Fatal overdose may occur when benzodiazepines are combined with other depressants such as opiates, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.
It is strongly discouraged to combine these substances, particularly in common to heavy doses.
|Summary sheet: Alprazolam|
|Common names||Xanax, Alprazolam, Ksalol|
|Routes of Administration|
Alprazolam (also known as Xanax) is a depressant substance of the benzodiazepine class. Its characteristic effects include anxiety suppression, sedation, disinhibition, and muscle relaxation.
Like other benzodiazepines, alprazolam binds to specific sites on the GABAA receptor. It is commonly used for the medical treatment of panic disorder, generalized anxiety disorder (GAD), or social anxiety disorder (SAD).
Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour of using in preparation for panic disorder and full peak effects are achieved in 1.5 and 1.6 hours respectively. Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week.
The sudden discontinuation of benzodiazepines can be potentially dangerous or life-threatening for individuals using regularly for extended periods of time, sometimes resulting in seizures or death. It is highly recommended to taper one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping abruptly.
Alprazolam is a drug of the benzodiazepine class. Benzodiazepine drugs contain a benzene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. The benzyl ring of alprazolam is substituted at R8 with a chlorine group. Further, the diazepine ring is bonded at R5 to a phenyl ring. Alprazolam also contains a 1-methylated triazole ring fused to and incorporating R1 and R2 of its diazepine ring. Alprazolam belongs to a class of benzodiazepines containing this fused triazole ring, called triazolobenzodiazepines, distinguished by the suffix "-zolam".
Alprazolam is substituted with a phenyl group at position 6, with a chlorine atom at position 8 and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the 'ortho' position of the phenyl ring. It is soluble in alcohol and insoluble in water.
Benzodiazepines 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. Alprazolam is a positive allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of alprazolam on the nervous system. The anticonvulsant properties of benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.
Alprazolam causes a marked suppression of the hypothalamic-pituitary-adrenal axis. Administration of alprazolam has been demonstrated to elicit an increase in striatal dopamine concentrations. This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarization. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.
The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties. This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used mainly as an anxiolytic.
Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.
The general head space of alprazolam is described by many as one of intense sedation, relaxation, anxiety suppression and decreased inhibition.
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 ☠.
- Sedation - Alprazolam is capable of producing strong sedation and can lead to a lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and need to fight to stay awake. This sleep deprivation increases proportionally to dosage and eventually becomes powerful enough to force the user into a deep state of unconsciousness.
- Perception of bodily heaviness - Alprazolam is reported to cause feelings of heaviness in the body. This effect can range from motor impairment and difficulty moving at lower doses to complete lethargy or inability to stand up or move at high doses.
- Appetite enhancement - Some users report that alprazolam is capable of enhancing appetite in a manner similar to alcohol and that it can have a synergistic effect with cannabis.
- Muscle relaxation - Alprazolam is reported to produce moderate muscle relaxation greater than that of alcohol but weaker than diazepam (Valium).
- Motor control loss - Alprazolam impairs motor control in a dose-dependent manner similar to alcohol. Higher doses significantly increase the risk of physical injury via falling over or stumbling into objects. This risk is especially prominent around stairs and slopes.
- Respiratory depression
- Dizziness - Dizziness is sometimes present with higher doses, although generally less than the dizzying effects of alcohol (colloquially known as "the spins").
- Seizure suppression - Alprazolam has seizure suppressing properties as a result of its GABA-mediated inhibitory effects on the nervous system.
- Analysis suppression
- Anxiety suppression
- Compulsive redosing - Alprazolam produces disinhibition which, along with its memory suppressing effects, can easily lead the user to black out and redose continually until their supply runs out or they lose consciousness. This effect can place the user at risk of fatal overdose from respiratory depression if they are consuming it with alcohol or other depressants.
- Confusion - Alprazolam can cause confusion at heavy doses. This effect is a result of the drug suppressing basic cognitive functions such as comprehension, memory, and reasoning skills.
- Delusions of sobriety - This is the false belief that one is perfectly sober despite obvious evidence to the contrary such as severe cognitive impairment and an inability to fully communicate with others. It most commonly occurs at heavy dosages.
- Dream suppression - Benzodiazepines like alprazolam generally inhibit REM sleep and suppress the experience of dreaming. Sleep on benzodiazepines is generally reported to be deep and refreshing, although it should be noted that the actual sleep quality is lower which is why the use of benzodiazepines as long-term sleep aids is not advised.
- Emotion suppression - Although alprazolam primarily suppresses anxiety, it also dulls other emotions in a manner which is distinct but less intensive than that of antipsychotics.
- Euphoria - A distinct portion of users report feeling a marked sense of emotional well-being and comfort while under the influence of this substance. Because this does not occur regularly or consistently for most users, it is speculated that this effect only manifests among those who have unusually high baseline levels of anxiety.
- Language suppression - Alprazolam is known to cause slurred speech and difficulty communicating words in a clear fashion.
- Memory suppression - Alprazolam primarily suppresses short-term memory, resulting in forgetfulness, and/or disorganized behaviors.
- Amnesia - Higher doses of alprazolam can easily lead to complete short-term amnesia (black out) similar to that of high doses of alcohol.
- Motivation suppression - Due to alprazolam's heavy sedation and lethargy, doing any type of activity that requires moving, or high amounts of effort may be difficult to do, especially at higher doses.
- Thought deceleration
- Visual acuity suppression - Like many depressants, alprazolam is known to cause blurred or otherwise suppressed visual acuity.
- Rebound anxiety - Rebound anxiety is a commonly observed effect with anxiety relieving substances like benzodiazepines. It typically corresponds to the total duration spent under the substance's influence along with the total amount consumed in a given period, an effect which can easily lend itself to cycles of dependence and addiction.
- Dream potentiation
- Residual sleepiness - While benzodiazepines can be used as an effective sleep-inducing aid, their effects may persist into the morning afterward, which may lead users to feeling "groggy" or "dull" for up to a few hours.
- Thought deceleration
- Thought disorganization
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%).
These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.
Anecdotal reports which describe the effects of this compound within our experience index include:
- Experience:15mg 4-AcO-DMT (oral) - the trees looked cool at least
- Experience:Alprazolam (24 mg) - Into the Void
- Experience:Alprazolam (~2mg on separate days, oral) - Not remembering going to sleep
Additional experience reports can be found here:
Toxicity and harm potential
This toxicity and harm potential section is a stub.
As a result, it may contain incomplete or even dangerously wrong information! You can help by expanding upon or correcting it.
Alprazolam has a low toxicity relative to dose. However, it is potentially lethal when mixed with depressants like alcohol or opioids.
It is strongly recommended that one use harm reduction practices when using this substance.
The acute oral LD50 in rats is 331–2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam.
Dependence and abuse potential
Alprazolam is extremely physically and psychologically addictive.
Tolerance will develop to the sedative-hypnotic effects within a couple of days of continuous use. After cessation, the tolerance returns to baseline in 7-14 days. However, in certain cases, this may take significantly longer in a manner which is proportional to the duration and intensity of one's long-term usage.
Alprazolam presents cross-tolerance with all benzodiazepines, meaning that after its consumption all benzodiazepines will have a reduced effect.
Benzodiazepine overdose may occur with extremely high doses or, more commonly, when it is taken with other depressants. This risk is especially present with other GABAergic depressants, such as barbiturates and alcohol, since they work in a similar fashion but bind to distinct sites on the GABAA receptor, resulting in significant cross-potentiation.
Benzodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly. Symptoms may include severe slurred speech, confusion, delusions, respiratory depression, and non-responsiveness. The user might seem like they are sleepwalking. The user is also more susceptible to consume more of the same or another substance due to their impaired judgement, which is typically not seen with other substances during overdose.
Benzodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Care is primarily supportive in nature, although overdoses are sometimes treated with flumazenil, a GABAA antagonist or additional procedures such as adrenaline injections if other substances are involved.
Benzodiazepine 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 high blood pressure, seizures, and death. Substances which lower the seizure threshold such as tramadol should be avoided during withdrawal. Abrupt discontinuation also causes rebound stimulation which presents as anxiety, insomnia and restlessness.
If one wishes to discontinue after a period of regular use, it is safest to reduce the dose each day by a very small amount for a couple of weeks until close to abstinence. If using a short half-life benzodiazepine such as alprazolam or etizolam, a longer acting variety such as diazepam or clonazepam can be substituted. Symptoms may still be present, but their severity will be reduced significantly.
For more information on tapering from benzodiazepines in a controlled manner, please see this guide. Small quantities of alcohol can also help to reduce the symptoms, but otherwise cannot be used as an effective tapering agent.
The duration and severity of withdrawal symptoms depend on a number of factors including the half-life of the substance used, tolerance and the duration of abuse. Major symptoms will usually start within just a few days after discontinuation and persist for around a week for shorter lasting benzodiazepines. Benzodiazepines with longer half-lives will exhibit withdrawal symptoms with a slow onset and extended duration.
Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).
Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
- Depressants (1,4-Butanediol, 2M2B, alcohol, benzodiazepines, barbiturates, GHB/GBL, methaqualone, opioids) - This combination potentiates the muscle relaxation, amnesia, sedation, and respiratory depression caused by one another. At higher doses, it can lead to a sudden, unexpected loss of consciousness along with a dangerous amount of depressed respiration. There is also an increased risk of suffocating on one's vomit while unconscious. If nausea or vomiting occurs before a loss of consciousness, users should attempt to fall asleep in the recovery position or have a friend move them into it.
- Dissociatives - This combination can unpredictably potentiate the amnesia, sedation, motor control loss and delusions that can be caused by each other. It may also result in a sudden loss of consciousness accompanied by a dangerous degree of respiratory depression. If nausea or vomiting occurs before consciousness is lost, users should attempt to fall asleep in the recovery position or have a friend move them into it.
- Stimulants - Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.
Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.
- Australia: Alprazolam was originally a Schedule 4 (prescription only) medication; however, as of January 2014, it will become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.
- Austria: Alprazolam is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).
- Czechia: Alprazolam is a Schedule IV  (List 7) substance. Sold on exclusively with a prescription "without a blue stripe" (§ 1, g), 1. of Nařízení vlády č. 463/2013 Sb.) 
- Germany: Alprazolam is controlled under Anlage III BtMG (Narcotics Act, Schedule III) as of August 1, 1986. It can only be prescribed on a narcotic prescription form, except preparations which contain up to 1 mg triazolam in each dosage form.
- Ireland: Alprazolam is a Schedule 4 medicine.
- Italy: Alprazolam is a schedule IV drug (Tabella 4) of the "Testo unico sulla droga (D.P.R. 309/90)". When prescribed for medical use it falls under Pharmaceuticals section B and E (Tabella medicinali sezione B ed E).
- Russia: In Russia, since 2013, alprazolam is a Schedule III controlled substance.
- Sweden: Alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).
- Switzerland: Alprazolam is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.
- Turkey: Alprazolam is a 'green prescription' only substance and illegal when sold or possessed without a prescription.
- The Netherlands: Alprazolam is a List 2 substance of the Opium Law and is available for prescription.
- United Kingdom: Alprazolam is classified as a controlled drug and listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription and, for such purposes, it is classified as a Class C drug.
- United States: Alprazolam is a prescription medication assigned to Schedule IV of the Controlled Substances Act by the DEA.
- Responsible use
- Diazepam (Valium)
- Clonazepam (Klonopin)
- The Ashton Manual - Useful information on safe withdrawal from long-term benzodiazepine use and dependence
- ↑ Risks of Combining Depressants - TripSit
- ↑ 2.0 2.1 Mandrioli, R., Mercolini, L., Raggi, M. A. (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. ISSN 1389-2002.
- ↑ Nuss, P. (17 January 2015). "Anxiety disorders and GABA neurotransmission: a disturbance of modulation". Neuropsychiatric Disease and Treatment. 11: 165–175. doi:10.2147/NDT.S58841. ISSN 1176-6328.
- ↑ FDA approved labeling for Xanax revision 08/23/2011 | http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s045lbl.pdf
- ↑ Smith, R. B., Kroboth, P. D., Vanderlugt, J. T., Phillips, J. P., Juhl, R. P. (1984). "Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration". Psychopharmacology. 84 (4): 452–456. doi:10.1007/BF00431449. ISSN 0033-3158.
- ↑ Sheehan, D. V., Sheehan, K. H., Raj, B. A. (2007). "The speed of onset of action of alprazolam-XR compared to alprazolam-CT in panic disorder". Psychopharmacology Bulletin. 40 (2): 63–81. ISSN 0048-5764.
- ↑ Verster, J. C., Volkerts, E. R. (7 June 2006). "Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature". CNS Drug Reviews. 10 (1): 45–76. doi:10.1111/j.1527-3458.2004.tb00003.x. ISSN 1080-563X.
- ↑ Lann, M. A., Molina, D. K. (June 2009). "A fatal case of benzodiazepine withdrawal". The American Journal of Forensic Medicine and Pathology. 30 (2): 177–179. doi:10.1097/PAF.0b013e3181875aa0. ISSN 1533-404X.
- ↑ Kahan, M., Wilson, L., Mailis-Gagnon, A., Srivastava, A. (November 2011). "Canadian guideline for safe and effective use of opioids for chronic noncancer pain. Appendix B-6: Benzodiazepine Tapering". Canadian Family Physician. 57 (11): 1269–1276. ISSN 0008-350X.
- ↑ Haefely, W. (29 June 1984). "Benzodiazepine interactions with GABA receptors". Neuroscience Letters. 47 (3): 201–206. doi:10.1016/0304-3940(84)90514-7. ISSN 0304-3940.
- ↑ McLean, M. J., Macdonald, R. L. (February 1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". The Journal of Pharmacology and Experimental Therapeutics. 244 (2): 789–795. ISSN 0022-3565.
- ↑ 12.0 12.1 Bentué-Ferrer, D., Reymann, J. M., Tribut, O., Allain, H., Vasar, E., Bourin, M. (February 2001). "Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam". European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 11 (1): 41–50. doi:10.1016/s0924-977x(00)00137-1. ISSN 0924-977X.
- ↑ Hitchings, A., Lonsdale, D., Burrage, D., Baker, E. (2014). Top 100 drugs: clinical pharmacology and practical prescribing. Churchill Livingstone. ISBN 9780702055164.
- ↑ Barbee, J. G. (October 1993). "Memory, benzodiazepines, and anxiety: integration of theoretical and clinical perspectives". The Journal of Clinical Psychiatry. 54 Suppl: 86–97; discussion 98–101. ISSN 0160-6689.
- ↑ Goyal, Sarita. "Drugs and Dreams." Indian Journal of Clinical Practice (n.d.): n. pag. Web. | http://medind.nic.in/iaa/t13/i3/iaat13i3p624.pdf
- ↑ Saïas, T., Gallarda, T. (September 2008). "[Paradoxical aggressive reactions to benzodiazepine use: a review]". L’Encephale. 34 (4): 330–336. doi:10.1016/j.encep.2007.05.005. ISSN 0013-7006.
- ↑ Paton, C. (December 2002). "Benzodiazepines and disinhibition: a review". Psychiatric Bulletin. 26 (12): 460–462. doi:10.1192/pb.26.12.460. ISSN 0955-6036.
- ↑ Bond, A. J. (1 January 1998). "Drug- Induced Behavioural Disinhibition". CNS Drugs. 9 (1): 41–57. doi:10.2165/00023210-199809010-00005. ISSN 1179-1934.
- ↑ Drummer, O. H. (February 2002). "Benzodiazepines - Effects on Human Performance and Behavior". Forensic Science Review. 14 (1–2): 1–14. ISSN 1042-7201.
- ↑ Nutt, D., King, L. A., Saulsbury, W., Blakemore, C. (24 March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". The Lancet. 369 (9566): 1047–1053. doi:10.1016/S0140-6736(07)60464-4. ISSN 0140-6736.
- ↑ Janicak, P. G., Marder, S. R., Pavuluri, M. N. (25 October 2010). Principles and Practice of Psychopharmacotherapy. Lippincott Williams & Wilkins. ISBN 9781605475653.
- ↑ Hoffman, E. J., Warren, E. W. (September 1993). "Flumazenil: a benzodiazepine antagonist". Clinical Pharmacy. 12 (9): 641–656; quiz 699–701. ISSN 0278-2677.
- ↑ Lann, M. A., Molina, D. K. (June 2009). "A fatal case of benzodiazepine withdrawal". The American Journal of Forensic Medicine and Pathology. 30 (2): 177–179. doi:10.1097/PAF.0b013e3181875aa0. ISSN 1533-404X.
- ↑ List of Psychotropic Substances under International Control | http://www.incb.org/documents/Psychotropics/green_lists/Green_list_ENG_2014_85222_GHB.pdf
- ↑ Alprazolam to be rescheduled from next year | http://www.australiandoctor.com.au/news/latest-news/alprazolam-to-be-rescheduled-from-next-year
- ↑ https://eur-lex.europa.eu/resource.html?uri=cellar:6b5e9beb-1d9b-11ea-95ab-01aa75ed71a1.0001.02/DOC_1&format=PDF
- ↑ https://www.zakonyprolidi.cz/cs/2013-463
- ↑ "Zweite Verordnung zur Änderung betäubungsmittelrechtlicher Vorschriften" (PDF) (in German). Bundesanzeiger Verlag. Retrieved December 26, 2019.
- ↑ "Anlage III BtMG" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 26, 2019.
- ↑ eISB, Misuse Of Drugs (Amendment) Regulations
- ↑ Tabella IV Sostanze stupefacenti http://www.salute.gov.it/imgs/C_17_pagineAree_3729_listaFile_itemName_3_file.pdf
- ↑ Tabella Medicinali D.P.R. 309/90 http://www.salute.gov.it/imgs/C_17_pagineAree_3729_listaFile_itemName_4_file.xls
- ↑ Постановление Правительства РФ от 04.02.2013 N 78 “О внесении изменений в некоторые акты Правительства Российской Федерации” - КонсультантПлюс
- ↑ "Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" [Medical Products Agency on the lists of drugs] | http://www.lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_2012_6.pdf
- ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020.
- ↑ YEŞİL REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/01.04.2019%20SKRS%20Ye%C5%9Fil%20Re%C3%A7eteli%20%C4%B0la%C3%A7lar%20Aktif%20SON%20-%20G%C3%9CNCEL_58b1ff4a-2e1c-4867-bad7-eec855d6162a.pdf
- ↑ Drugs licensing
- ↑ DEA, Drug Scheduling | http://www.deadiversion.usdoj.gov/schedules/index.html