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It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: [[Drunkenness]] itself causes blackouts, sleepiness, and a reduction in [[Social inhibition|inhibitions]]. Only a timely screening for flunitrazepam can demonstrate its use. It has been shown that alcohol alone is the substance used in the vast majority of cases of date-rape. A recent study conducted by doctors in the U.K. found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with drug assisted rape such as [[gamma-Hydroxybutyric acid|GHB]]. However, flunitrazepam is not prescribed in the UK and the study size was only based on 75 people which may in part account for the findings. The study results however, do suggest that [[binge drinking]] is much more commonly to blame for drug assisted rapes than pharmaceutical drugs.<ref>[http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=436592&in_page_id=1770 Drug rape myth exposed as study reveals binge drinking is to blame | the Daily Mail<!-- Bot generated title -->]</ref>
It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: [[Drunkenness]] itself causes blackouts, sleepiness, and a reduction in [[Social inhibition|inhibitions]]. Only a timely screening for flunitrazepam can demonstrate its use. It has been shown that alcohol alone is the substance used in the vast majority of cases of date-rape. A recent study conducted by doctors in the U.K. found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with drug assisted rape such as [[gamma-Hydroxybutyric acid|GHB]]. However, flunitrazepam is not prescribed in the UK and the study size was only based on 75 people which may in part account for the findings. The study results however, do suggest that [[binge drinking]] is much more commonly to blame for drug assisted rapes than pharmaceutical drugs.<ref>[http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=436592&in_page_id=1770 Drug rape myth exposed as study reveals binge drinking is to blame | the Daily Mail<!-- Bot generated title -->]</ref>
In June 2009 used in Iranian Kahrizak prison for rape to presidential election results protests [49].


===Drug-facilitated robbery===
===Drug-facilitated robbery===

Revision as of 00:39, 20 August 2009

Flunitrazepam
Clinical data
Pregnancy
category
  • AU: C
Routes of
administration		Oral
Legal status
Legal status
Pharmacokinetic data
Elimination half-life18-26 hours
Identifiers
  • 6-(2-fluorophenyl)- 2-methyl- 9-nitro- 2,5-diazabicyclo [5.4.0] undeca- 5,8,10,12- tetraen- 3-one
CompTox Dashboard (EPA)
ECHA InfoCard100.015.089 Edit this at Wikidata

Flunitrazepam (Template:Pron-en) is marketed as a hypnotic drug and has sedative, anticonvulsant, anxiolytic, amnestic, hypnotic and skeletal muscle relaxant properties.[1] A short-intermediate acting benzodiazepine derivative, flunitrazepam is prescribed for the treatment of severe insomnia, marketed by Roche most commonly under the trade name Rohypnol (informally Rufinol[2]) -also marketed in some countries under the trade names Hipnosedon, Hypnodorm, Flunipam, Nilium, Vulbegal, Silece, Darkene, Ilman and Insom.

The prescription of flunitrazepam as a hypnotic is generally intended to be for short-term treatment of chronic, or severe insomnias that are not responsive to other hypnotics, especially in inpatients. It is considered to be one of the most effective benzodiazepine hypnotics on a dose basis.

Just as with other hypnotics, flunitrazepam should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[3]

The drug is sometimes used as a date rape drug (commonly referred to in street slang as a "roofie").[4]

Flunitrazepam is classed as a nitrobenzodiazepine. It was developed by combining nitrazepam with fluorine. Other nitrobenzodiazepines include nitrazepam and clonazepam.[5]

The Dutch, British and French use a system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy, adverse effects, pharmacokinetic properties, toxicity and drug interactions. A Dutch analysis using the system found that flunitrazepam is unsuitable to be included in drug prescribing formularies.[6]

Medical uses

  • In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug.[4][7][8]
  • In the United Kingdom, the drug is available only by private prescription.[9] Though Rohypnol was discontinued in 1986, Flunitrazepam use is still present in modern culture; among other uses, it is used in some hospitals to sedate patients undergoing colonoscopy.
  • In the Netherlands, flunitrazepam is a List 2 substance of the Opium Law and is available for prescription as 1 mg Rohypnol brand tablets by Roche, and as 1 mg and 2 mg generic tablets.
  • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.[10]
  • In Singapore, flunitrazepam is a Class C controlled drug (Schedule II), making it illegal to possess without a proper medical prescription.
  • In Japan, flunitrazepam is marketed by the Japanese pharmaceutical company Chugai under the tradename Rohypnol, and is indicated for the treatment of insomnia as well as used for preanesthetic medication.[11]
  • In Greece, flunitrazepam is available as Hipnosedon in 1 mg preparation and as Vulbegal and Nilium in 2 mg preparations.[12]
  • In Australia, prescription is restricted as a Schedule 8 medicine.[13][14] It is used primarily for the treatment of severe insomnia that has not responded to other treatments. In some states, it is also manufactured in generic form by Alphapharm under the name Hypnodorm. As a Schedule 8 medicine, it is illegal to have this drug in possession without an authority prescription from a registered doctor.
  • In South Africa, Rohypnol is classified as a schedule 6 drug.[15] It is available by prescription only, and restricted to 1 mg doses. Travelers from South Africa to the United States are limited to a 30-day supply. The drug must be declared to US Customs upon arrival. If a valid prescription cannot be produced, the drug may be subject to Customs search and seizure, and the traveler may face criminal charges or deportation.
  • In Norway, flunitrazepam is available as a prescription drug to treat insomnia under the brand name Flunipam 1 mg. It is a Class B substance under Norway's Narcotics Act. Only four hypnotics are prescribable in Norway: flunitrazepam, nitrazepam, zolpidem and zopiclone.[16]
  • In Sweden, the brand Rohypnol has been withdrawn from the domestic market. It is available as a generic and under the name Fluscand. It's listed as a List III (Schedule III) under the Narcotics Control Act (1968). Although it has for a long time been a first line drug for the treatment of insomnia, it has seen declines in prescriptions in recent years. Much more common are nitrazepam but above all zopiclone and zolpidem.
  • In Mexico, Rohypnol is approved for medical use,[8] however there have been many cases of trafficking of Rohypnol to the United States and other developed nations, most of it originating from Mexico.[17]
  • In Germany, flunitrazepam is available as the Roche-Brand Rohypnol 1 mg Film-Coated Tablets and several generic 1 mg tablets (e.g. Fluninoc, Flunitrazepam ratiopharm, Flunitrazepam neuraxpharm).

Adverse effects

Adverse effects of flunitrazepam include dependence, both physical and psychological; reduced sleep quality resulting in somnolence; and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. When used in pregnancy, it might cause floppy infant syndrome.

Dependence

Flunitrazepam as with other benzodiazepine drugs can lead to physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome.

Discontinuation may result in the appearance of withdrawal symptoms when the drug is discontinued. Abrupt withdrawal may lead to a severe benzodiazepine withdrawal syndrome characterised by seizures, psychosis, severe insomnia and severe anxiety. Rebound insomnia, worse than baseline insomnia, typically occur after discontinuation of flunitrazepam even after short term single nightly dose therapy.[18]

Sleep depth

Flunitrazepam produces a decrease in delta wave activity. The effect of benzodiazepine drugs on delta waves, however, may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; increased levels of delta sleep reflects better quality of sleep. Thus flunitrazepam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies.[19] This may lead to somnolence.

Paradoxical effects

Flunitrazepam may cause a paradoxical reaction in some individuals causing symptoms including anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behavior, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour.[20]

Floppy infant syndrome

See also: Floppy infant syndrome

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.[21]

Other

After discontinuation of flunitrazepam a rebound effect may occur about 4 days after stopping flunitrazepam.[22] (See benzodiazepine withdrawal syndrome)

Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia. It can be described as a hangover-like effect, with impairment of mental arithmetic abilities.

Impaired psychomotor functions is another adverse effect, affecting reaction time and driving skill. This may also be expressed as impaired coordination, impaired balance and dizziness.

Other adverse effects include:

Special precautions

Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important adverse effect. This side effect is not unique to flunitrazepam but also occurs with other hypnotic drugs. Flunitrazepam seems to have a particularly high risk of road traffic accidents compared to other hypnotic drugs. Extreme caution should be exercised by drivers after taking flunitrazepam.[23]

Pharmacology

Benzodiazepines, including flunitrazepam, bind to mouse glial cell membranes with high affinity.[24] Flunitrazepam induces melanogenesis in B16/C3 mouse melanoma cell cultures via modulating high affinity binding sites.[25] Benzodiazepines, including flunitrazepam have been shown to act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat brain cell components. This has been conjectured as a mechanism for high-dose effects against seizures in a study. [26]

Mechanism of action

The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABAA receptor.[27] Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.

Flunitrazepam's effects are approximately 7 to 10 times more potent than diazepam on a dose basis. The effects of flunitrazepam appear approximately 15 to 20 minutes after oral administration, and last for approximately four to six hours. Some residual effects can persist up to 12 hours or more after administration.

Pharmacokinetics

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.[28]

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes.

Flunitrazepam has a long half-life of 18 – 26 hours and an active metabolite which has a half life of 36-200 hours, which means flunitrazepam effects after nighttime administration persist throughout the next day.[29] Residual 'hangover' effects after nighttime administration of flunitrazepam, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely, and increase risks of falls and hip fractures.[30]

Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism.[31]

Interactions

The use of flunitrazepam in combination with alcohol synergizes the adverse effects, and can lead to toxicity and death.

Overdose

See also: Benzodiazepine overdose

Flunitrazepam is a drug which is frequently involved in drug intoxication, including overdose.[32][33] Overdose of flunitrazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if flunitrazepam is taken in combination with alcohol, opiates or other CNS depressants.

This lethal effect of flunitrazepam overdose in particular in combination with other drugs is commonly used in suicide, as seen in Abuse potential section.

Flunitrazepam overdose responds to the benzodiazepine receptor antagonist flumazenil, which thus can be used as a treatment.

Abuse potential

See also: Benzodiazepine drug misuse
Hypnodorm 1mg Flunitrazepam tabs, Australia
Rohypnol

Despite the fact that flunitrazepam is a Schedule IV controlled substance, it is not commercially available in the United States. Currently the DEA is recommending that Rohypnol be reclassified to Schedule I. [citation needed]

Drug-facilitated sexual assault

Flunitrazepam is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under the influence of the drug. This effect is particularly dangerous when flunitrazepam is used to aid in the commission of sexual assault; victims may not be able to clearly recall the assault, the assailant, or the events surrounding the assault.

It is difficult to estimate just how many flunitrazepam-facilitated rapes have occurred in the past. Very often, biological samples are taken from the victim at a time when the effects of the drug have already passed and only residual amounts remain in the body fluids. These residual amounts are difficult, and sometimes impossible, to detect using standard screening assays available in the United States. If flunitrazepam exposure is to be detected at all, urine samples need to be collected within 72 hours and subjected to sensitive analytical tests. The problem is compounded by the onset of amnesia after ingestion of the drug, which causes the victim to be uncertain about the facts surrounding the rape. This uncertainty may lead to critical delays or even reluctance to report the rape and provide appropriate biological samples for testing. If a person suspects that he or she is the victim of a flunitrazepam-facilitated rape, he or she should get laboratory testing for flunitrazepam as soon as possible. In recent news it has been discovered that scientists can now detect flunitrazepam and related compounds in urine at least up to 5 days after administration of a single dose of Rohypnol and up to a month in hair.[34]

It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: Drunkenness itself causes blackouts, sleepiness, and a reduction in inhibitions. Only a timely screening for flunitrazepam can demonstrate its use. It has been shown that alcohol alone is the substance used in the vast majority of cases of date-rape. A recent study conducted by doctors in the U.K. found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with drug assisted rape such as GHB. However, flunitrazepam is not prescribed in the UK and the study size was only based on 75 people which may in part account for the findings. The study results however, do suggest that binge drinking is much more commonly to blame for drug assisted rapes than pharmaceutical drugs.[35] In June 2009 used in Iranian Kahrizak prison for rape to presidential election results protests [49].

Drug-facilitated robbery

In the United Kingdom, the use of flunitrazepam and other "date rape" drugs has been connected to stealing from sedated victims. One expert quoted in a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives,[36] making drug-assisted robbery a more common problem than drug-assisted rape.

Criminals sometimes use flunitrazepam before committing robbery as it has a calming and anti-emotive effect. This allows the criminal to perform the robbery without becoming anxious. Flunitrazepam is also known to induce anterograde amnesia making police interrogations more difficult.[37][38][39]

In a notable flunitrazepam related case, Selina Hakki was found guilty in December 2004 of using flunitrazepam to drug wealthy men and rob them of their clothes and accessories in the UK.

Recreational drug

Although flunitrazepam has become widely known in USA for its use as a date-rape drug, it is used more frequently as a recreational drug. It is used by high school and college students, rave party attendees, and heroin and cocaine users (who call a dose of flunitrazepam a "roofie") for recreational purposes, including:

  • To produce profound intoxication (Kurt Cobain overdosed on a mixture of flunitrazepam and champagne several weeks before his death)
  • To increase sedative effect in combination with heroin, or ease the anxiety and/or sleeplessness of withdrawal
  • To counteract the side effects of stimulants (e.g. insomnia, paranoia, jitteriness)
  • To "soften" the so-called "crash" which follows heavy usage of stimulants, such as cocaine or methamphetamine

Flunitrazepam is usually consumed orally, and is sometimes combined with alcohol (benzodiazepines and alcohol combined intensify each others' CNS depression to the point of being deadly). It is also occasionally insufflated (i.e. tablets are crushed into powder and snorted). In some European countries, there was an alcohol solution of flunitrazepam (Darkene), taken by injection, with very strong effects.

Benzodiazepines, including diazepam, nitrazepam, oxazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse. Nitrazepam and flunitrazepam accounted for the vast majority of forged prescriptions.[40]

Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines (anxiolytic or hypnotic) and zolpidem and zopiclone, (as well as similar hypnotic and anxiolytic drugs from the non-benzodiazepine families Cyclopyrrolones, Imidazopyridines, and Pyrazolopyrimidines) are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and similar drugs.[41]

Street names for Rohypnol include "rowies", "rophy", "ruffles", "roachies", "roofies", "ruffies", "ruff up", "rib", "roach 2 (R2)", "roche", "rope", "ropies", "circles", "circes", "forget it" ,"poppers", "forget-me-pill", "Mexican Valium" and more recently "rapies" as a reference to the movie The Hangover.[42][43]

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 15% of cases.[44] In a retrospective study of deaths, when benzodiazepines were implicated, the benzodiazepines flunitrazepam and nitrazepam were the most common benzodiazepines involved. In four of the cases benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines.[45]

Flunitrazepam is currently a Schedule III drug under the international Convention on Psychotropic Substances of 1971;[46] in the United States, it is on Schedule IV

According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:[47]

Flunitrazepam was "temporarily controlled in Schedule IV pursuant to a treaty obligation under the 1971 Convention on Psychotropic Substances. At the time flunitrazepam was placed temporarily in Schedule IV . . . there was no evidence of abuse or trafficking of the drug in the United States."

Rohypnol is currently under consideration to be rescheduled to Schedule I, and is already considered such in the States of Florida, Idaho, Minnesota, New Hampshire, New Mexico, North Dakota, Oklahoma, and Pennsylvania.

21 U.S.C. § 841 and 21 U.S.C. § 952 provide for stiff prison terms for the possession of flunitrazepam; penalties for use or distribution include life in prison, should death or serious injury occur.

In Australia, flunitrazepam is a schedule 8 drug, along with amphetamines and narcotic analgesics. All other benzodiazepines (except Temazepam) are schedule 4 drugs. Unauthorized possession of certain quantities of the drug is punishable by criminal sanctions in New South Wales under Schedule 1 of the Drug Misuse and Trafficking Act 1985.

On January 1, 2003, flunitrazepam was moved up one level in the schedule of controlled drugs in Norway, and on August 1, 2004, the manufacturer Roche removed Rohypnol from the market there altogether.[48]

Alternatives

Intermediate half life benzodiazepines are also useful for patients with difficulty in maintaining sleep e.g. loprazolam, lormetazepam, temazepam and may be preferable to long half life benzodiazepines which typically cause next day sedation and impairments.

History

Flunitrazepam was first synthesized in 1972 by Roche and was used in hospitals when deep sedation was needed. It first entered the commercial market in Europe in 1975 as Rohypnol produced by Roche, and in the 1980s it began to be available in other countries. It first appeared in the U.S. in the early 1990s. It originally came in 1 mg and 2 mg doses, but due to its potency and potential for abuse the higher doses of Rohypnol were soon taken off the market by its producer, Roche, and it is now only available as 1 mg tablets. In the countries where flunitrazepam is available for prescription as both 1 mg and 2 mg tablets, such as the Netherlands, generic alternatives are available for the 2 mg tablets.

See also

References

Footnotes

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  2. ^ http://earthops.org/rohypnol5.html
  3. ^ Rickels K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica Suppl. 332: 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.
  4. ^ a b DEA Resources, For Law Enforcement Officers, Intelligence Reports, Rohypnol
  5. ^ Robertson MD (1995). "Postmortem drug metabolism by bacteria". J Forensic Sci. 40 (3): 382–6. PMID 7782744. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  6. ^ Janknegt R, van der Kuy A, Declerck G, Idzikowski C (1996). "Hypnotics. Drug selection by means of the System of Objectified Judgement Analysis (SOJA) method". Pharmacoeconomics. 10 (2): 152–63. PMID 10163418. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Rohypnol Fast Facts
  8. ^ a b Women's Health.gov: Date Rape Drugs
  9. ^ "UK Rohypnol: The date rape drug". BBC News Online. May 20, 1999. Retrieved 2006-03-13.
  10. ^ Irish Statute Book, Statutory Instruments, S.I. No. 342/1993 — Misuse of Drugs (Amendment) Regulations, 1993
  11. ^ "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. 2007. Retrieved 2008-08-11. {{cite web}}: Unknown parameter |month= ignored (help)
  12. ^ Å.Ï.Ö. ÁíáæÞôçóç öáñìáêåõôéêþí éäéïóêåõáóìÜôùí
  13. ^ "Authorisation to Supply or Prescribe Drugs of Addiction: Flunitrazepam". Statutory Medical Notifications. Department of Health, Government of Western Australia. 13 August 2004. Retrieved 2006-03-13.
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  15. ^ "Drug Wars - About Drugs". 11 October 2006.
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  17. ^ DEA Briefs & Background, Drugs and Drug Abuse, State Factsheets, Texas
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  20. ^ Bramness JG, Skurtveit S, Mørland J (2006). "Flunitrazepam: psychomotor impairment, agitation and paradoxical reactions". Forensic Sci. Int. 159 (2–3): 83–91. doi:10.1016/j.forsciint.2005.06.009. PMID 16087304. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Kanto JH. (1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs. 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID 6124415. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  22. ^ Hindmarch I. (1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication". Acta Psychiatrica Scandinavica. 56 (5): 373–81. doi:10.1111/j.1600-0447.1977.tb06678.x. PMID 22990. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  23. ^ Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J (2008). "Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam". Sleep Med. 9 (8): 818–22. doi:10.1016/j.sleep.2007.11.011. PMID 18226959. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Tardy M (1981). "Benzodiazepine receptors on primary cultures of mouse astrocytes". J Neurochem. 36 (4): 1587–9. doi:10.1111/j.1471-4159.1981.tb00603.x. PMID 6267195. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  25. ^ Matthew E (1981). "Benzodiazepines have high-affinity binding sites and induce melanogenesis in B16/C3 melanoma cells". Proc Natl Acad Sci USA. 78 (6): 3935–9. doi:10.1073/pnas.78.6.3935. PMID 6267610. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  26. ^ Taft WC (1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proc Natl Acad Sci USA (PDF). 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMID 6328498. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  27. ^ Oelschläger H. (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. doi:10.1002/jps.2600680119. PMID 2570451. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  28. ^ Cano J. P. (1977). "Bioavailability from various galenic formulations of flunitrazepam". Arzneimittelforschung. 27 (12): 2383–8. rohypnol. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  29. ^ Benzodiazepine Equivalents Table - A list of Equivalent Doses of Benzodiazepines
  30. ^ Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115. {{cite journal}}: Cite has empty unknown parameters: |month= and |coauthors= (help)
  31. ^ CYP3A4 Is the Major CYP Isoform Mediating the in Vitro ...
  32. ^ Zevzikovas A (2002). "[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography]". Medicina (Kaunas). 38 (3): 316–20. PMID 12474705. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  33. ^ Jonasson B, Saldeen T (2002). "Citalopram in fatal poisoning cases". Forensic Sci. Int. 126 (1): 1–6. doi:10.1016/S0379-0738(01)00632-6. PMID 11955823. {{cite journal}}: Unknown parameter |month= ignored (help)
  34. ^ Detection of "Date-Rape" Drugs in Hair and Urine, Final Report
  35. ^ Drug rape myth exposed as study reveals binge drinking is to blame | the Daily Mail
  36. ^ 'Rape drug' used to rob thousands | Special reports | Guardian Unlimited
  37. ^ "Bankrånare stärkte sig med Rohypnol?". DrugNews.
  38. ^ "Mijailovic var påverkad av våldsdrog". Sydsvenskan.
  39. ^ "Mijailovic var påverkad av våldsdrog". Expressen.
  40. ^ Bergman U (1989). "Use of prescription forgeries in a drug abuse surveillance network". Eur J Clin Pharmacol. 36 (6): 621–3. doi:10.1007/BF00637747. PMID 2776820. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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  42. ^ Rohypnol fact sheet at About.com Teen Advice
  43. ^ Facts about Rohypnol and other date rape drugs - Facts on Rohypnol
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  46. ^ Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation Of The
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