Diazepam

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Death may result when benzodiazepines are combined with other depressants such as opiates, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Summary sheet: Diazepam
Diazepam
Diazepam.svg
Chemical Nomenclature
Common names Valium, Diastat, "Mother's Little Helper", Apaurin
Substitutive name Diazepam
Systematic name 7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one
Class Membership
Psychoactive class Depressant
Chemical class Benzodiazepine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.



Oral
Dosage
Threshold 1 mg
Light 2.5 - 5 mg
Common 5 - 15 mg
Strong 15 - 30 mg
Heavy 30 mg +
Duration
Total 4 - 8 hours
Onset 20 - 40 minutes
Peak 60 - 90 minutes
After effects 12 - 36 hours









DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions

Diazepam (also known as Valium) is a depressant substance of the benzodiazepine class. Its mechanism of action is to increase the effects of the inhibitory neurotransmitter GABA.

Diazepam was patented in 1955 by the pharmaceutical company Hoffman-La Roche.[2] It has been one of the most frequently prescribed medications in the world since its launch in 1963.[3] It is commonly used to treat a wide range of conditions including anxiety, panic attacks, insomnia, seizures, muscle spasms, and restless legs syndrome. Diazepam is a core medicine in the World Health Organization's Essential Drugs List, the minimum medical needs for a basic health-care system.[4]

Subjective effects include anxiety suppression, sedation, and muscle relaxation.[5] Diazepam has a rapid onset of action compared to other benzodiazepines. However, it is generally considered to have lesser recreational effects compared to benzodiazepines like clonazepam (Klonopin) and alprazolam (Xanax).

Diazepam is considered to have low toxicity.[citation needed] However, it has moderate abuse potential and produces physical and psychological dependence with extended use. Additionally, it can contribute to death by respiratory depression if combined with alcohol, opiates, and other depressants. It is highly advised to use harm reduction practices if using this substance.

It should be noted that 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.[6] 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.[7]

History and culture

Following chlordiazepoxide (Librium), which was approved for use in 1960, diazepam was the second benzodiazepine invented by Leo Sternbach of pharmaceutical company Hoffman-La Roche. Released in 1963 as an improved version of Librium, diazepam became incredibly popular and quickly surpassed it in sales, helping Roche to become a pharmaceutical industry giant. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[8]

The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids).[9] Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.[10]

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler,[11] diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion Valium tablets.[8] While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity.[citation needed]

Chemistry

Diazepam 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. At R1, diazepam is substituted with methyl group. Further, the benzodiazepine ring is bonded at R5 to an aromatic phenyl ring. The benzyl ring of the bicyclic core is substituted at R7 with a chlorine group. Diazepam also contains an oxygen group double bonded to R2 of its diazepine ring to form a ketone. This oxygen substitution at R2 is shared with other benzodiazepine drugs with the suffix -azepam.

Pharmacology

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.[12] As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of diazepam 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.[13]

Subjective effects

Disclaimer: The effects listed below are cited from the subjective effect index, which is based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be treated with a healthy degree of skepticism. It is worth noting that these effects will rarely (if ever) occur all at once, although higher doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects
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Visual effects
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Paradoxical effects
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Cognitive effects
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After effects
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Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Toxicity and harm potential

Radar plot showing relative physical harm, social harm, and dependence of benzodiazepines in comparison to other drugs.[19]

Diazepam has a low toxicity relative to dose.[20] However, it is potentially lethal when mixed with depressants like alcohol or opioids.

It is strongly recommended that one use harm reduction practices, such as volumetric dosing, when using this substance to ensure the administration of the intended dose.

Lethal dosage

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[21] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications in spite of having high concentrations of diazepam and its metabolites esmethyldiazepam, oxazepam, and temazepam (according to samples taken in the hospital and as follow-up).[22]

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary.[23][24][25][26]

Tolerance and addiction potential

Diazepam is extremely physically and psychologically addictive.

Tolerance will develop to the sedative-hypnotic effects within a couple of days of continuous use.[27] 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.

Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction.[28][29] For more information on tapering from benzodiazepines in a controlled manner, please see this guide.

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 hypertension, seizures, and death.[30] Drugs which lower the seizure threshold such as tramadol should be avoided during withdrawal.

Diazepam presents cross-tolerance with all benzodiazepines, meaning that after its consumption all benzodiazepines will have a reduced effect.

Overdose

Benzodiazepine overdose may occur when a benzodiazepine is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as barbiturates and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABAA receptor, thus their effects potentiate one another. Benzodiazepines increase the frequency in which the chlorine ion pore opens on the GABAA receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer[31]. Benzodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly.

Symptoms of a benzodiazepine overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death. Benzodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Benzodiazepine overdoses are sometimes treated with flumazenil, a GABAA antagonist[32], however care is primarily supportive in nature.

Dangerous interactions

Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before= consumption.

  • Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Stimulants - It is dangerous to combine benzodiazepines with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of benzodiazepines, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of benzodiazepines will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of benzodiazepines per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.

Legal status

Internationally, diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[33] Diazepam is regulated in most countries as a prescription drug.

  • Austria: Diazepam is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • United Kingdom: The drug 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.[34]
  • Germany: Diazepam is classified as a prescription drug, or in high dosage, as a restricted drug (Betäubungsmittelgesetz, Anhang III).[35]

See also

External links

Literature

  • Calcaterra, N. E., & Barrow, J. C. (2014). Classics in Chemical Neuroscience: Diazepam (Valium). ACS Chemical Neuroscience, 5(4), 253-260. PMID: 24552479 https://doi.org/10.1021/cn5000056

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. Wick, J. (2013). The history of benzodiazepines. The Consultant Pharmacist®, 28(9), 538-548. https://doi.org/10.4140/TCP.n.2013.538
  3. Calcaterra, NE; Barrow, JC (16 April 2014). "Classics in chemical neuroscience: diazepam (valium)". ACS Chemical Neuroscience. 5 (4): 253–60. PMID 24552479. https://doi.org/10.1021/cn5000056.
  4. WHO Model List (2005) | http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf
  5. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  6. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  7. Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain - Appendix B-6: Benzodiazepine Tapering | http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html
  8. 8.0 8.1 Sample, I. (2005). Leo Sternbach’s Obituary. The Guardian (Guardian Unlimited) Oct, 3. Retrieved 2019-07-08.
  9. Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 978-0-19-515130-5.
  10. Marshall KP, Georgievskava Z, Georgievsky I (June 2009). "Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption". Research in Social and Administrative Pharmacy. 5 (2): 94–107. PMID 19524858. https://doi.org/10.1016/j.sapharm.2008.06.005.
  11. "How the American opiate epidemic was started by one pharmaceutical company". Theweek.com. 4 March 2015. Retrieved 10 January 2018.
  12. Benzodiazepine interactions with GABA receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6147796
  13. Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/2450203
  14. http://www.ncbi.nlm.nih.gov/pubmed/18922233 | Saïas T, Gallarda T | Paradoxical aggressive reactions to benzodiazepine use: a review
  15. Paton C | Benzodiazepines and disinhibition: a review | Psychiatr Bull R Coll Psychiatr | http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf
  16. Bond AJ | Drug-induced behavioural disinhibition: incidence, mechanisms and therapeutic implications | CNS Drugs
  17. Drummer OH | Benzodiazepines—effects on human performance and behavior | Forensic Sci Rev
  18. Goyal, Sarita. "Drugs and Dreams." Indian Journal of Clinical Practice (n.d.): n. pag. Web. | http://medind.nic.in/iaa/t13/i3/iaat13i3p624.pdf
  19. Development of a rational scale to assess the harm of drugs of potential misuse (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0140673607604644
  20. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  21. http://www.drugs.com/diazepam.html
  22. Rapid recovery from massive diazepam overdose (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/357765
  23. http://www.inchem.org/documents/pims/pharm/pim181.htm
  24. http://www.drugs.com/diazepam.html
  25. Diazepam Injection | http://www.rxlist.com/diazepam-injection-drug/overdosage-contraindications.htm
  26. Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0-19-515130-5.
  27. Principles and Practice of Psychopharmacotherapy | http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535
  28. Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature | http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00003.x/pdf
  29. The American Psychiatric Publishing Textbook of Substance Abuse Treatment | http://books.google.com/books?id=6wdJgejlQzYC&pg=PA222&hl=en#v=onepage&q&f=false
  30. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  31. Barbiturates and benzodiazepine effects | https://www.ncbi.nlm.nih.gov/pubmed/2471436
  32. Flumazenil, a benzodiazepine antagonist | https://www.ncbi.nlm.nih.gov/pubmed/8306565
  33. International Narcotics Control Board (2003) | http://infoespai.org/wp-content/uploads/2014/12/green.pdf
  34. https://www.gov.uk/government/publications/controlled-drugs-list
  35. https://web.archive.org/web/20141018085805/http://www.gesetze-im-internet.de/btmg_1981/anlage_iii_61.html