U.S.); manufacturers; and popularity.
- Available formats: Etizolam and Xanax are each manufactured in the format of immediate-release tablets that deliver an effect ranging from approximately 4 to 7 hours. Though immediate-release tablet is the only available format of Etizolam, several additional formats of Xanax are available, including: orally-disintegrating tablet, extended-release tablet (ER or XR), and oral solution.
- Drug classification: Though Etizolam and Xanax function similarly as positive allosteric modulators of GABAA receptor subunits, the chemical classifications of these agents differ. Etizolam is considered a “thienodiazepine” due to its thiophene ring fused to a triazole ring – and Xanax is considered a “triazolobenzodiazepine” due to its benzene ring fused to a triazole ring.
- Ingredients: Etizolam is the active ingredient in the brand name medication “Depas” (originally marketed in Japan) and the active ingredient in Xanax is the chemical “alprazolam.” Etizolam is a “thienodiazepine” (thiophene ring plus triazole ring) and Xanax is a “triazolobenzodiazepine” (benzene ring plus triazole ring).
- Legal status: In the United States, the legal status of Etizolam and Xanax differs significantly. Etizolam is considered an unregulated research chemical at the federal level (as of 2018) and Xanax is considered a “Schedule IV” substance. In select states, Etizolam is considered a “Schedule IV” substance (Georgia and Texas); “Schedule I” substance (Alabama, Arkansas, Florida, Louisiana, Mississippi, Ohio); or a “scheduled” substance (Arizona and Indiana).
- Manufacturers: Etizolam was originally developed and manufactured by a Japanese pharmaceutical company – hitting the market in 1983. Xanax was originally developed and manufactured by Upjohn (a company acquired by Pfizer Inc.) – hitting the market in 1981.
- Popularity: Prescribing data revealed that over 27 million prescriptions were filled for generic Xanax (alprazolam) in 2015, making it the most-prescribed benzodiazepine in the United States. Though prescribing data are unavailable for Etizolam, research suggests that it is rarely prescribed in India (a country where it is medically approved).
Which medication is “better” for anxiety disorders? (Etizolam vs. Xanax)
International medical research (conducted in Japan, India, and Italy) suggests that Etizolam is safe, tolerable, and more effective than a placebo for the treatment of anxiety disorders. Outside of the United States, Etizolam is medically approved as a treatment for generalized anxiety disorder, panic disorder, acute anxiety, and insomnia.
Similarly, well-designed trials in the U.S. (double-blind, randomized, controlled) with large sample sizes consistently support the idea that Xanax is safe, tolerable, and more effective than a placebo for the treatment of generalized anxiety disorder and panic disorder. For this reason, Xanax is commonly prescribed in the United States to help manage a variety of anxious conditions.
Although standards for clinical trials in the United States may be higher than standards for drug trials in other countries, there’s no data to substantiate the idea that Etizolam is of inferior safety, tolerability, or efficacy – relative to Xanax for the treatment of anxiety. In multiple studies that directly compare Etizolam to Xanax among patients with anxiety – safety, tolerability, and therapeutic efficacy do not differ between the agents.
However, it may be worth noting that Pariante et al. (1989) reported a trend for greater alleviation of “somatization” symptoms of anxiety with Etizolam versus Xanax – and Bertolino et al. (1989) documented a significantly greater antidepressant effect with Etizolam versus Xanax. Still, despite the fact that these studies were small-scale (30 and 45 patients) and short-term (4 and 5 weeks), results are consistent in suggesting that Etizolam and Xanax (at equal doses) are equally efficacious as anxiolytics.
In domains of abuse/addiction potential; primary mechanism of action; onset of action; potency; and tolerability (frequency and/or severity of side effects) – there’s no evidence to suggest that Etizolam and Xanax differ. While the adverse reaction of “blepharospasm” is associated with long-term Etizolam use, blepharospasm is also associated with long-term Xanax use; there are no data to suggest differences in rates of blepharospasm as an adverse reaction among Etizolam and Xanax users.
In terms of formatting, there are substantial differences between Etizolam and Xanax. Unlike Etizolam which is solely available as an immediate-release tablet, Xanax is available as an: immediate-release tablet; extended-release tablet (ER or XR); orally-disintegrating tablet (ODT); and oral solution. Xanax is clearly advantageous over Etizolam in the domain of formatting based on the fact that: (1) certain Xanax formats deliver a longer duration of action (extended-release) and (2) other Xanax formats may be more convenient to administer (orally-disintegrating tablet and oral solution) than standard tablets.
Even though limited data from non-human studies have been extrapolated by some researchers to suggest that Etizolam may be less likely than benzodiazepines to: (1) induce tolerance OR rapid tolerance; and/or (2) cause severe withdrawal symptoms following cessation – there’s no evidence from human studies to substantiate the favorability of Etizolam over Xanax in aspects of tolerance development and withdrawal severity.
Although the primary route of metabolism for Etizolam and Xanax involves the CYP3A4 enzyme, the enzymes CYP2C18 and CYP2C19 aid CYP3A4 in the metabolism of Etizolam – but not in the metabolism of Xanax. Because genetically-mediated abnormalities in CYP2C19 expression can alter Etizolam metabolism, it’s reasonable to suspect that Xanax would exhibit superior efficacy and/or tolerability in persons with CYP2C19 abnormalities – relative to Etizolam. Risk of pharmacokinetic interactions might also be lower in Xanax users than Etizolam users due to the sole involvement of CYP3A4 versus CYP3A4, CYP2C18, and CYP2C19 in metabolism.
Moreover, there may be subtle differences in the secondary neurochemical actions exerted by Etizolam and Xanax (following GABAA receptor modulation) – potentially leading a subset of users to report greater efficacy and/or tolerability with one medication compared to the other. A combination of: gene expression, epigenetics, baseline neurochemistry, medical status, and concurrent substance ingestion – may explain why some persons respond better to Etizolam or Xanax – relative to the other.
In summary: Etizolam may be advantageous over Xanax in addressing somatic symptoms of anxiety and facilitating an antidepressant effect. However, Xanax may be advantageous over Etizolam in its: variety of available formats; availability and legal status in the United States; and route of metabolism (limited to CYP3A4). At this juncture, Etizolam and Xanax should be regarded as clinically equal in aspects of safety, tolerability, and efficacy in the management of anxiety – unless proven otherwise.
Which medication do you prefer: Etizolam or Xanax?
If you have personally tried Etizolam and Xanax, distinctly, as treatments for anxiety (or another medical condition), leave a comment about your experience. In your comment, discuss some similarities and/or differences between the medications and state whether you’ve developed a preference for using one medication over the other.
From your perspective, did you find that one medication (Etizolam or Xanax) was more effective than the other as a medical treatment? If you found one medication to be more effective than the other, did you control for variables such as: dosing, formatting, duration of administration, concurrent substance use, etc.?
Have you considered that genetic polymorphisms (e.g. CYP2C19) affecting metabolism of Etizolam could account for differences in perceived effectiveness? If you prefer using Etizolam or Xanax (relative to the other), are there specific reasons for this preference?
Possible explanations might include: faster onset of action; variety of available formats; availability (e.g. easier to attain in your location); slower or less significant tolerance onset; fewer side effects; lower-priced (in your location); and/or fewer discontinuation symptoms.
To better understand your experiences with Etizolam and Xanax, mention things like: (1) dosages and formats used; (2) respective durations of administration; (3) concurrent substance use; and/or (4) the medical condition for which these agents were administered.