Benzodiazepine misuse

Benzodiazepines
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.
Benzodiazepine
List of benzodiazepines
Benzodiazepine overdose
Benzodiazepine dependence
Benzodiazepine drug misuse
Benzodiazepine withdrawal syndrome
Long-term effects of benzodiazepines

Benzodiazepine drug misuse
Classification and external resources
ICD-10	F13.1
eMedicine	article/290585

Benzodiazepine drug misuse, sometimes called benzodiazepine drug abuse (both terms are merely nominal, and cover all non-medical uses of the drugs), is defined as using benzodiazepines for recreational purposes i.e. to get "high" or continuing benzodiazepines long term against medical advice.^[1][2] The level of benzodiazepine misuse is as high as other common drugs of misuse. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication^[2][3] and in tests in pentobarbital trained rhesus monkeys benzodiazepines also produced effects similar to barbiturates.^[4] In a 1991 study, triazolam had the highest self-administration rate in cocaine trained baboons, among the five benzodiazepines examined: alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam.^[5]

A 1991 study indicated that diazepam, in particular, had a greater abuse liability than many of the other benzodiazepines. Some of the available data also suggested that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard.^[6]

A 1991-1993 British study found that flurazepam and temazepam were the most toxic benzodiazepines in overdose.^[7]

A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines.^[8]

Benzodiazepines have been abused both orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was ‘strong’ and that it gave a good ‘high’.^[9]

According to Dr Chris Ford the clinical director of Substance Misuse Management in General Practice, among drugs of abuse, benzodiazepines are often seen as the 'bad guys' by drug and alcohol workers. Illicit users of benzodiazepines have been found to take higher methadone doses, as well as showing more HIV/HCV risk-taking behaviour, greater poly-drug use, higher levels of psychopathology and social dysfunction. However, there is only limited research into the adverse effects of benzodiazepines in drug misusers and further research is needed to demonstrate whether this is the result of cause or effect.^[10]

Background

Benzodiazepines are a commonly abused class of drugs, although there is debate as to whether certain benzodiazepines have higher abuse potential than others.^[11] In animal and human studies the abuse potential of benzodiazepines is classed as moderate in comparison to other drugs of abuse.^[12] Benzodiazepines are commonly abused by poly drug users, especially heroin addicts or alcoholics but sometimes are misused in isolation as the primary drug of misuse. They can be misused to achieve the high that benzodiazepines produce or more commonly they are used to either enhance the effects of other CNS depressant drugs, to stave off withdrawal effects of other drugs or combat the effects of stimulants. As many as 30–50% of alcoholics are also benzodiazepine misusers.^[13] Drug abusers often abuse high doses which makes serious benzodiazepine withdrawal symptoms such as psychosis or convulsions more likely to occur during withdrawal.

Benzodiazepine abuse increases risk taking behaviours such as unprotected sex and sharing of needles amongst intravenous abusers of benzodiazepines. Abuse is also associated with blackouts, memory loss, aggression, violence, and chaotic behaviour associated with paranoia. There is little support for long-term maintenance of benzodiazepine abusers and thus a withdrawal regime is indicated when benzodiazepine abuse becomes a dependence or addiction. The main source of illicit benzodiazepines are diverted benzodiazepines obtained originally on prescription; other sources include thefts from pharmacies and pharmaceutical warehouses. Benzodiazepine abuse is steadily increasing and is now a major public health problem. Benzodiazepine abuse is mostly limited to individuals who abuse other drugs, i.e. poly-drug abusers. Most prescribed users do not abuse their medication, however, some high dose prescribed users do become involved with the illicit drug scene. Abuse of benzodiazepines occurs in a wide age range of people and includes teenagers and the old. The abuse potential or drug-liking effects appears to be dose related, with low doses of benzodiazepines having limited drug liking effects but higher doses increasing the abuse potential/drug-liking properties.^[14]

Health related complications

See also: Long-term effects of benzodiazepines

Complications of benzodiazepine abuse include drug related deaths due to overdose especially in combination with other depressant drugs such as opiods. Other complications include: blackouts and memory loss, paranoia, violence and criminal behaviour, risk-taking sexual behaviour, foetal and neonatal risks if taken in pregnancy, dependence, withdrawal seizures and psychosis. Injection of the drug carries risk of: thrombophlebitis, deep vein thrombosis, deep and superficial abscesses, pulmonary microembolism, rhabdomyolysis, tissue necrosis, gangrene requiring amputation, hepatitis B and C, as well as blood borne infections such as HIV infection (caused by sharing injecting equipment).^[13] Long-term use of benzodiazepines can worsen pre-existing depression and anxiety and may potentially also cause dementia with impairments in recent and remote memory functions.^[15]

Use is widespread among amphetamine users, with those that use amphetamines and benzodiazepines having greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug misusers.^[16] Poly-drug users who also use benzodiazepines appear to engage in more risk taking behavior. Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs.^[17]

Rates of misuse

Little attention has focused on the degree that benzodiazepines are abused as a primary drug of choice, but they are frequently abused alongside other drugs of abuse especially alcohol, stimulants and opiates.^[18] The benzodiazepine most commonly abused can vary from country to country and depends on factors including local popularity as well as which benzodiazepines are available. Nitrazepam for example is commonly abused in Nepal and the United Kingdom,^[19][20] whereas in the United States of America where nitrazepam is not available on prescription other benzodiazepines are more commonly abused.^[6] In the United Kingdom and Australia there have been epidemics of temazepam abuse. Particular problems with abuse of temazepam are often related to gel capsules being melted and injected and drug related deaths.^[21][22][23] Injecting most benzodiazepines is dangerous because of their relative insolubility in water (with the exception of midazolam), leading to potentially serious adverse health consequences for users.^[24][25]

Benzodiazepines are a commonly misused class of drug. A study in Sweden found that benzodiazepines are the most common drug class of forged prescriptions in Sweden.^[26] Concentrations of benzodiazepines detected in impaired motor vehicle drivers often exceeding therapeutic doses have been reported in Sweden and in Northern Ireland.^[27][28] One of the hallmarks of problematic benzodiazepine drug misuse is escalation of dose. Most licit prescribed users of benzodiazepines do not escalate their dose of benzodiazepines.^[29]

A 2004 US government study of nationwide ED visits conducted by SAMHSA found that sedative-hypnotics in the USA are the most frequently misused pharmaceutical drug with 35% of drug related visits to the Emergency Department involving sedative hypnotics. Benzodiazepines accounted for the majority of these. Benzodiazepines are more commonly misused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. Males and females misuse benzodiazepines equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. Alprazolam is the most commonly misused benzodiazepine, followed by clonazepam, lorazepam and diazepam as the 4th in the USA.^[30]

Motivations for drug misuse

Benzodiazepines reduce the tolerance to reward delay in rats.^[31] Humans are motivated to misuse benzodiazepines to achieve a sedative-hypnotic high which often produces effects including feeling energetic, relaxed, drunken, talkative and euphoric. In India up to 50–60% of heroin addicts use benzodiazepines and 20% of injecting substance misusers also inject benzodiazepines.^[32] Benzodiazepines can be used counter effects of other drugs e.g. to "come down" from stimulants or enhance the effects of other CNS depressant drugs e.g. alcohol, or heroin in rats.^[33][34][35] Compulsive benzodiazepine use is believed to be due to adaptational changes in the GABA_A receptor and possibly also its effects on the opioid system. The abuse potential of sedative-hypnotics are governed mainly by their effects on the alpha1 containing GABA_A receptors.^[36]

Risk factors for misuse

See also: List of benzodiazepines

Individuals with a substance abuse history are at an increased risk of misusing benzodiazepines.^[37] Individuals with a history familial abuse of alcohol or who are siblings or children of alcoholics appear to respond differently to benzodiazepines than genetically healthy persons, with males experiencing increased euphoric effects and females having exaggerated responses to the adverse effects of benzodiazepines.^{[38][39][40][41]}

Whilst all benzodiazepines have abuse potential, certain characteristics increase their potential for abuse. A short elimination half-life, high potency and a rapid onset of action are characteristics which increase the abuse potential of benzodiazepines.^[42] The following table provides the elimination half-life, relevant potency to other benzodiazepines, speed of onset of action and duration of behavioural effects.^[43][44]

Drug Name	Common Brand Names*	Onset of action	Duration of action (h)**	Elimination Half-Life (h) [active metabolite]	Approximate Equivalent Dose***
Alprazolam	Xanax, Xanor, Tafil, Alprox,	Fast	3–5	6–12 hours	0.5 mg
Chlordiazepoxide	Librium, Tropium, Risolid, Klopoxid	Intermediate	???	5–30 hours [36–200 hours]	25 mg
Clonazepam	Klonopin, Klonapin, Rivotril, Iktorivil	Intermediate	10–12	18–50 hours	0.5 mg
Clorazepate	Tranxene	Intermediate	???	[36–100 hours]	15 mg
Diazepam	Valium, Apzepam, Stesolid, Vival, Apozepam, Hexalid, Valaxona	Fast	4–6	20–100 hours [36–200]	10 mg
Estazolam	ProSom	Slow	6–8	10–24 h	1–2 mg
Flunitrazepam	Rohypnol, Fluscand, Flunipam, Ronal	Fast	6–8	18–26 hours [36–200 hours]	1 mg
Flurazepam	Dalmadorm, Dalmane	Fast	7–10	[40–250 hours]	15–30 mg
Lorazepam	Ativan, Temesta, Lorabenz	Fast	4–6	10–20 hours	1 mg
Midazolam	Dormicum, Versed, Hypnovel	Fast	0.5–1	3 hours (1.8–6 hours)	5 mg
Oxazepam	Seresta, Serax, Serenid, Serepax, Sobril, Oxascand, Alopam, Oxabenz, Oxapax	Slow	4–6	4–15 hours	30 mg
Prazepam	Lysanxia, Centrax	Slow	???	36–200 hours	20 mg
Quazepam	Doral	Slow	6	39–120 hours	20 mg
Temazepam	Restoril, Normison, Euhypnos, Tenox	Fast	5–6	8–22 hours	20 mg
Triazolam	Halcion, Rilamir	Fast	0.5–1	2 hours	0.25 mg

*Not all trade names are listed. Click on drug name to see a more comprehensive list.
**The duration of apparent action is usually considerably less than the half-life. With most benzodiazepines, noticeable effects usually wear off within a few hours. Nevertheless, as long as the drug is present it will exert subtle effects within the body. These effects may become apparent during continued use or may appear as withdrawal symptoms when dosage is reduced or the drug is stopped.^{[citation needed]}
***Equivalent doses are based on clinical experience but may vary between individuals.^{[45][citation needed]}

Drug dependence and withdrawal effects

See also: Benzodiazepine withdrawal syndrome and Benzodiazepine dependence

Benzodiazepines can induce a severe benzodiazepine withdrawal syndrome as well as drug seeking behaviour.

Sedative hypnotics such as alcohol, benzodiazepines and the barbiturates are notorious for the severe physical dependence that they are capable of inducing which can result in severe withdrawal effects.^{[46][citation needed]} This severe neuroadaptation is even more profound in high dose drug users and misusers. A high degree of tolerance often occurs in chronic benzodiazepine abusers due to the typically high doses they consume which can lead to a severe benzodiazepine dependence. The benzodiazepine withdrawal syndrome seen in chronic high dose benzodiazepine abusers is similar to that seen in therapeutic low dose users but of a more severe nature. Extreme antisocial behaviours in obtaining continued supplies and severe drug-seeking behaviour when withdrawing occurs. The severity of the benzodiazepine withdrawal syndrome has been described by one benzodiazepine drug misuser who stated that^[13]

I'd rather withdraw off heroin any day. If I was withdrawing from benzos you could offer me a gram of heroin or just 20mg of diazepam and I'd take the diazepam every time - I've never been so frightened in my life.

Those who use benzodiazepines intermittently are less likely to develop a dependence and withdrawal symptoms upon dose reduction or cessation of benzodiazepines than those who use benzodiazepines on a daily basis.^[13]

Misuse of benzodiazepines is widespread amongst drug misusers; however, many of these people will not require withdrawal management as their use is often restricted to binges or occasional misuse. Benzodiazepine dependence when it occurs requires withdrawal treatment. There is little evidence of benefit from long-term substitution therapy of benzodiazepines, and conversely, there is growing evidence of the harm of long-term use of benzodiazepines, especially higher doses. Therefore gradual reduction is recommended, titrated against withdrawal symptoms.^[47] For withdrawal purposes, stabilisation with a long acting agent such as diazepam is recommended before commencing withdrawal. Chlordiazepoxide (librium), a long-acting benzodiazepine, is gaining attention as an alternative to diazepam in substance abusers dependent on benzodiazepines due to its decreased abuse potential.^[18] In individuals dependent on benzodiazepines who have been using benzodiazepines long-term, taper regimes of 6–12 months have been recommended and found to be more successful. More rapid detoxifications e.g. of a month are not recommended as they lead to more severe withdrawal symptoms.^[48]

Tolerance leads to a reduction in GABA receptors and function; when benzodiazepines are reduced or stopped this leads to an unmasking of these compensatory changes in the nervous system with the appearance of physical and mental withdrawal effects such as anxiety, insomnia, autonomic hyperactivity and possibly seizures.^[42]

Some common withdrawal symptoms which can occur when stopping the use of benzodiazepines include:^[13]

Depression Shaking Feeling unreal Appetite loss Muscle twitching Memory loss Motor impairment Nausea Muscle pains Dizziness

Apparent movement of still objects Feeling faint Noise sensitivity Light sensitivity Peculiar taste Pins and needles Touch sensitivity Sore eyes Hallucinations Smell sensitivity

All sedative-hypnotics, e.g. alcohol, barbiturates, benzodiazepines and the nonbenzodiazepine Z-drugs have a similar mechanism of action, working on the GABA_A receptor complex and are cross tolerant with each other and also have abuse potential. Use of prescription sedative-hypnotics e.g. the non-benzodiazepine Z-drugs often leads to a relapse back into substance misuse with one author stating this occurs in over a quarter of those who have achieved abstinence.^[48]

Drug-related crime

See also: Drug-related crime

Problem benzodiazepine use can be associated with various deviant behaviors, including drug-related crime. In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full time work and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year. Benzodiazepines were sometimes reported to be used alone, but most often formed part of a poly drug-using problem. Female users were more likely than men to be using heroin, whereas male users were more likely to report amphetamine use. Benzodiazepine users were more likely than non-users to claim government financial benefits and benzodiazepine users who were also poly-drug users were the most likely to be claiming government financial benefits. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit temazepam, with some who reported injecting prescribed benzodiazepines. Injection was a concern in this survey due to increased health risks. The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines.^[49]

Benzodiazepines are also sometimes used for drug facilitated sexual assaults and robbery, however, alcohol remains the most common drug involved in drug facilitated assaults. The muscle relaxant, disinhibiting and amnesia producing effects of benzodiazepines are the pharmacological properties which make these drugs effective in drug-facilitated crimes.^[50][51]

Drug regulation and enforcement

Europe

Temazepam abuse and seizures have been falling in the UK probably due to its reclassification as Schedule 3 controlled drug with tighter prescribing restrictions and the resultant reduction in availability.^[52] A total of 2.75 million temazepam capsules were seized in the Netherlands by authorities between 1996 and 1999.^[53] In Northern Ireland statistics of individuals attending drug addiction treatment centers found that benzodiazepines were the 2nd most commonly reported main problem drugs (31 percent of attendees). Cannabis was the top with 35 percent of individuals reporting it as their main problem drug. The statistics showed that treatment for benzodiazepines as the main problematic drug had more than doubled from the previous year and was a growing problem in Northern Ireland.^[54]

Oceania

Benzodiazepines are common drugs of abuse in Australia and New Zealand, particularly among those who may also be using other illicit drugs. The intravenous use of temazepam poses the greatest threat to those who misuse benzodiazepines. Simultaneous consumption of temazepam with heroin is a potential risk factor of overdose. An Australian study of non-fatal heroin overdoses, noted that 26% of heroin users had consumed temazepam at the time of their overdose. This is consistent with a NSW investigation of coronial files from 1992. Temazepam was found in 26% of heroin-related deaths. Temazepam, including tablet formulations, are used intravenously. In an Australian study of 210 heroin users who used temazepam, 48% had injected it. Although abuse of benzodiazepines has decreased over the past few years, temazepam continues to be a major drug of abuse in Australia. In certain states like Victoria and Queensland, temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary. Darke, Ross & Hall found that different benzodiazepines have different abuse potential. The more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference for a benzodiazepine were that it was the ‘strongest’ and that it gave a good ‘high’.^[9]

North America

Abuse of benzodiazepine drugs is a serious problem in North America. The most frequently abused of the benzodiazepines in both the United States and Canada are alprazolam, clonazepam, lorazepam and diazepam.^[55]

East and Southeast Asia

Abuse of benzodiazepines is a serious problem throughout East and Southeast Asia.

The Central Narcotics Bureau of Singapore seized 94,200 nimetazepam tablets in 2003. This is the largest nimetazepam seizure recorded since nimetazepam became a controlled drug under the Misuse of Drugs Act in 1992. In Singapore nimetazepam is a Class C controlled drug.^[56]

In Hong Kong abuse of prescription medicinal preparations continued in 2006 and seizures of midazolam (120,611 tablets), nimetazepam/nitrazepam (17,457 tablets), triazolam (1,071 tablets), diazepam (48,923 tablets) and chlordiazepoxide (5,853 tablets) were made. Heroin addicts used such tablets (crushed and mixed with heroin) to prolong the effect of the narcotic and ease withdrawal symptoms.^[57]

Legal status

In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain states and temazepam prescriptions require specially coded pads in certain states. In Canada, all benzodiazepines are in Schedule 4 of the Controlled Drugs and Substances Act.^[58]

In the United Kingdom, the benzodiazepines are schedule 4 controlled drugs, except for flunitrazepam, temazepam and midazolam, which are schedule 3 controlled drugs and carry stronger penalties for possession and trafficking.^[59][60]

In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20 mg of temazepam, are all placed on List 2 of the Opium Law. A prescription is needed for possession of all benzodiazepines. Temazepam formulations containing 20 mg or greater of the drug are placed on List 1, thus requiring prescriptions to be written in the List 1 format.^[61]

In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.^[62] Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.^[63]

Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.^[64]

See also

• Drug abuse
• Benzodiazepine overdose
• Long term effects of benzodiazepines

References

1. ^ Tyrer, Peter; Silk, Kenneth R., eds (24 January 2008). "Treatment of sedative-hypnotic dependence". Cambridge Textbook of Effective Treatments in Psychiatry (1st ed.). Cambridge University Press. pp. 402. ISBN 978-0521842280. http://books.google.co.uk/books?id=HLPXELjTgdEC&pg=PA402. 
2. ^ ^{a b} Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds" (PDF). J Clin Psychiatry 66 Suppl 9: 31–41. PMID 16336040. http://neuroscience.jhu.edu/griffiths%20papers/v66s0906.pdf. 
3. ^ Sheehan MF, Sheehan DV, Torres A, Coppola A, Francis E (1991). "Snorting benzodiazepines". Am J Drug Alcohol Abuse 17 (4): 457–68. doi:10.3109/00952999109001605. PMID 1684083. 
4. ^ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology (Berl.) 122 (3): 230–6. doi:10.1007/BF02246544. PMID 8748392. 
5. ^ Griffiths RR, Lamb RJ, Sannerud CA, Ator NA, Brady JV (1991). "Self-injection of barbiturates, benzodiazepines and other sedative-anxiolytics in baboons". Psychopharmacology (Berl.) 103 (2): 154–61. doi:10.1007/BF02244196. PMID 1674158. 
6. ^ ^{a b} Griffiths RR, Wolf B (August 1990). "Relative abuse liability of different benzodiazepines in drug abusers". J Clin Psychopharmacol 10 (4): 237–43. doi:10.1097/00004714-199008000-00002. PMID 1981067. 
7. ^ Serfaty M, Masterton G (January 1994). "Fatal poisonings attributed to benzodiazepines in Britain during the 1980s.". British Journal of Psychiatry 164 (1): 128-129. PMID 8104653. 
8. ^ N A Buckley, Dr; A H Dawson; I M Whyte; D L O'Connell (1995). "Relative toxicity of benzodiazepines in overdose.". British Medical Journal (BMJ) 310 (6974): 219. http://www.bmj.com/content/310/6974/219.full?view=long&pmid=7866122. 
9. ^ ^{a b} Australian Government; Medical Board (2006). "ACT MEDICAL BOARD - STANDARDS STATEMENT - PRESCRIBING OF BENZODIAZEPINES" (PDF). Australia: ACT medical board. http://www.legislation.act.gov.au/ni/2006-175/current/pdf/2006-175.pdf. Retrieved 13 September 2011. 
10. ^ Chris Ford (2009). "What is possible with benzodiazepines". UK: Exchange Supplies, 2009 National Drug Treatment Conference. http://www.exchangesupplies.org/conferences/NDTC/2009_NDTC/speakers/chris_ford.html. 
11. ^ Dart, Richard C. (1 December 2003). Medical Toxicology (3rd ed.). USA: Lippincott Williams & Wilkins. p. 819. ISBN 978-0781728454. http://books.google.com/?id=qDf3AO8nILoC. 
12. ^ Griffiths RR, Weerts EM (November 1997). "Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse". Psychopharmacology (Berl.) 134 (1): 1–37. doi:10.1007/s002130050422. PMID 9399364. http://link.springer.de/link/service/journals/00213/bibs/7134001/71340001.htm. 
13. ^ ^{a b c d e} Professor C Heather Ashton (2002). "BENZODIAZEPINE ABUSE". Drugs and Dependence. Harwood Academic Publishers. http://www.benzo.org.uk/ashbzab.htm. Retrieved September 25, 2007. 
14. ^ Caan, Woody; Belleroche, Jackie de, eds (11 April 2002). "Benzodiazepine abuse". Drink, Drugs and Dependence: From Science to Clinical Practice (1st ed.). Routledge. pp. 197–211. ISBN 978-0415278911. http://books.google.co.uk/books?id=nPvbDUw4w5QC&pg=PA197. 
15. ^ Galanter, Marc; Kleber, Herbert D. (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 197. ISBN 978-1585622764. http://books.google.com/?id=6wdJgejlQzYC. 
16. ^ Darke S, Ross J, Cohen J (1994). "The use of benzodiazepines among regular amphetamine users". Addiction 89 (12): 1683–90. doi:10.1111/j.1360-0443.1994.tb03769.x. PMID 7866252. 
17. ^ Williamson S, Gossop M, Powis B, Griffiths P, Fountain J, Strang J (1997). "Adverse effects of stimulant drugs in a community sample of drug users". Drug Alcohol Depend 44 (2–3): 87–94. doi:10.1016/S0376-8716(96)01324-5. PMID 9088780. 
18. ^ ^{a b} Karch, Steven B. (20 December 2006). Drug Abuse Handbook (2nd ed.). USA: CRC Press. p. 572. ISBN 978-0849316906. http://books.google.com/?id=F0mUte90ATUC. 
19. ^ Chatterjee A; Uprety L, Chapagain M, Kafle K (1996). "Drug abuse in Nepal: a rapid assessment study". Bull Narc 48 (1-2): 11–33. PMID 9839033. 
20. ^ Garretty DJ; Wolff K, Hay AW, Raistrick D (January 1997). "Benzodiazepine misuse by drug addicts". Annals of clinical biochemistry 34 (Pt 1): 68–73. PMID 9022890. 
21. ^ Wilce H (June 2004). "Temazepam capsules: What was the problem?". Australian Prescriber 27 (3): 58–9. http://www.australianprescriber.com/magazine/27/3/58/9/. 
22. ^ Ashton H (2002). "Benzodiazepine Abuse". Drugs and Dependence. London & New York: Harwood Academic Publishers. http://www.benzo.org.uk/ashbzab.htm. Retrieved 2007-11-25. 
23. ^ Hammersley R, Cassidy MT, Oliver J (1995). "Drugs associated with drug-related deaths in Edinburgh and Glasgow, November 1990 to October 1992". Addiction 90 (7): 959–65. doi:10.1046/j.1360-0443.1995.9079598.x. PMID 7663317. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0965-2140&date=1995&volume=90&issue=7&spage=959. 
24. ^ Eric C; Wang, Felix S, Chew. (2006). "MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis" (pdf). Radiology Case Reports 1 (3). http://www.radiologycasereports.net/index.php/rcr/article/viewPDFInterstitial/33/187. 
25. ^ "DB00404 (Alprazolam)". Canada: DrugBank. August 26, 2008. http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00280. 
26. ^ Bergman U; Dahl-Puustinen ML (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. 
27. ^ Jones AW; Holmgren A, Kugelberg FC (April 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Ther Drug Monit 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081. 
28. ^ Cosbey SH (December 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Sci Int 32 (4): 245–58. doi:10.1016/0379-0738(86)90201-X. PMID 3804143. 
29. ^ Lader MH (1999). "Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified?". European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 9 Suppl 6: S399–405. doi:10.1016/S0924-977X(99)00051-6. PMID 10622686. 
30. ^ United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2004). "Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. Archived from the original on 31 March 2008. http://web.archive.org/web/20080331184508/http://dawninfo.samhsa.gov/files/DAWN2k4ED.htm. Retrieved 9 May 2008. 
31. ^ Thiébot MH; Le Bihan C, Soubrié P, Simon P. (1985). "Benzodiazepines reduce the tolerance to reward delay in rats.". Psychopharmacology (Berl). 86 (1-2): 147–52. doi:10.1007/BF00431700. PMID 2862657. 
32. ^ PRAVIN SHANKER PRASAD; RAJAT RAY, RAKA JAIN, B.S.CHAVAN (2001). "ABUSE LIABILITY OF NITRAZEPAM: A STUDY AMONG EXPERIENCED DRUG USERS" (PDF). Indian Journal of Pharmacology (India: MedInd) 33: 357–362. http://medind.nic.in/ibi/t01/i5/ibit01i5p357.pdf. 
33. ^ Walker, Bm; Ettenberg, A (Apr 2003). "The effects of alprazolam on conditioned place preferences produced by intravenous heroin.". Pharmacology, biochemistry, and behavior 75 (1): 75–80. doi:10.1016/S0091-3057(03)00043-1. PMID 12759115. 
34. ^ Wright State University and the University of Akron (January 2008). "OSAM - O- GRAM Highlights of Statewide Drug Use Trends" (PDF). USA: Ohio Government. http://www.odadas.state.oh.us/WebManager/UltimateEditorInclude/UserFiles/WebDocuments/Planning/Jan05ExecSummry.pdf. Retrieved 10 December 2008. 
35. ^ Detective Eladio M. Paez (15 June 2008). "STATEMENT ON RAVES AND CLUB DRUGS TO THE SUBCOMMITTEE ON CRIME, CONGRESS OF THE UNITED STATES, HOUSE OF REPRESENTATIVES". USA: GOV House Judiciary. http://judiciary.house.gov/Legacy/paez0615.htm. Retrieved 10 December 2008. 
36. ^ Galanter, Marc; Kleber, Herbert D. (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 221. ISBN 978-1585622764. http://books.google.com/?id=6wdJgejlQzYC. 
37. ^ Hoffmann–La Roche. "Mogadon". RxMed. http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20M)/MOGADON.html. Retrieved 26 May 2009. 
38. ^ Ciraulo, Da; Barnhill, Jg; Greenblatt, Dj; Shader, Ri; Ciraulo, Am; Tarmey, Mf; Molloy, Ma; Foti, Me (Sep 1988). "Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men.". The Journal of clinical psychiatry 49 (9): 333–7. PMID 3417618. 
39. ^ Ciraulo, Da; Sarid-segal, O; Knapp, C; Ciraulo, Am; Greenblatt, Dj; Shader, Ri (Jul 1996). "Liability to alprazolam abuse in daughters of alcoholics.". The American journal of psychiatry 153 (7): 956–8. PMID 8659624. 
40. ^ Evans, Sm; Levin, Fr; Fischman, Mw (Jun 2000). "Increased sensitivity to alprazolam in females with a paternal history of alcoholism." (PDF). Psychopharmacology 150 (2): 150–62. doi:10.1007/s002130000421. PMID 10907668. http://www.springerlink.com/content/8n02e8ldfugnr9cc/fulltext.pdf. 
41. ^ Streeter, Cc; Ciraulo, Da; Harris, Gj; Kaufman, Mj; Lewis, Rf; Knapp, Cm; Ciraulo, Am; Maas, Lc et al. (May 1998). "Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism.". Psychiatry research 82 (2): 69–82. doi:10.1016/S0925-4927(98)00009-2. PMID 9754450. 
42. ^ ^{a b} Longo LP, Johnson B (April 2000). "Addiction: Part I. Benzodiazepines—side effects, abuse risk and alternatives". Am Fam Physician 61 (7): 2121–8. PMID 10779253. http://www.aafp.org/afp/20000401/2121.html. 
43. ^ Galanter, Marc; Kleber, Herbert D. (1 July 2008). The American Psychiatric Publishing Textbook of Substance Abuse Treatment (4th ed.). United States of America: American Psychiatric Publishing Inc. p. 216. ISBN 978-1585622764. http://books.google.com/?id=6wdJgejlQzYC. 
44. ^ Shader RI, Greenblatt DJ (1981). "The use of benzodiazepines in clinical practice" (PDF). Br J Clin Pharmacol 11 Suppl 1: 5S–9S. PMC 1401641. PMID 6133535. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1401641&blobtype=pdf. 
45. ^ http://www.benzo.org.uk/bzequiv.htm
46. ^ Dr Ray Baker. "Dr Ray Baker's Article on Addiction: Benzodiazepines in Particular". http://www.benzo.org.uk/can-drb.htm. Retrieved 14 Febrruary 2009. 
47. ^ National Treatment Agency for Substance Misuse (2007). "Drug misuse and dependence - UK guidelines on clinical management" (PDF). United Kingdom: Department of Health. http://www.nta.nhs.uk/publications/documents/clinical_guidelines_2007.pdf. 
48. ^ ^{a b} Gitlow, Stuart (1 October 2006). Substance Use Disorders: A Practical Guide (2nd ed.). USA: Lippincott Williams and Wilkins. pp. 103–121. ISBN 978-0781769983. http://books.google.com/?id=rbrSdWVerBUC. 
49. ^ Loxley W (2007). "Benzodiazepine use and harms among police detainees in Australia" (PDF). Trends Issues Crime Crim Justice (Canberra, A.C.T.: Australian Institute of Criminology) (336). ISBN 978-1-921185-39-7. http://www.aic.gov.au/documents/4/3/3/%7B4336A1AE-AFEC-4D82-A1D9-EB94ECC5B008%7Dtandi336.pdf. Retrieved 2009-06-10. 
50. ^ Schwartz, RH.; Milteer, R.; LeBeau, MA. (Jun 2000). "Drug-facilitated sexual assault ('date rape').". South Med J 93 (6): 558–61. PMID 10881768. 
51. ^ Goullé, JP.; Anger, JP. (Apr 2004). "Drug-facilitated robbery or sexual assault: problems associated with amnesia.". Ther Drug Monit 26 (2): 206–10. PMID 15228166. 
52. ^ The Scottish Government (3 June 2008). "Statistical Bulletin - DRUG SEIZURES BY SCOTTISH POLICE FORCES, 2005/2006 AND 2006/2007" (PDF). Crime and justice series. Scotland: scotland.gov.uk. http://www.scotland.gov.uk/Resource/Doc/226306/0061258.pdf. Retrieved 13 February 2009. 
53. ^ INCB (January 1999). "Operation of the international drug control system" (PDF). incb.org. http://www.incb.org/pdf/e/ar/1999/incb_report_1999_2.pdf. Retrieved 13 February 2009. 
54. ^ Northern Ireland Government (October 2008). "Statistics from the Northern Ireland Drug Misuse Database: 1 April 2007 – 31 March 2008" (PDF). Northern Ireland: Department of Health and Social Services and Public Safety. http://www.dhsspsni.gov.uk/dmd_bulletin_2007-08.pdf. 
55. ^ United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. http://dawninfo.samhsa.gov/files/ed2006/DAWN2k6ED.htm. Retrieved 9 February 2009. 
56. ^ Central Narcotics Bureau; Singapore Government (2003). "Drug Situation Report 2003". Singapore: cnb.gov.sg. 
57. ^ Hong Kong Government. "Suppression of Illicit Trafficking and Manufacturing" (PDF). Hong Kong: nd.gov.hk. http://www.nd.gov.hk/text/en/report/pdf/2006/chapter4_e.pdf. Retrieved 13 February 2009. 
58. ^ "Benzodiazepines". DEA Briefs & Background, Drugs and Drug Abuse, Drug Descriptions. U.S. Drug Enforcement Administration. http://www.usdoj.gov/dea/concern/benzodiazepines.html. Retrieved 2009-05-27. 
59. ^ Blackpool NHS Primary Care Trust (2008-05-01). "Medicines Management Update". United Kingdom National Health Service. http://www.blackpool.nhs.uk/images/uploads/CD-update-GP-v2-may08.pdf. Retrieved 2009-05-27. 
60. ^ UK, Gov. "List of Drugs Currently Controlled Under The Misuse of Drugs Legislation". Misuse of Drugs Act UK. http://www.homeoffice.gov.uk/documents/cdlist.pdf?view=Binary. Retrieved 2009-05-27. 
61. ^ "Opium Law". Dutch Government. 2004-11-29. http://www.cannabisbureau.nl/pdf/Opiumwet_EN_29nov2004.pdf. Retrieved 2009-05-27. ^{[dead link]}
62. ^ Hong Kong Government; Hong Kong Ordinances. "DANGEROUS DRUGS ORDINANCE - SCHEDULE 1". Hong Kong: hklii.org. http://www.hklii.org/hk/legis/en/ord/134/sch1.html. 
63. ^ Lee KK, Chan TY, Chan AW, Lau GS, Critchley JA (1995). "Use and abuse of benzodiazepines in Hong Kong 1990–93—the impact of regulatory changes". J. Toxicol. Clin. Toxicol. 33 (6): 597–602. doi:10.3109/15563659509010615. PMID 8523479. 
64. ^ International Narcotics Control Board (August 2003). "List of psychotropic substances under international control" (PDF). incb.org. http://www.incb.org/pdf/e/list/green.pdf. Retrieved 2008-12-17.