Diazepam

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Death may occur 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
Molecular structure of 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 - 2.5 mg
Light 2.5 - 5 mg
Common 5 - 15 mg
Strong 15 - 30 mg
Heavy 30 mg +
Duration
Total 12 - 24 hours
Onset 30 - 90 minutes
After effects 24 - 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.

Diazepam, first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine drug. It possesses anxiolytic, anticonvulsant, sedative, muscle relaxant, depressant and amnestic properties.[2] It is commonly used to treat a wide range of conditions including anxiety, panic attacks, insomnia, seizures, muscle spasms, and restless legs syndrome. It may also be used in some surgical procedures to induce amnesia. Diazepam is a core medicine in the World Health Organization's Essential Drugs List, the minimum medical needs for a basic health-care system.[3] Diazepam, first synthesized by Leo Sternbach,[4] has been one of the most frequently prescribed medications in the world since its launch in 1963.

Advantages of diazepam in comparison to certain other benzodiazepines are a rapid onset of action[5] and high efficacy rates, which are important for managing acute seizures and panic attacks.

It's worth noting 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]

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.[8] 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.[9]

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances and are more likely to induce 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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Paradoxical effects
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Cognitive effects
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After effects
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Experience reports

There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:

Potentially 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.

Toxicity and harm potential

Radar plot showing relative physical harm, social harm, and dependence of benzodiazepines in comparison to other drugs.[15]

Diazepam has a low toxicity relative to dose.[16] 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.[17] 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).[18]

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.[19][20][21][22]

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.[23] 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.[24][25] 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.[26] 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[27]. 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[28], however care is primarily supportive in nature.

Legal issues

Diazepam is regulated in most countries as a prescription drug.

  • International: Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[29]
  • Austria: Diazepam is legal for medical use and illegal when sold or possessed without a prescription under the AMG (Arzneimittelgesetz Österreich).[citation needed]
  • UK: 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.[30]
  • Germany: Diazepam is classified as a prescription drug, or in high dosage, as a restricted drug (Betäubungsmittelgesetz, Anhang III).[31]

Preparation methods

  • Volumetric liquid dosing - If one's benzodiazepines are in powder form, they are unlikely to weigh out accurately without the most expensive of scales due to their extreme potency. To avoid this, one can dissolve the benzodiazepine volumetrically into a solution and dose it accurately based upon the methodological instructions linked within this tutorial here.

See also

External links

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  3. WHO Model List (2005) | http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf
  4. http://pubs.acs.org/doi/abs/10.1021/jo01069a069
  5. http://www.bjmp.org/content/benzodiazepines-revisited
  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. Benzodiazepine interactions with GABA receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6147796
  9. 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
  10. http://www.ncbi.nlm.nih.gov/pubmed/18922233 | Saïas T, Gallarda T | Paradoxical aggressive reactions to benzodiazepine use: a review
  11. Paton C | Benzodiazepines and disinhibition: a review | Psychiatr Bull R Coll Psychiatr | http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf
  12. Bond AJ | Drug-induced behavioural disinhibition: incidence, mechanisms and therapeutic implications | CNS Drugs
  13. Drummer OH | Benzodiazepines—effects on human performance and behavior | Forensic Sci Rev
  14. Goyal, Sarita. "Drugs and Dreams." Indian Journal of Clinical Practice (n.d.): n. pag. Web. | http://medind.nic.in/iaa/t13/i3/iaat13i3p624.pdf
  15. Development of a rational scale to assess the harm of drugs of potential misuse (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0140673607604644
  16. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  17. http://www.drugs.com/diazepam.html
  18. Rapid recovery from massive diazepam overdose (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/357765
  19. http://www.inchem.org/documents/pims/pharm/pim181.htm
  20. http://www.drugs.com/diazepam.html
  21. Diazepam Injection | http://www.rxlist.com/diazepam-injection-drug/overdosage-contraindications.htm
  22. Barondes SH (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0-19-515130-5.
  23. Principles and Practice of Psychopharmacotherapy | http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535
  24. 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
  25. 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
  26. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  27. Barbiturates and benzodiazepine effects | https://www.ncbi.nlm.nih.gov/pubmed/2471436
  28. Flumazenil, a benzodiazepine antagonist | https://www.ncbi.nlm.nih.gov/pubmed/8306565
  29. International Narcotics Control Board (2003) | http://infoespai.org/wp-content/uploads/2014/12/green.pdf
  30. https://www.gov.uk/government/publications/controlled-drugs-list
  31. http://www.gesetze-im-internet.de/btmg_1981/anlage_iii_61.html