CE ARTICLE: 3 CE CREDITS By Jonathan J. Lipman, PhD, DABFE, DABFM, DABPS TRANQUILIZER Addiction, dependence, withdrawal syndromes, memory disturbances, amnesia, dis- inhibited behavior, violence, impulsivity, automatistic and somnambulistic states, and cognitive and neuropsychological impairments result at least in part from activation of receptors in the brain for the neurotransmitter Gama Aminobutyric Acid (GABA) This mechanism is responsible for many of the common, shared, and similar actions of various tranquillizing drugs used for relief of anxiety, for night-time sedation, as anticonvulsants, as a muscle-relaxant, and for surgical anesthetic purposes. These tranquillizing drugs of superficially very different chemical classes share this GABA mechanism, and they produce effects similar to beverage , ethanol. These drug effects, alone and in interaction with other drugs, combine with idiosyn- cratic neurobiological vulnerabilities to bring the user’s behavior to forensic notice in a wide variety of criminal and civil cases.

The recent death of singer Michael Jackson availability and prevalence of illicit (non- has focused popular attention on the drug prescribed) or non-medical use of tranquil- (Diprivan) that is relatively un- izing drugs has paralleled their emergence known outside of hospital anesthesiology. into medical markets and constitutes a ma- This drug shares many pharmacological jor problem in drug abuse. This review ad- similarities with a number of tranquilizing dresses a common mechanism, and certain drugs that are widespread and common common effects, shared by the majority of in use and abuse and form the bulk of the currently-available tranquilizing drugs of pharmaceutical money train. The relative widely different chemical families’ action

This article is approved by the following for continuing education credit: (ACFEI) The American College of Forensic Examiners International provides this continuing education credit for Diplomates.

After studying this article, participants should be better able to do the following: 1. Understand the common pharmacological mech- anisms and effects of tranquilizing drugs acting at the brain’s GABA-A receptors. 2. Understand how drug adverse effects of different tranquillizer classes can be involved in forensically- relevant behavior. 3. Appreciate the growth of illicit drug abuse that parallels the ethical, licit, market.

KEY WORDS: , anxiety, tranquillizer, benzodiazepene, , (Ambien), gamma aminobutyric acid (GABA) receptor, automatism, amnesia, disinhibition, hostility, rage TARGET AUDIENCE: Behavioral scientists, forensic examiners, pharmacologists PROGRAM LEVEL: Basic DISCLOSURE: The authors have nothing to disclose. PREREQUISITES: None

www.acfei.com DRUG FORENSICS

at the brain’s GABAA receptors (described lepsy treatment (anticonvulsants), night- tion of GABA at the “Type A” GABA re-

more fully below). Notwithstanding these time relief (), conscious ceptor (the GABAA receptor). They share mechanistic similarities or commonalities, surgical sedation (sedation and amnesia), this mechanism with ethanol, also known however, different members of the class and complete surgical anesthesia (uncon- as beverage alcohol.

also exert actions at non-GABAA sites and sciousness, insensibility). Given in deliber- Like beverage alcohol, the acute effects mechanisms in addition. ate overdose, they are used for pest control of tranquilizing drugs may be forensical- The purpose of this article is to provide and animal euthanasia and—in the United ly relevant in criminal and civil law cases an understanding and appreciation of the States—for prisoner execution, either as a involving driving or operating machin-

shared and common GABAA mechanisms component of a serial drug mixture, or, as ery or other intoxicated, dis-coordinated and effects that tranquilizing drugs medi- recently adopted by the state of Ohio and or disinhibited or impulsive behavior or ate on brain, mind, and behavior in cir- perhaps in other states to come, as a sin- misbehavior or in poisoning, homicide cumstances of forensic relevance. Although gle drug injection (thiopentone). In many or suicide issues. When chronically used the incidence rate of disabling psychotox- cases, the same drug is used for more than (repeatedly taken over time) other com-

ic effects caused by GABAA stimulation is one such intended purpose and most of plex forensic neuropharmacological is- relatively rare in the general population of these tranquilizing drugs—at least in a sues emerge, including dependence and therapeutically-prescribed users, it is higher portion of their pharmacological spec- withdrawal states resulting from changes in the drug abuser population, and in both trum—have in common a shared or closely in brain biochemistry caused by repeated populations of users and abusers, the crimi- related mechanism of action at the recep- use of the tranquilizer. In addition, the nal and civil justice systems act as a sieve to tors on nerve cells in the brain and spi- adaptive changes wrought by these drugs select and concentrate these cases of forensic nal cord for the neurotransmitter GABA. in the brain over time and their interac- interest. Therefore, regardless of the tranquilizing tions with other drugs taken or co-admin- Tranquilizing drugs are used for a vari- drugs’ structural class (barbiturate or car- istered typically need to be accounted for ety of medical purposes: relief of muscle bamate or or imidazopyri- and understood in neuro-behavioral terms spasm (spasmolytics), anxiety relief, treat- dine etc.), they all, to some extent and in (see below) in order to evaluate their fo- ment of panic attacks (anxiolytics), epi- part, act in the brain to facilitate the ac- rensic relevance.

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 17 ta and rho, α, β, γ, δ and ρ subunits) sur- rounding a central pore or channel in the nerve membrane through which chloride ions pass (Levitan et al 1988, cited in Crews (2004)1. In different parts of the brain, and on different nerves, different assemblies of these subunits allow a wide variety of dif-

ferent types of GABAA receptor-linked ionophores to be formed by varying the type and number of subunits. The receptor complex spans the postsynaptic membrane as illustrated schematically in Fig 1, and receptors—neurotransmitter recognition patches for various chemicals or ligands— are formed either on the subunits, or where subunits meet or within the chloride pore itself. In this article, the chloride pore as- sembly responsive to GABA or drug stimu-

lation is referred to as the “GABAA receptor complex.” In contrast to the , benzodi- azepines cannot directly open the chloride channel, but they facilitate GABA’s ability

to do so. Chloride influx at the GABAA receptor complex hyperpolarizes the cell membrane, making it more negatively charged on the interior relative to the ex- Figure 1 terior, which renders it less likely to conduct Schematic representation of the GABAA receptor complex comprised of α, β and γ, subunits forming the chloride an action potential, and thus the effect of ion pore, spanning the nerve cell membrane. Flow of chloride ion (Cl¯) is from outside to inside the cell when GABA binds to its receptor. Receptors are schematically shown for steroid, barbiturate, benzodiazepine, ω = any ligand binding (GABA or ethanol or omega, ethanol (alcohol), picrotoxin and GABA (Gamma Aminobutyric Acid) ligands. drug) is inhibitory on the nerve.

Tranquilizing drug effects on cognitive ticipation of the likely drug effects, and in Common mechanisms, function can influence alleged cognitive either case drug interactions may be para- cross-tolerance disability as relevant to brain injury claims mount in an interpretation and understand- The different types of sedative tranquilizers or compensation issues, or employment ing of consequences on the mind, brain and discussed here each exert a similar facilitato- disability claims, and can interfere with behavior of the consumer. ry effect on the GABAA receptor complex, performance in the neuropsychological but when the tranquilizers are used in com- tests used to evaluate such brain function. Shared mechanisms of different bination, their interaction is multiplicative

Under certain circumstances and in certain tranquilizer types: the GABAA (either additive or potentiated, synergistic, individuals—described more fully below­ receptor complex see below for discussion). It follows, too, —tranquilizer intoxication can influence Gamma Aminobutyric Acid (GABA) is from their shared and common site of ac- “competence at the time of the crime” or the most abundant neurotransmitter in the tion that there is functional cross-tolerance “competence to be tried” and drug-influ- central nervous system, and GABA recep- between these different drugs. Thus a with- enced memory or the absence of this (am- tors are widely distributed throughout the drawal syndrome resulting from discon- nesia) may enter into insanity and legal brain, with high concentrations in the cor- tinuation of ethanol (beverage alcohol) in competence considerations. Where guilt is tex and limbic system. There are two types a dependent alcoholic (“delirium tremens”) not at issue in a criminal case, the effects of GABA receptor (“A” and “B”) of which can be arrested by administering a benzo- of these drugs may nevertheless bear upon the B-type is a metabotropic G-protein cou- diazepine such as or a defendant’s culpability and at sentenc- pled complex and the “A” type (GABAA) is or . Although not recommended, ing may be relevant to mitigation of pun- a ligand-gated chloride ionophore, a chlo- the reverse is probably true as well: alcohol ishment. The issue of voluntary versus in- ride ion channel spanning the thickness of suppressing the withdrawal syndrome re- voluntary intoxication is frequently raised the nerve membrane, which channel pumps sulting from chronic benzodiazepine dis- in forensic cases involving the intended or chloride ion into the nerve-cell upon stimu- continuation. unintended consequences of tranquilizing lation by GABA. drug use, either through lack of notice giv- The chloride ionophores on which Problems of use and abuse en to the user by the prescriber (if medical, GABAA receptors occur are a family of re- The different families of sedative drugs that or the perpetrator, if criminal) or because lated complexes composed of several types act as agonist facilitators, or stimulators, of the illicit user had no understanding or an- of subunits (called alpha, beta, gamma, del- GABA transmission at the GABAA receptor

18 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com fects may relate to competence, disability, or injury evaluation. In the majority of forensic cases involving sedative tranquilizers, including death due to overdose, the drug is combined and interact- ing with another drug. Popular illicit combi- nations include beverage alcohol, stimulants (called “speedballing”), and opiates (called “boosting”, see below for discussion). Forensic cases involving sedative tran- quilizer use (licit) and abuse (illicit) are found throughout the entire spectrum of drug interactions and criminal misbehav- iors. Though their acute use is behaviorally and psychoactively intoxicating, a host of different problems confound their chronic use including sustained memory dysfunc- tion and other cognitive impairments, ex- acerbation of depressed mood, tolerance, dependence, and withdrawal states on dis- continuation of the drug.

History and prevalence of the

GABAA agonist drugs: Current problems of forensic concern caused by tranquilizing drug action are merely the leading edge of an historical wave. In seeking to understand the pres- ent context and future direction of this wave it helps to have an historical under- standing of the evolution, use, and abuse of these drugs. The 1966 novel Valley of the Dolls by Jacqueline Susanne, later made into a film, depicts the recreational, and later compul- sive, use of tranquilizing drugs (the “dolls”) by three young women, who combined these drugs with stimulants . Figure 2 The “dolls” of the story were barbiturates, Schematic illustrating the concept of “therapeutic index” for sedative drugs. Upper graph shows the dose-effect Seconal and Nembutal, and notwithstand- curves for a drug whose death or lethality curve overlaps with the dose-range of the drug’s sedative effect range. ED50 = Effective (sedative) Dose for 50% of the population treated, LD50 = Lethal Dose for 50% of the population ing their calming, euphoric, and subjec- treated. The therapeutic index is small. Lower graph illustrates the case for a drug where sedative and lethal dose tively delicious effect on the anxious user, effect ranges do not overlap. The therapeutic index is larger. their therapeutic index (the ratio, derived in laboratory animals, of therapeutic dose to complex include barbiturates, , and ataxic gait; and neuropsychological and toxic dose, see Fig 2) is quite low. The dif- some anesthetics and steroids, all benzodiaz- cognitive impairment. Cognitive impair- ference between effective and lethal dose is epines, and the now proliferating ‘Z’ drugs ment produced by these drugs, or with- small, and their potential for causing death such as zolpidem (Ambien) and its relatives, drawal from a dependent state on these on overdose is very high. including . GABAA stimulating drugs, may affect a person’s competence and Given the demonstrated market potential drugs have been both used and abused for ability to testify, which becomes relevent in of tranquilization and the public thirst for many years, and the intended and unin- civil and criminal cases. In certain people anxiolytic drugs, the lethal disadvantages tended effects often produce disinhibited and under certain circumstances, violent of the barbiturates led the pharmaceutical and impulsive behavior that exceeds so- rage is provoked by these drugs. Forensic industry into a driven search for less-lethal cially acceptable bounds, such as memory cases involving sedative tranquilizer drug alternatives and in the mid-twentieth cen- impairment; outright amnestic states that effects may involve any one or more of tury several functional analogues of the confound criminal investigation, prosecu- these drug-induced dysfunctions in perpe- barbiturates were introduced: methylpyry- tion and defense; automatisms and som- trators, victims, or witnesses to crime or in lon (Noludar) in 1948 2, followed by glu- nambulistic (“sleepwalking”) states; chemi- law enforcement, judges, counsel, or court tethimide (Doriden) in 1954, then ethyl- cal submission; discoordinated movement personnel. In civil cases, traquilizer drug ef- chlorvynol (Placidyl 3, to which the late

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 19 U.S. Supreme Court Justice Rehnquist less lethal than the barbiturates they quali- sual euphoric state and relaxed intimate was famously addicted) and tatively presented the same spectrum of dis- mood,” and by 1965, it was the best selling (Miltown) in 1955. Meprobamate was the advantages. Pharmaceutical innovation rap- sedative in the U.K. market. By 1972 it was first of the carbamates, having been dis- idly led to the introduction of the sixth most popular in the U.S. market covered serendipitously in 1946 4. Though (Soma, which is still very popular), which and its abuse had reached “almost epidem- these drugs differ chemically and structur- is in fact both a drug and a pro-drug: active ic” proportions (Foltz, Fentiman & Foltz, 7 ally, all are agonists at the GABAA receptor, itself, the body metabolizes it, transforms 1980) . It has since been withdrawn from like alcohol and barbiturates. it, to meprobamate, the barbiturate-like the US market, being placed in “Schedule By 1957 more than 36 million prescrip- described above. Carisoprodol 1” in 1984. tions had been filled for meprobamate in and meprobamate are advertised as muscle Although barbiturates continue as a the United States alone, a billion doses had relaxants, yet they have no direct effect on mainstay of general anesthesia and for use been manufactured, and the drug account- muscles. Their relaxant effect, like that of as anticonvulsants and anti-epileptics, they ed for fully one-third of all prescriptions barbiturates, is mediated at the brain and and their relatives were largely supplanted written in that year 5. It did not take long, spinal cord. for daytime tranquilizer and use however, before the realization dawned that Competing with these agents for the by the following intro- addiction and dependence, with a with- nighttime hypnotic (sleeping pill) market duction of the first of this class, chlordi- drawal syndrome resembling the barbitu- was , another GABAA ago- azepoxide (Librium) in 1960, which dis- rate on discontinuation, had followed the nist drug (synthesized in 1951 and called covery emerged serendipitously from work carbamate family into the marketplace 6. Quaalude or Sopor in the United States and on dyestuffs by Hoffman-LaRoche (now Other than being technically describable Mandrax in Britain). Its specific binding known as Roche) scientists in the mid- for marketing purposes as “nonbarbiturate site on the GABAA receptor complex was 1950s. Subsequent work on the metabo- in structure” (a marketing ploy that which not well defined, but the drug enhanced lite of Librium, , led to the would later be used with the non-benzodi- benzodiazepine binding, which revealed development of diazepam (Valium) about azepine, z-drugs such as its allosteric action at the GABAA com- four years later. Valium was wildly popu- zolpidem, and zopiclone, see be- plex. Methaqualone was introduced in the lar, and by the mid 1970s about 8,000 tons low), the carbamate drugs and their suc- United Kingdom in 1956 and to the Unied of benzodiazepines were sold every year. cessors acted pharmacologically in a simi- States market in 1965. It was described as a Valium maintained the lead for a decade lar way to the barbiturates at the GABAA “safe non-addictive barbiturate substitute.” until Upjohn’s 1981 introduction of alpra- chloride ionophore and, while markedly Drug users and abusers appreciated its “sen- zolam (Xanax) displaced the Roche product as the most popular. Balkrishnan and his colleagues gath- ered six years of outpatient office visit da- ta—between 1996 and 2001—from the National Ambulatory Medical Care Survey (NAMCS) and analyzed the treatment pat- terns of patients 18 and older who report- ed sleep problems. They found that nearly two-thirds of those doctor visits resulted in medication prescriptions for a person’s sleep difficulties, and three-quarters of those pre- scriptions were for a benzodiazepine. (Five of the 13 kinds of benzodiazepines on the market in the United States are indicated for treating insomnia) 8. According to the BioVenturist database, a pharmaceutical industry research tool, worldwide sales of alprazolam, a drug which went generic in 1993, were US$409 mil- lion in 2005, US$316 million in 2006 and US$325 million in 2007. According to IMS Health Data, a pharmaceutical marketing intelligence agency, annual sales of alpra- zolam ER tablets (the “extended release” form) in the United States were approxi- mately $53.9 million for the 12 months ending December 2006 9. As with earlier generations of sedative tranquilizers, illicit use has paralleled licit use: In this same year, 2006, as reported by the National Forensic

20 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com Laboratory Information System 10, state and not occur in isolation. Thus ‘automatism’ but the active metabolite desalkylfluraze- local drug laboratories analyzed 24,057 al- invariably involves ‘amnesia’ and amnesia pam has a half-life of 47-100h (average 89 prazolam, 6,360 , 5,886 diaz- may involve confabulation and the organ- hours). epam, 1,444 lorazepam, and 333 temaze- ic brain disorder that is the intoxication In contrast to these, the short acting ben- pam exhibits. These exhibits, of course, are itself impairs neuropsychological and cog- zodiazepines such as alprazolam (t ½ 6-27 but a very small fraction of the number of nitive function. Any or all of these may be hours, average 12 hours), (t ½ doses actually seized by law enforcement. present when the drugged individual dis- 4-11 hours, average 8 hours) and triazo- Z-drugs such as zolpidem (the tartrate plays disinhibited behavior, which may be lam (t ½ 1.8-3.9 hours, average 2.5 hours) salt of which is trade-named Ambien in violent. In this article these different facets do not generate active metabolites. Of the the United States and Stilnox or Stilnoct of drug effect are addressed as separate yet z-drugs currently available, , elsewhere) is one of several structurally related entities in order to more clearly de- sold as the hypnotic Lunesta, has the lon- imidazopyridine GABAA agonist drugs to fine them, but the reader is cautioned that gest half-life of 4-9 hours. Nightly dosing be recently introduced. The development this distinction is artificial. of long-lived drugs inevitably leads to an of this ‘non-benzodiazepine’ imidazopyri- accumulation of drug in the body during dine family of drugs, added greatly to our Neuropsychological impairment daytime hours and unintentional carry- understanding of the GABAA receptor com- and kinetics over of daytime effects and drug interac- plex and led to the discovery that there were At higher doses than typically employed tions may occur, for instance with alcohol three subtypes of what had been hitherto therapeutically in the ambulant patient, consumed the day following a long-acting called benzodiazepine receptors on the the barbiturates and benzodiazepines pres- drug’s nighttime use. This likelihood in-

GABAA complex, at one of which zolpi- ent a similar alcohol-like clinical picture of creases, of course, the earlier in the day that dem shared agonist (stimulating) properties. intoxication with sluggish movement, in- alcohol is consumed, and early drinking is Flumazenil (then known as Ro-151788), coordination, difficulty in thinking, slow- not uncommon in alcohol abusers. the ‘specific antagonist’ of benzodiazepine ness of speech, faulty judgment, drowsiness, An appreciation of pharmacokinetic dura- binding to its GABAA receptor, also antago- staggering gait, and shallow breathing, with tion is vital to an assessment of drug influ- nizes the action of z-drugs, such that they unconsciousness and coma occurring at the ence on the neuropsychological evaluation are pharmacologically, to all intents and largest doses. Death at these higher doses (Stein & Strickland 1998)14. For patients purposes “non-benzodiazepine benzodiaz- occurs due to respiratory depression of the taking chronic doses steady state concentra- epines.” This nomenclatural dilemma was brain’s medullary respiratory centers or po- tions in blood are reached after about four resolved by renaming the benzodiazepine sitional asphyxia or inhalation of vomitus half-lives. Depending on dose schedule this receptors to which z-drugs bind “omega” while unconscious, or some combination of can be a period as long as several weeks for a (ω) receptors, of which z-drugs are now these. At lower doses the acute neuro-be- healthy young adult. Recently discontinued said to have activity at the brain’s ω 1 sub- havioral intoxication resulting from sedative use also introduces considerations of neu- type. Z-drugs such as zolpidem differ from tranquilizer drug effects can be measured ropsychological relevance because complete the benzodiazepines in exerting a sedative by tests of neurocognitive performance, drug elimination takes approximately six effect at a dose much lower than their an- similar to the tests used by neuropsycholo- half-lives. Further, since discontinuation of ticonvulsant effect (Depoortere 1986)11. gists to assess brain dysfunction resulting short-acting agents produces a more precipi- Zolpidem has a very short half-life and from trauma. tous drop in serum level than long-acting is marketed as a hypnotic (a sleeping pill). Benzodiazepines adversely affects mem- agents, the withdrawal syndrome and men- It was the second z-drug to be introduced, ory, a fact first reported by Greenblatt & tal and cognitive disequilibrium caused by debuting in 1992 after zopiclone (1989) Shader (1974)12 and later confirmed in the former is more intense than the latter. which was not introduced to the U.S. mar- clinical trials. The intensity of this amnestic Least affected by benzodiazepine action ket but was popular elsewhere. The third effect varies according to route of adminis- is short-term memory storage capacity, as was zaleplon (Sonata, a pyrazolopyrimi- tration, dose and pharmacokinetics (Roth et required for digit recall, and procedural dine) and the fourth to be introduced was al 1984)13. In general, the benzodiazepines memory (recollection of previously-learned the S-isomer of zopiclone, called ‘eszopi- with the longest mean duration of effect actions, such as how to drive a car). While clone’ and sold in the United States under have long-lasting parent molecules, active information learned prior to drug use is the trade name Lunesta. A fifth, indiplon, and persistent metabolites, or both. Thus retrievable, recollection of information has 10 to 15 times the binding capacity of (Librium) has a half-life (t learned under drug influence is impaired zolpidem or zaleplon, and has not yet been ½ ) of 6-27 h (average 20 hours) and diaz- (see amnesia below). Most importantly: sed- commercially released at time of writing. All epam (Valium) has a t ½ of 21-37 h (aver- ative effects do not predict amnestic effects, of these z-drugs seem to act in the same way age 24 hours), and (Tranxene) which occur with or without sedation. pharmacologically at the GABAA receptor, has a t ½ of only 2 hours, yet each of these (Versed), in many ways a

ω subtype. drugs are converted, metabolized, in the liv- typical GABAA agonist benzodiazepine, is

er to active GABAA stimulating compounds used for intravenous sedation prior to sur- The various forensic aspects of including nordiazepam, which has an ex- gery. Anesthesiologists, surgeons and den- tranquilizer intoxication tremely variable and protracted half-life of tists are well aware that perioperative recall In actual practice the different concepts 31-96 hours (average about 60 hours) [see of information is reduced or obliterated in explained below, the range of forensically- Table 1]. Likewise, (Dalmane) patients who have undergone midazolam relevant effects that GABAA drugs exert, do has a half-life in blood of only 1-3 hours, sedation. The amnestic effect also occurs

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 21 Table 1 Drugs referred to in this article (in alphabetic order) showing their chemical class, their GABAA activity and their marketed purposes. Note that all benzodiazepines (=Benzo) exert , anxiolytic, sedative and anticonvulsant effects regardless of marketed purpose. Abbreviations used: Barb = barbiturate, Metab = metabolite, Dep = dependant, Half-lives taken from Baselt (2008)69 Marketed Purpose

t ½ Trade GABA Generic A Half-life CLASS Name activity Name (hours) hypnotic anxiolytic Anti-convulsant Muscle relaxant Muscle Surgical

Alprazolam Xanax Yes 6-27 Benzo • • Alphaxolone Althesin Yes 6-8 min • • Alphadolone (mixture) Yes 30min Neurosteroid • • Amylobarbitone Amobarbitone Yes 15-40 (dose dep) Barb • • Buprenorphine Subutex No 18-49 (sublingual) Opiate Carisoprodol Soma Yes 0.9-2.4 Carbamate • hydrate alphachlor Yes 4min (10h • trichloroethanol)) Chlordiazepoxide Librium Yes 6-27 Benzo • Clonazepam Klonopin Yes 19-60 Benzo • • Clorazepate Tranxene Yes 2h( metab 31-97h) Dexamphetamine amphetamine No 7-34 (urine pH) stimulant Diazepam Valium Yes 21-37 Benzo • • • • Eszopiclone Lunesta Yes (w) 4 - 9 z-drug • Placidyl Yes 16-32 Carbinol • Fentanyl Duragesic No 3-12 Opiate Flumazenil Anexate Yes 0.7-1.3 Benzo Antagonist Overdose rescue Rohypnol Yes 9-25 Benzo • Flurazepam Dalmane Yes 1-3 (47-100 Benzo • metabolite) Indiplon (not yet named) Yes (w) 1.5-2.0 z-drug • Lorazepam Ativan Yes 9-16 Benzo • • Meprobamate Miltown Yes 6-17 Carbamate • • Methadone Methadose No 15-55 Opiate Methaqualone Quaalude Yes 20-60 • Methylprylon Noludar Yes 7-11 Piperinedione • Midazolam Versed Yes 1-4 Benzo • • • Oxazepam Serax Yes 4-11 Benzo • Nembutal Yes 15-48 Barb • Propofol Diprivan Yes 1.5-2.5 diisopropylphenol • • Rozerem No 0.5-2.4 -mimetic • Seconal Yes 22-29 Barb • • • • Restoril Yes 3-13 Benzo • Thiopentone Pentothal Yes 6-46 Barb • Halcyon Yes 1.8-3.9 Benzo • • • Zolpidem Ambien Yes (w) 1.4-4.5 z-drug • Zopiclone Imovane Yes (w) 3.6 - 6.5 z-drug •

22 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com Figure 3 Multiplicative effect of drug combinations: schematic illustration of additive (left) and potentiated or synergistic (right) drug interaction. In the case of additivism; combining drugs “A” and “B” gives an effect that is the additive sum of the component drug effects. In the case of potentiation the effect of combining drugs C and D is to give a more- than-additive effect. The case is illustrated where an entirely sub-effective dose of drug C is combined with an effective dose of drug D to produce an effect vastly greater than either drug combined (dotted line). with lower-than-surgical doses. Thompson cause similar neuropsychological impair- the 1950s, and there is evidence for larger et al (1999)15 employed a computerized ments. Wilkinson (1995)16 investigated the doses producing additivism of effect while neuropsychological test battery to assess effect of a 10mg dose of zolpidem (the typi- the lower doses produce a potentiation or the effect of midazolam on normal volun- cal hypnotic dose) and a 15mg dose on 24 more-than-additive synergism. The dis- teers administered 3mg of the drug intra- normal volunteers subjected to a cognitive tinction is illustrated schematically in Fig venously, contrasting this with the effect test battery, comparing responses to place- 3. Thus: while an ethanol dose of 3 mg/ of (“laughing gas”). They bo. Subjects were assessed at peak time (45 kg in rats has no effect on sleeping time found that both simple reaction time and minutes) and again at 130 and 230 minutes in this species, and 30 mg/kg thiopentone choice reaction time are significantly ex- post-dose. At 45 minutes the drug degraded (Pentothal) produces an average 24 min- tended by midazolam. The drug signifi- divided attention performance, impaired in- ute sleeping time, the combination of these cantly impairs decision time and signifi- formation processing rate (measured with doses causes an average sleeping time of cantly degrades digit vigilance and impairs a visual backward masking task), impaired 217 minutes (Wiberg et al 1969, cited in the ability of subjects to retain spatial infor- immediate memory (measured with the Calabrese 1991)17. Likewise Seconal (seco- mation as measured by the spatial working Sternberg task) and degraded sustained at- ) at a 50 mg/kg dose in mice pro- memory test, although they found that it tention measured with a vigilance task. duces sleep lasting 11 minutes on average, does not affect spatial recognition accuracy. Clearly, a person—either perpetrator or and a 1.95 mg/Kg dose of ethanol produces Immediate word recall performance was se- victim or witness—under the influence of no sleep in this species, yet the combina- verely affected by midazolam, and subjects a drug acting as an agonist at the GABAA tion results in 137 minutes of sleep (Gruber committed significantly more word recall receptor could suffer memory and recall 1955)18. Otherwise non-lethal doses of al- errors (“remembering” words that had not impairments that could interfere with cohol when combined with a GABAA tran- been presented) compared with controls. their ability to function as a as a witness. quilizer can readily cause death, as separate- Delayed word recall performance was sig- Although likely of little practical conse- ly befell musicians Janice Joplin and Jimi nificantly impaired, was actually abolished quence in the day-to-day life of the general Hendrix, with alcohol plus barbiturate, in by midazolam—because subjects could population, who might forget where they 1970, and the persistent vegetative state recall no words at all—and delayed word parked their car, or placed their keys, such into which Carol Ann Quinlan slipped in recognition performance was markedly im- deficits may have major importance in a 1976 followed a diazepam-alcohol interac- paired, as were response latencies in tests of criminal forensic context. tion. She died of pneumonia nine years later picture recognition. They found a signifi- without regaining consciousness. cant degradation of the ability of subjects Drug interactions At sub-lethal doses the interactive ef- to discriminate between original and newly : Abusers of sedative tranquiliz- fect of GABAA tranquilizers and alcohol presented stimuli. ers very commonly intentionally consume is largely additive in man when measured The z-drugs of the Ambien (zolpidem) them with alcohol which markedly increases using performance tests at post-peak blood family of hypnotics – including zopiclone, the subjective “high” of both drugs. The ef- concentrations. Linnoila et al (1990)19 test- eszopiclone, zolpidem etc. (see above)— fect was first noted with the barbiturates in ed the acute effects of alprazolam (Xanax,

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 23 speed, both drugs impaired performance and the combination was again additive. Likewise with the vigilance task; alcohol and zolpidem produced additive impair- ment. Interestingly, at the final evaluation four hours after zolpidem administration, performance on all tasks was within the normal range, except for the divided atten- tion task: thus, although the zolpidem effect had dissipated and the alcohol effect had dissipated, the combination still impaired divided attention even though sedation or drowsiness (measured by the backward masking test) was no longer present.

Stimulants: Among abusers of stimulant drugs (cocaine, amphetamines, meth- ylphenidate) sedative tranquilizers blunt the agitation and anxiety which occurs as a side effect of stimulant action, allays to some extent the paranoia attendant on chronic use and adds a dimension of tran- quility to their jaw-grinding state of hyper- excitability and tension. In this they follow the designs of the pharmaceutical compa- nies such as SmithKline, developer of the Dexamyl (or Drinamyl) formulation that combined amylobarbitone with dexam- phetamine until this was withdrawn from the market in 1981 (see below). The illicitly co-administered combination is generically 2mg) in the presence and absence of alcohol the number of words correctly recognized called “speedballing,” although that term in normal volunteers, measuring psychomo- (recognition memory). The effect of etha- can also be used to refer to opiate-stimu- tor and cognitive performance. Ethanol was nol, in this paradigm, appeared to be addi- lant combinations. Stimulant abusers also administered three hours after drug, thus tive with that of the benzodiazepines. employ GABAA agonists to self-medicate avoiding the initial period of synergism or A similar additive effect has been found the psychically painful ‘crash’ of withdraw- potentiation sought by abusers who typi- when alcohol is co-administered with zolpi- al when their stimulant supply has dried cally consume the drugs together. These dem (Ambien). Wilkinson (1995)20 admin- up or they otherwise need to end a speed authors employed a continuous tracking istered to normal volunteers a dose of etha- run, having been continuously sleepless for task resembling a driving simulator, test- nol calculated to produce a blood alcohol many days. ed verbal information processing with a concentration of 0.08g% (80 mg/dl, the Although tranquilizer abuse, unlike stim- word-choice reaction time task and provid- legal level of presumptive intoxication for ulant abuse, does not as a rule itself provoke ed a verbal memory task using a list of 12 fitness-to-drive purposes in the USA for outright psychosis, the ameliorative effect words, six of which were presented twice. non-commercial drivers) over 30 minutes of combining tranquilizers with stimulants The subject was to indicate their recogni- of consumption, following this with either can enable the combined user to take more tion of the repeated word and the word list 10mg or 15mg of zolpidem (Ambien) or of the stimulant for a longer time and to served also to assess recognition memory placebo. Subjects were then subjected to a suffer more severely from chronic stimulant and delayed recall. Blood ethanol concen- neurocognitive performance battery at 45, psychotoxicity. Such psychotoxicity can in- tration was assessed by Breathalyzer, and the 130, and 230 minutes post-dose. The de- volve many of the features usually associated study began with a blood concentration of sign was fully blocked, so that the effect of with the acute psychotic break of a chronic 65 mg/dl. Measured 4 hours after drug ad- drug or alcohol alone could be compared schizophreniform psychosis, with paranoia, ministration (1h after ethanol) alprazolam with the combination, and a placebo bev- hallucinations (auditory, visual and tactile), produced a severe deficit in performance erage drunk from a glass externally scented delusions, grandiosity and hostility born of on the word tests (memory) and the effect with vodka served as the alcohol control. irrational fear. of ethanol on this performance was to de- Measured at peak zolpidem time (45 min- grade it further. Immediate verbal memory utes) both zolpidem and alcohol degraded Opiates: The combined use of tranquil- was unimpaired, but at 2 hours there was a divided attention, and the combination was izers and opiate drugs is not strictly con- significant reduction of related word recall additive. On the visual backward masking traindicated in medical treatment and the (free recall) and a significant reduction of task, testing for information processing combination of midazolam (Versed) with

24 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com an opiate such as fentanyl is common in istration. Rapeli et al (2009)23 followed a and alcohol are also anticonvulsant (anti- surgery where the effect is carefully super- group of anxiolytic-prescribed patients who epileptic) in their effects, withdrawal from vised and controlled. Likewise chronic pain were also enrolled in an opiate substitution a dependence on these drugs can precipi- patients are often prescribed both opiates program. Thirteen took daily methadone tate a seizure state, and this can be provoked and GABAA drugs (benzodiazepines, car- and 15 daily buprenorphine as opiate sub- even in individuals who did not suffer from bamates, barbiturates or “muscle relaxants”) stitution. The GABAA drugs used by the epilepsy before tranquilizer use. for an extended time without experiencing group included alprazolam, clonazepam, The withdrawal symptoms that occur on too many problems in performing activi- diazepam, oxazepam, midazolam, temaze- discontinuation have “rebound” intensity, ties of daily living although they do suffer pam, zopiclone and zolpidem. The authors greater than existed before tolerance to the neuropsychological impairments as a result studied these patients initially upon enroll- drug had developed. Thus anxiety treated (see below). The same is true of patients in ment into the substitution program with benzodiazepines is more intense after opiate substitution programs equipped and and again between 6-9 months after admis- drug withdrawal than it was before treat- staffed to handle “multiple drug” abusers. sion. Patient groups were compared with ment began, and panic attacks (discrete The combination is not without hazards, a parallel group of non-drugged normal periods of intense fear and discomfort) however, as epitomized by the 2007 death subjects tested at the same time intervals. can be precipitated by abstinence (Bashir of Anna Nicole Smith, who expired under Rapeli et al found that Working Memory & Schwartz, 2002)14. the influence of prescribed methadone and (the short-term store that maintains infor- benzodiazepines. The greatest problems of mation that is lost without repetition), test- Addiction: The word “addiction” has un- forensic concern arise when tranquilizers ed with the Letter-Number Sequencing task dergone some linguistic contortions in re- are used intermittently or abusively in the from the Wechsler Memory Scale III, was cent years. Current medical policy in the opiate-consuming population. The com- markedly impaired in patients compared pain management field is to avoid using the bination acutely enhances the euphorically with normal controls. This deficit was per- word to describe the craving a patient feels subjective “high” of the opiate experience sistent across 6-9 months of constant drug for a legally prescribed drug and to use the and is particularly attractive to opiate ad- dosing, and no tolerance was shown to the term “pseudo-addiction” instead (Weissman dicts or poorly-controlled chronic pain pa- effect. List-learning was more impaired in and Haddox 199326, Fishbain 200327), re- tients. Illicit combined use is considered a the buprenorphine-treated group, and this serving the word “addiction” to characterize major problem by opiate treatment provid- confirmed an earlier finding by Lintzeris et the dependence state and resulting behav- ers in single-modality opiate (methadone al: that buprenorphine combined with diaz- iors of the illicit (non-medical, non-pre- or buprenorphine) substitution programs, epam impairs delayed verbal memory more scribed) drug user. Pharmacologically this where users may illicitly self-medicate with than buprenorphine given alone (Lintzeris, is probably a distinction without a differ- tranquilizers before reporting for their dai- Mitchell, Bond et al, 2006)24. ence. Behaviorally, however, addiction (as ly supervised opiate dose, a practice called opposed to dependence) is usually mani- “boosting” (Kleber, 1994) 21. Addiction and dependence fest as a lack of self-control over dose esca- Although substitution programs perform Dependence: The tranquil relief of anxiety lation despite adverse consequences. The urine testing on patients, they typically do that GABAA drugs induce is dependence- term “pseudoaddiction” as applied to opi- not test blood and unrinalysis results do forming, in the sense that tolerance devel- oid-treated pain patients taking more drug not indicate current intoxication. Thus ops to their effects when used chronically, than prescribed in pursuit of adequate pain behavioral intoxication involving over-se- and changes in the brain which underlie relief is now the preferred term adopted by dation resulting from “boosting” can lead this tolerance reflect a readjustment of the the International Association for the Study to traffic accidents, and overdose death due homeostatic balance of brain chemistry of Pain (IASP 1993)28. Since there is rarely to combined respiratory depression is not counter to the action of the drug. Once any medical need to prescribe beverage al- uncommon. Backmund et al (2005)22 stud- adapted to the drug’s effect, the brain of the cohol, the term is unlikely to gain currency ied the records of 1,685 patients admitted user undergoes a withdrawal syndrome in in the alcohol addiction field. for opiate detoxification, finding that dai- the absence of the drug, and it is this con- In a protocol for which it would be im- ly intake of benzodiazepines was reported dition from which the withdrawal state is possible to get Institutional Review Board in 44.4% of the patients. Patients treated precipitated that is called “dependence.” approval nowadays; a study performed in with methadone or codeine medications The withdrawal syndrome takes the form normal volunteers in 1958 gave the GABAA reported daily intake of benzodiazepines of symptoms opposite to the drug effect. drug meprobamate several times daily for significantly more often than the heroin- Whereas GABAA stimulation is tranquiliz- 40 days before the drug was then abruptly dependent patients. ing, peaceful and soporific the withdrawal withdrawn. The subjects suffered insomnia, Forensic consequences of combined use syndrome is anxious, agitated and insom- vomiting, tremor, muscle twitching, overt may relate to malpractice claims when the niac. The development of early-morning anxiety and some of these subjects suffered drugs are prescribed unsupervised or in er- awakening that occurs after triazolam (a convulsions 36 to 48 hours after discontin- ror and to civil liability issues when a traf- benzodiazepine) is used for two weeks as uation (Hazilip & Ewing 1958)29. These fic accident or death or injury occurs, and a bed-time hypnotic is an example of the signs and symptoms are facets of, and com- third-party claims may be involved. effect of tolerance. Once this change has mon to, the alcohol withdrawal syndrome In neuropsychological terms, the memory occurred and the brain has adapted to the or “delirium tremens” and the commonality deficits caused by the GABAA stimulating drug’s presence, abstinence from use causes lies mechanistically at the GABAA receptor drugs are magnified by opiate co-admin- insomnia. As barbiturates, benzodiazepines complex.

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 25 tirely lose consciousness, appears tranquil, intoxicated, often talkative prior to receiv- ing their later anesthesia, yet none of this is later recalled as a result of anterograde am- nesia. To proceed with surgery actual loss of consciousness is required, often induced by intravenous propofol, a non-benzodi- azepine anesthetic agent also acting at the

GABAA receptor. This is a white-colored, milky, oil emulsion that is sometimes jok- ingly described by anesthesia staff as “milk of amnesia” which, as earlier mentioned, recently achieved notoriety in the death of singer Michael Jackson (Mundy 2009)30. Flunitrazepam (Rohypnol), the aforemen- tioned benzodiazepine often abused by youth for its drunken alcohol-like intoxicat- ing effect, is likewise known on the street as “mind eraser” and “forget pills’”(Daderman & Lidberg 1999)31. Although the 10mg dose of zolpidem is typically used for night- time sedation, larger doses have been em- ployed as pre-operative tranquilization. In one such study comparing 20mg of oral zolpidem with 15 mg of IV midazolam, zolpidem produced significant anterograde amnesia from 30-60 minutes after adminis- tration in 45% of patients, nearly the same percentage as those given 15mg of midazo- lam (Pahud et al 1988)32. The anterograde amnesia phenomenon has been well studied in the laboratory, and in regular users of the drug is most well associated with rising blood levels in the period following dose administra- tion. An early reported study (Kumar et al 1987)33 gave either alprazolam 0.5mg or lorazepam 1 mg to normal volunteers three times daily. On the sixth day they were The anxiety, craving, panic, and despera- dation. Memories are not later retrievable, tested using a 16-word-list in an immedi- tion that the dependent sedative/tranquil- because they were never transferred from ate and a delayed recall paradigm before izer abuser suffers can drive them to breach short-term to long-term storage. The am- and 2 hours after dosing. On this repeat- laws and conventions to maintain their sup- nesia is anterograde, proceeding forward in ed dosing schedule no deficit was found ply, either by theft or deception. Such in- time from the intoxication, and in this it in immediate recall pre-drug (when blood dividuals can easily find themselves outside differs from the retrograde amnesia of brain levels were lowest) but there was impair- the law and subject to forensic evaluation. concussion. The “alcoholic blackout” phe- ment of delayed recall for the list learned

nomenon is an example of GABAA agonist 2 hours after dosing (when blood levels Amnesia and automatism anterograde amnesia. Amnesia can either were highest). No deficit was found in the Generally speaking, amnesia is never a be an unfortunate and problematic side ef- recall of already-learned material. defense to a crime, yet automatism may fect of treatment or drug use or abuse, or it Amnesia resulting from GABAA agonism be a complete defense, and the forensic can be intentional, as for instance when the leaves the subject with a memory blank that challenges presented by investigation of a benzodiazepine midazolam (Versed, men- is discovered after the drug intoxication, yet case in which the defendant or victim has tioned above) is medically used to produce during the course of the intoxication im- no memory of the offense can be quite tranquility and amnesia in patients under- mediate (short-term) memory is intact, and formidable. going surgery. The last thing the patient the subject may function in an automatistic Resulting from an action on the hip- recalls on awakening in the recovery room state, able to walk, talk, respond and engage pocampus, where short-term memory is having received their midazolam injec- in often apparently complex tasks although is consolidated into long-term storage, tion in the preoperative suite. Under the these cannot later be recalled. The subject

GABAA agonist drugs prevent this consoli- drug’s influence the patient does not en- does not appear to be sleepwalking to an

26 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com observer (but see below) and can respond lished examples of GABAA stimulated au- criminal culpability. He was described by to conversation in an apparently superfi- tomatisms include: friends and family at the trial as otherwise cially meaningful way. Numerous examples “taking a bath with a raincoat on… the “politest, gentlest person imaginable.” of such automatisms with residual amnesia Dr. Ian Hindmarch of the University of have been published in the scientific liter- …going to the dentist at night, having con- Surrey, professor of human psychophar- ature, often self-reports of a scientist trav- fused 11 AM and 11 PM… macology, testified for the defense regard- eling to a professional meeting and taking ing ‘non-insane automatism’ induced by the drug on their outbound international … pruning rosebushes in the middle of the Ambien (BBC 2003) 38. air travel to assist with jet lag: they arrive at night… cutting up furniture with a chain- their destination, clear customs and pass- saw” (Pompidou 2001, infra41) … Disinhibition port control, taxi to their hotel, attend a re- The frontal lobes of the brain exert inhibi- ception, and on awakening the next morn- …crawling in the hallway at night, the pa- tory influence on lower brain areas, and ing their last recollection was of being in tient told the nurse he was going to mass (Yang serve executive functions in decision-mak- the aircraft (Morris & Estes 1987)34. It is et al 2005)37 ing, planning, prioritizing, and execution. only through eye-witness reports that the GABAA agonist drugs, in common with amnestic, automatistic, episode can be re- When the subject is well-known and the beverage alcohol, reduce this inhibition. constructed. event occurs in public, the popular press is The effect can be intentionally produced,

Although apparently genuine cases of involved. This was the case in March 2003 as in the prescription of GABAA agonists “sleepwalking” have been reported to have when Peter Buck, the then-45-year-old gui- to reduce the anxiety component of path- been induced by z-drugs, particularly zolpi- tarist for the musical band REM, went on ological ‘shyness,’ or the use of alcohol as a dem, the majority of such nocturnal ambu- trial after being charged in April 2003 with social lubricant. Persons acting under the latory episodes are most probably autom- a string of bizarre and out-of-character inci- influence of GABAA agonism are more im- atisms. The distinction between the two dents attributed to him while flying the 10- pulsive, more spontaneous and more likely can be subtle, but in sleepwalking speech is hour trip from Seattle to London, Heathrow to act without regard to consequences (see usually incoherent and the subject is largely (BBC 2003)38. He pled not guilty to one below). This was earlier noted in regard to unresponsive to their environment, their charge of being drunk on the aircraft, two the barbiturates (Baraclough 1976)39 and behavior incongruous to circumstances counts of common assault involving head has continued through the evolutionary (Harazin & Berigan 1999)35 and this is not steward Mario Agius and steward Holly and sequential introduction of other, new- the case in automatisms. Ward (covering them in yogurt), and one er, GABAA agonists. This disinhibition can Automatisms with residual amnesia usu- charge of damaging British Airways crock- be particularly problematic in individuals ally occur when the subject has taken more ery. The trial took place at west London’s with pre-existing frontal lobe impairment of the drug than prescribed or is prudent, Isleworth Crown Court. Cabin staff aboard such as frontal dementia or an attention often inadvertently, and the interaction of the British Airways 747 spoke of him try- deficit disorder, but even in persons not so the GABAA drug with alcohol has a similar ing to load a CD into a hostess trolley, up- afflicted the effect of GABAA agonism is of- effect to drug overdose through an addi- ending it and sending a cascade of crockery ten a component in impulsive crimes. The tive or synergistic process described pre- and food across the floor, and then attempt- subject usually describes their behavior as viously (supra). The phenomenon may or ing to slip a knife up his sleeve as he helped being “out of character.” Perpetrators un- may not be characterized by behavioral clear up the mess. At another stage, it was der the influence of GABAA agonists may dyscontrol (which, when it occurs, can claimed, Mr. Buck had to be pulled away impulsively steal and victims of involuntary be violent). More commonly the subject from an exit door after announcing he intoxication acting under GABAA agonist simply walks, talks and acts in an unchar- wanted to “go home,” before swearing at influence may impulsively and disinhib- acteristic manner and has no memory for Captain Tom Payne when presented with itedly have sex with relative strangers or the events after waking from the sleep that a “yellow card” warning him to change his persons they normally would not choose follows. Adverse experience reports (AERs) behavior or face arrest. as sex partners. If the dose is high enough of the more behaviorally deranged cases Mr. Buck had been flying to London to they may not later recall their “voluntary” abound in the scientific literature, how- perform at the Nelson Mandela concert in participation (amnesia, see above) 40. Other ever. An early report was of the case of Trafalgar Square. He said that he “blacked examples of disinhibition reported in the “Ms. A,” who while treated with alprazo- out” until he woke up in a police cell. The scientific literature include: lam (Xanax), drank approximately three court was told that he did not remember ounces of 80-proof whisky, broke into allegedly upending a hostess trolley, did not “very high-society Mrs. Z defecated in her bed her neighbors’ house an hour later, and remember swearing at the captain, and did with great satisfaction while being examined “smashed everything in sight,” destroying not remember ripping up a “yellow card” by [an eminent doctor] approximately $50,000 worth of property warning him to behave or face arrest. and inadvertently sustaining lacerations to Mr. Buck asserted that he had taken a … a 36-year-old man engaged, in front of a both wrists from broken glass. Returning tablet of Ambien with a glass of wine at the witness and without restraint, in a sexual act then to her house she fell asleep and upon beginning of the trip, and through his attor- normally practiced alone wakening had no memory of the offense— ney claimed that what followed constituted only vague recollections of the sounds of a state of “non-insane automatism,” which … after receiving a 30mg dose of diazepam a breaking glass (Terrell 1988)36. Other pub- under English law is an absolute defense to 30-year-old woman removed her clothes and

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 27 made lewd and direct propositions, in front randomized to alprazolam experienced early investigated using diazepam (Valium) of a witness… “paradoxical’”rage reactions, compared with by Cherek et al (1987)58 who used a finan- … a doctor uncharacteristically swearing none given placebo (Gardner & Cowdry cial game paradigm in which subjects sat during a [morning] vaccination session—at 1985)51. A Swedish study of juvenile offend- before a console having two response but- midday he was under the impression he had ers who abuse flunitrazepam (Rohypnol, or tons labeled A and B. They were told that not gone to work that morning” (Pompidou “roofies”), usually in combination with alco- they were randomly paired with another, 2001)41. hol, found that impulsive violence was asso- unseen, person in a situation described ciated with high scores on verbal aggression to them as one in which they could earn Very rarely the form of disinhibitory be- and boredom susceptibility in personality money (“points”) by pushing button A havior may have qualities of mania; a par- tests (Daderman & Lidberg 1999)52. Even and could influence the amount of money oxysmal excitement, with insomnia, racing in individuals not psychiatrically diagnosed, (“points”) earned by the other individual thoughts and increased energy, and this however, extreme interpersonal frustration they were paired with by subtracting mon- has been reported in patients both with is a recognized trigger of GABAA agonist- ey from them (punishing them) by pushing and without pre-existing bipolar disorder. associated hostile outbursts (Karch 1979)53. button B. They were told the other person Reported initially as a rare manic reaction Neuropsychological dysfunction may also could do the same to them. Pressing but- to benzodiazepines (Strahan, Rosenthal, provide a constitutional vulnerability to ton A was in fact maintained by a fixed ra- 42 Kaswan & Winston 1985) , the same has GABAA agonist induced rage: in a study of tio (FR) 100 schedule of point presentation. occasionally been reported in persons who 38 patients given clonazepam (Klonopin), Each point delivery (“earned”) was indicat- have taken zolpidem (Hill, Oberstar & eight subjects who experienced aggres- ed on a counter mounted next to Button Dunn 2004)43. sive outbursts were found to have mean A and each point was given a value of ten differences of 17.5 points between verbal cents. Pressing button B ostensibly delivered Violent dyscontrol, hostility IQ (VIQ) and performance IQ (PIQ) as point subtraction (punishment) to the oth- and rage measured by the (adult or child) Weschler er person and was defined as “aggressive”— Rage and violent dyscontrol are a special Intelligence Scales. The 30 patients who completion of each 10 presses on button B case of GABAA agonist-induced disinhi- did not react with rage had mean VIQ-PIQ ostensibly subtracted one point (ten cents) bition. The production of violent rage re- differences of only 6.5 points (Rosenfeld from the paired opponent participant and quires both a lack of self-restraint and the et al 1987)54. Such a VIQ-PIQ difference started a provocation-free interval of 125 or presence of a motivating anger. In certain is often associated with antisocial person- 500 seconds. persons and under certain circumstances ality traits. Unknown to the participants was that

GABAA agonism evokes both. Ingram and A history of anger management prob- there was no “other” opponent, and point Timbury (1960)44 first reported danger- lems and of alcohol abuse may predispose subtractions (provocations) were automati- ously aggressive dyscontrol and rage under the individual to belligerence under GABAA cally scheduled to occur at random times benzodiazepine influence resulting from drug influence. A recovered female alcoholic throughout the session. In the absence of chlordiazepoxide (Librium) use. DiMascio given midazolam preoperatively for dental any aggressive action (pressing button B) & Shader (1970)45 reported the same result- surgery became so abusive and aggressive on their part, subjects were scheduled to ing from diazepam (Valium) use and Bladin after receiving an 18mg dose that surgery receive 40 point subtractions per session. (1973)46 reported on clorazepate provoking had to be aborted (Fiset et al 1992)55. Her Thirty minutes prior to each session sub- such hostile dyscontrol, and the phenom- belligerence continued for 24 hours and the jects received a gelatin capsule containing enon came to be recognized as a rare “rage woman afterward claimed no recollection of either placebo or diazepam at a dose of 2.5 reaction” (Gardos 1968 47, 1980 48). The the events. Yet no such predisposing history mg, 5 mg, or 10 mg per 70Kg of their body phenomenon was originally thought to was reported in the case of a similar surgi- weight. be—and was called—“paradoxical” rage, cal misadventure, with amnesia following, Subjects completed two questionnaires: since these drugs typically reduce, or were of a woman under conscious sedation with a self-inventory (Profile of Mood States, expected to reduce, the emotional condi- midazolam undergoing breast implant in- POMS) and the Buss-Durkee Hostility tions from which hostility might emerge. It sertion. Surgeons reported that force was Questionnaire at the end of the study. early became apparent, however, that albeit required to control her (Rodrigo 1991)56. Five of the seven subjects tested had re- rare in the general population, the reaction Hostility has also been reported in con- duced aggressive responding under diaz- is not in fact “paradoxical” but is reliably trol subjects and in normals under labora- epam influence at the highest dose, one produced in certain persons under certain tory conditions. Although such laboratory subject demonstrated no change in aggres- circumstances (Hall & Zisook 1981)49. studies are a far cry from the circumstances sive responding, and one subject expressed Pre-existing hostility level is a determinant in which hostility is provoked in the “real increased aggressive responding in the ab- (Covi & Lipman 1977)50, as is a past his- world,” they may be useful for purposes of sence of provocation that did not occur in tory of poor impulse control, yet the setting modeling the phenomenon and for study this subject, under placebo conditions and of drug use is also relevant. Subjects suffer- of predispositional correlates and drug in- which was not seen in the other subjects. ing a predisposing borderline syndrome, in- teractions relevant to the effect. Alprazolam The Buss-Durkee Hostility score of this in- cluding borderline personality disorder, are is the benzodiazepine most often implicat- dividual was much higher than any other particularly vulnerable and in a study of the ed in this adverse reaction (Cole & Kando subject. effectiveness of alprazolam as a treatment in 1993)57, and certainly it is the best studied Bond et al (1995)59 investigated the phe- borderline personality disorder, fully 58% in the laboratory. The phenomenon was nomenon of alprazolam hostility in 23 pa-

28 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com tients with a diagnosis of panic disorder […] outweighed by the frequent appearance O’Connor waived his Miranda rights and that had been treated with alprazolam or of paradoxical rage reactions and increase in made statements to police while he was un- placebo for eight weeks. Using question- hostility and aggressive tendencies in these in- der influence of the GABAA agonist drug naires and self-ratings, alprazolam-treated dividuals.” (Brown 1978)60 propofol, was most likely a case of chemi- patients reported at baseline feeling less hos- cal submission: in a state of organic deliri- tility after eight weeks of drug treatment. Chemical submission um he acceded readily to police request that The subjects were then subjected to what Drugging an unwilling victim into a state he incriminate himself in a crime. A similar they were told was a reaction-time competi- of unconsciousness for the purpose of rob- situation pertained in the 2009 case of State tion against an unseen opponent in another bery or rape has a long literary and folk- (Georgia) v John David Clay, where the de- room. The subjects wore headphones and loric history, popularized by the ‘Mickey fendant was under the influence of a self- were told to select, at the beginning of each Finn” of the 1918 Chicago restaurant poi- administered benzodiazepine overdose when trial, one of eight intensities of sound that sonings, and in novels such as the 1930’s interviewed by police. Neither O’Connor would be administered to their opponent The Maltese Falcon and the 1941 film of the nor Clay later recalled being interviewed, if the subject’s reaction time was faster than same name. This, however, is not what is they were amnestic. their opponent’s. They were told their op- meant by “chemical submission,” which is The picture of a chemical submission ponent had similar privileges. In fact, there the name given to a state of willing compli- most publicized in the popular press, that of was no opponent: noise level was increased ance, usually against the user’s best interest, a perpetrator surreptitiously drugging an un- throughout the experiment over six trial that GABAA agonist drugs can induce in a willing victim, probably happens less often blocks and the subject heard the noise 50% person, the victim or subject of this intoxi- than is claimed or believed, since in practice of the time within each block, regardless of cation. Recent reports of chemical submis- drug abusers, particularly youths and young reaction time, and whenever their reaction sion have been most particularly associated adults, intentionally abuse GABAA agonist time was 20% slower than their own aver- with the above-mentioned benzodiazepine drugs socially, often willingly consuming age. The paradigm was thus provocative of flunitrazepam (Rohypnol or “Roofies”) in them with alcohol. They may have no later aggression using noise as a punishment that connection with its use as a “date rape” recollection, or understanding, of what they the subject could inflict on their nonexis- drug when combined with alcohol, but his- did under its influence. tent opponent. As measured by loudness torically the state has been associated with selection patients on alprazolam behaved barbiturates or , and more Confabulation more aggressively in response to perceived recently, zolpidem (Ambien). Hoffmann In chronic abusers of GABAA drugs, as provocation than did placebo-treated con- LaRoche, the manufacturer of Rohypnol, with chronic alcoholics, the user’s history trol subjects. Provocation, or perceived reformulated their tablet in 1997 with a is often a patchwork of half-remembered provocation, is thus an essential element bright blue dye (cloudy in dark colored facts, memory gaps and confabulations. of alprazolam-induced hostility, even in drinks), which together with its bitter taste Confabulations are not “real” memories, subjects who report less baseline hostility is said to render it detectable in most alco- although to the user they feel real. They are under drug influence when not provoked. holic drinks. more properly thought of as unconsciously

Although the proportion of individu- Since the subject/victim under GABAA manufactured or imagined memories that als vulnerable to experiencing ‘paradoxical agonist influence is in an altered state of “make sense” to them, that fill the amnes- rage’ is likely very small in the general pa- consciousness their consent to sex or other tic voids left by drug eradication of mem- tient population, the criminal justice system intrusions on their liberty cannot be said ory. These recollections may not comport tends to select and concentrate these indi- to be entirely voluntary, yet the subject is with the evidence of consensus reality, are viduals with attributes of set that include not unconscious or asleep at the time and not true in an objective sense, yet the user personality disorder, hostile traits, neurop- the purpose of the assault, if it is assualt, relating them is not consciously lying. In sychological impairments, impulse control is to induce a state of loss of self-control. the recent Alaska case of U.S. v Lusk & disorders and other neurobiological vulner- Submission entails making a person act as O’Connor referred to above; the defen- abilities to GABAA agonism-induced rage one wishes; it is not a matter of exploiting dant O’Connor made statements to law and disinhibition of its control. The tense an individual who falls into a deep sleep and enforcement following medical treatment, and punitive circumstances in which such remains passive and incapable of action. It and while he was still under the influence people often find themselves, confined by follows, too, that where the state is deliber- of the GABAA agonist drug propofol in demographic, institutional and legal con- ately induced in another unknowingly the the hospital. His admissions in this state straints outside of their locus of control, subject victim is in a state of involuntary of organic delirium were bizarre; his speech also adds an additional environmental con- intoxication. slipped tangentially from one thought to tributing factor of setting. A disastrous ear- The victim in submission can be manipu- another, and was delivered in a poetically ly experience in the 1970s with using the lated into revealing their credit card number, rhyming cadence. Some of his admissions

GABAA agonist tranquilizing drugs oxaze- can be induced to walk around with their could be—and were —interpreted by police pam (Serax) and diazepam (Valium) in an aggressor without drawing attention in pub- as incriminating, but considering the en- attempt to control prisoners in the Utah lic and can be convinced to sign checks, all tirety of his performance, which was audio- state prison system found that: without later recollection or only fragmen- taped, it seemed clear to this examiner, and tary memory for these events (Pompidou to the U.S. magistrate judge presiding, that “the benefits derived from the administra- 2001, supra). The below-mentioned 2005 O’Connor was delirious, that much of his tion of these drugs in prisoner control were case of USA v Matthew O’Connor, wherein speech content was confabulatory in con-

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 29 tent, and none of it was reliable. His “con- verbal memory were not solely attributable controls or normative data?” Mean dura- fession,” for which he was later amnestic, to benzodiazepine use and may have been tion of drug use in this data set was 8.9 was properly suppressed. influenced by the elevated anxiety levels years and the median drug-free period was present in both the case group and the anx- 3 months. They concluded that compared Persistent effects beyond ious control group. to normals or controls, patients who had withdrawal Other studies that compared neuropsy- withdrawn from long-term benzodiazepine Chronic use of sedative tranquilizing drugs chological performance during treatment use continued to perform more poorly in is the norm: an estimated past-year preva- and after graded withdrawal have found dif- most areas of cognition than did controls lence of use in the USA was reported in ferent results. Some found improvements in or normative data except for sensory pro- 1982 from a cross-national survey con- task performance measuring attention, vigi- cessing. The residual cognitive impairment ducted in over 2,000 households as being lance, and speed of information processing, resulting from chronic benzodiazepine use 12.9% of the population, with 14.2% of as in the report of Sokol & Power (1988)63 is therefore measurable after three months this group taking the drug for 12 or more who studied 12 long-term benzodiazepine of drug-free living. months. Prevalence has increased since users (mean 9 years). Such studies have been then. In the 1982 statistics prevalence of criticized however on grounds of poor ex- Involuntary intoxication use in the United States fell in the middle ecution and design. Sokol and Power, for Involuntary intoxication occurs when an of the international distribution surveyed: instance, tested only 7 of the patients at 4 individual becomes inebriated or intoxi- rates for past-year prevalence of use varied weeks of withdrawal, when not all subjects cated on a drug that they consumed un- from 17.6% in Belgium to 7.4% in the were drug-free. knowingly or, if knowingly, without knowl- Netherlands. (Balter et al 1984)61. Even at Rickels et al (1999)64 compared two edge or warning of the drug’s likely effect. normal anxiolytic or hypnotic doses, chron- groups of chronic (8 year) benzodiazepine Involuntary intoxication can occur, for in- ic users of these drugs develop tolerance and users: one group who had successfully with- stance, if a pharmacist inadvertently dis- dependence, and a withdrawal syndrome drawn and one who had not. They report- penses the wrong drug in error to a patient, similar to the alcohol/barbiturate type en- ed that successful taper patients (drug-free) or if the physician negligently prescribes sues on abrupt discontinuation, as earlier performed better on a digit-symbol substi- the wrong drug in error. The intoxication reported for meprobamate (supra). tution task and a symbol copy task, and, resulting from surreptitious drugging of an Prospective studies on chronic sedative/ furthermore, were observed to be more unknowing victim is of course also ‘invol- tranquilizer drug users are complicated by alert, more relaxed, and less anxious than untary.’ The victim of involuntary intoxi- the patient’s unavailability to research meth- those still taking the drug. cation may claim to have been assaulted, ods before they start using the drugs. Barker Salzman et al (1992)65 reported recovery and misbehavior they engage in as a result et al (2005)62 employed in the alternative of impaired cognitive function in 13 nurs- of such victimization is not their fault but a case-matching design in studying a co- ing home residents withdrawn from their resides, rather, with the administrator or hort of twenty participants evaluated after benzodiazepine medication, compared with provider of the drug causing the intoxica- withdrawal from benzodiazepines, compar- a control group of 12 who did not with- tion that resulted in the misbehavior. The ing each participants’ neuropsychological draw. The authors also reported a signifi- rare phenomenon of “pathological intoxi- test performance to that of two (one “anx- cant improvement in short-term memory cation” can be considered a special case of ious” and one “non-anxious”, both psycho- as measured by the digit span and vigilance involuntary intoxication. In pathological metrically defined) age, sex, and education test methods, which improvement was read- intoxication the subject has a heightened matched control subjects who had never ily apparent to staff and family members: sensitivity to inebriation on a drug, usu- used sedative tranquilizer drugs. Mean du- withdrawn patients appearing brighter, less ally alcohol, and becomes excessively in- ration of drug use in the patient group was dysphoric, more energetic and more intel- toxicated after voluntary consumption of 108 months, and the battery of neuropsy- lectually alert. a small amount, sometimes as little as a chological tests was administered at a mean More definitively, however, Barker et single drink. The essence of the diagnosis of 42 months after drug withdrawal. Their al (2004)66 performed a meta-analysis of of pathological intoxication lies in the id- results indicated that long-term benzodiaz- published research on the subject of seda- iosyncratic state of heightened vulnerabil- epine use may lead to impairments in the tive tranquilizer effects, surveying 34 arti- ity to the drug. For this to be intoxication areas of verbal memory, motor control/per- cles published between 1980 and 2000, of to be considered involuntary, however, the formance, and nonverbal memory but not which 15 met all inclusion eligibility cri- subject would need to have been unaware visuospatial skills and attention/concentration. teria. They found that previous long-term of their idiosyncratic vulnerability. This finding contrasts with the acute mea- benzodiazepine users appeared to improve Common claims of involuntary intoxica- sured effect of sedative tranquilizer use on in tested cognitive function in all domains tion involving tranquilizing drugs are rarely performance testing (see above, Thompson examined, with indications that as age in- clear-cut, however, particularly when am- et al 1999), under which both attention/ creases post-withdrawal the patient’s recov- nesia is involved, and often result from a concentration and visuospatial memory ery decreases on tasks of attention/concen- patient knowingly consuming alcohol with was found to be impaired. In view of the tration. As to the degree of improvement: a properly prescribed GABAA tranquilizer length of abstinence, their findings indicate where studies employed a within-subject or hypnotic, with disastrous consequences that these impairments persist well beyond design it was possible to ask the question: resulting from the combination. If the pa- cessation of benzodiazepine use. However, “are previous long-term benzodiazepine us- tient was truly given no warning of an ad- observed impairments in the area of non- ers still impaired at follow-up compared to verse interaction then a claim of involun-

30 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com tary intoxication may be validly made, yet Ambien franchise was predicted to de- References this can be difficult to prove or disprove cline from 2006 onwards to approxi- 1. Levitan ES (1988) cited in Crews FT (2004) Ef- and the situation contrasts markedly from mately half the value it is today by 2014. fects of alcohol abuse on the brain. Chapter 4 in Brick J (editor), Handbook of the Medical Con- that where both of the interacting drugs are The industry’s “prospective players” [phar- sequences of Alcohol and Drug Abuse, Taylor & medically prescribed (an opiate and a ben- maceutical manufacturers] were warned that Francis (pubs) zodiazepine, for instance, taken for the first by 2014 stiff competition is to be expect- 2. Ellmont B, Struder RA, & Jurgens R (1955) Nolu- dar, a New Sedative-Hypnotic: A Piperidine Deriva- time) and responsibility for giving notice is ed from numerous generics, worth nearly tive. Schweiz med. Wchnschr. 85. 350 well defined at the physician and pharma- US$800 million, as well as a number of 3. Justice William Rehnquist was addicted to Placidyl, and suffered several hospitalizations as a result.[ see: cist level. non-GABAA, non-scheduled hypnotics with Involuntary intoxication also occurs revenues topping US$700 million. In such http://abovethelaw.com/2007/01/breaking_was_ chief_justice_reh.php?show=comments retrieved where an inappropriate drug is improperly a crowded market, “innovation is key and 28 May 2009] mandated by law or compulsory process to product differentiation, demonstration of cost- 4. Carey, B (2008) “Frank Berger, 94, Miltown Cre- be taken by a patient against their will. In effectiveness and niche strategies are essential.” ator, Dies” 21 Mar 2008, New York Times, re- the Texas death penalty trial of Ernest Ray The report identified such a niche, a new trieved 5 May 2009 online at: http://www.nytimes. com/2008/03/21/health/research/21berger.html?_r Willis the defendant’s drugged and unre- sub-market within the user population, the =1&partner=permalink&exprod=permalink sponsive demeanor in the court room was “transient insomniac” which population, 5. Dokoupil, Tony (2009-01-22). “How Mother cited by the prosecutor to illustrate to the they reported: Found Her Helper”. Newsweek. http://www.news- jury that Willis was cold, calculating and “…is severely under served, and presents an week.com/id/180998. Retrieved on 2009-05-01. 6. Dobkin AB (1958) Efficacy of ataractic drugs in disdainful of the court and the jury. There ideal niche for manufacturers. If manufactur- clinical anesthesia: A review, Can Anaes. Soc. J., was no medical reason for this prescription ers can increase the proportion of individu- vol. 5, no. 2, April, 1958 and Willis, who was innocent (the offense als using prescription hypnotics at least a few 7. Foltz RL, Fentiman AF, Folts RB (1980), Methaqua- was committed by another, who confessed), nights a month, to the level of those who use lone, Chapter 4 in NIDA Drug Research Mono- graph #32, GC/MS assays for abused drugs, US was too obtunded by the drug to offer any them at least a few times a week, usage of pre- Public Health Service (pubs) assistance in his defense. Willis’ conviction scription hypnotics could increase by 50%.” 8. http://www.medicalnewstoday.com/articles/25416. was overturned, and he was released, 17 Of the hypnotic drugs currently at the php, retrieved 6 Aug 09 years later. forefront of the market only Rozerem (ra- 9. http://www.medicalnewstoday.com/articles/63064. php, retrieved 6 Aug 09 Tranquilizing drugs are also used to in- melton) does not stimulate the GABAA re- 10. http://www.deadiversion.usdoj.gov/drugs_con- voluntarily pacify agitated patients and ceptor, but relies on the melatonin system. cern/benzo_1.htm\ retrieved 6 Aug 09 nursing-home residents, often more for A novel and under-explored target for tran- 11. Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, staff convenience than the patient’s medi- quilizer drug action at the GABA com- Perrault G, Langer SZ, Bartholini G. (1986) Zolpi- A dem, a novel hypnotic. I. Neu- cal need. Since benzodiazepines exacerbate plex is the neurosteroid receptor (see Fig ropharmacological and behavioral effects. J Pharma- the cognitive confusion of the dementias, 1). The industry has previously marketed col Exp Ther. 1986 May;237(2):649-58. forensic questions may be raised regarding drugs which act directly at this locus, such 12. Greenblatt DJ & Shader RI (1974) Benzodiazepines the patient’s competence to sign wills and as Althesin, a mixture of two : in clinical practice, New York, Raven Press. 13. Roth T, Roehrs T, Wittig R & Zorig F (1984), other instruments under tranquilizing drug alphaxolone and alphadolone, sold as a sur- Benzodiazepines and memory. Brit. J. Clin Phar- influence. gical sedative. It was withdrawn from hu- macol. 18 45S-94S man use in 1984 due to toxic reactions and 14. Stein RA & Strickland TL (1998) A review of the has now been‘re-branded’ for veterinary use neuropsychological effects of commonly used pre- The future of tranquilizing drugs scription medications. Arch. Clin. Neuropsychol- According to a 2006 pharmaceutical indus- under the name “Saffan”. Current research ogy 13(3):259-284 try business report (Business Wire 2006)67 is directed however not at direct stimula- 15. Thompson JM, Neave N, Moss MC et al (1999) Cognitive properties of sedation agents: comparison of addressing the hypnotics market and the tion of the GABAA receptor complex’ neu- future drug pipeline: rosteroid receptor but at stimulating pro- the effects of nitrous oxide and midazolam on memory “the insomnia market and mood, Brit. Dental J. 187(10):557-562 has been dominated by Ambien (zolpidem), duction of the brain’s own enurosteroid 16. Wilkinson CJ (1995), The acute effects of zolpi- Sonata (zaleplon) and Imovane (zopiclone), neurotransmitter(s), in the hope that en- dem administered alone and with alcohol on cog- and the older hypnotics such as benzodiaz- dogenous regulatory processes will prevent nitive and psychomotor function, J. Clin. Psychia- try 56: 309-318 epines. However, the global insomnia market tolerance and dependence from developing. 17. Calabrese EJ (1991) Alcohol interactions with is set to grow from $3.7 billion in 2005 to One such compound, currently known as drugs and chemicals, Lewis (Pubs) p11 $5.5 billion by 2014 driven primarily by the “XBD173” is in the pipeline and shows an- 18. Gruber CM Jr (1955) A theoretical consideration of launch and adoption of Lunesta (eszopiclone), tipanic effects in animals – apparently with- additive and potentiated effects between drugs with a practical example using alcohol and barbiturates. Arch Rozerem (ramelteon) and Ambien CR as well out sedation and tolerance (Ruprecht et al Int Pharmacodyn Ther. Jun 1;102(1-2):17-32. 68 as pipeline drugs from 2006 onwards” 2009) . Similar safety claims, of course, 19. Linnoila M, Stapleton JM, Lister R, Moss H, Lane Ambien had U.S. revenues of $2 bil- were previously made for the barbiturates, E, Granger A, Eckardt MJ (1990) Effects of single lion in 2004 but faced competition from carbamates, benzodiazepines and z-drugs. doses of alprazolam and diazepam, alone and in combination with ethanol, on psychomotor and recently launched hypnotics, and the Only time will tell, yet the history of the cognitive performance and on autonomic nervous drug became generic in 2006, its revenue field suggests that if the drug gets to mar- system reactivity in healthy volunteers. Eur J Clin evaporating. In an attempt to hold onto ket, humans will find some way to abuse it, Pharmacol. 1990;39(1):21-8. the residue of the market -Aventis and forensic examiners will be dealing with 20. Wilkinson CJ (1995) The acute effects of zolpi- dem, administered alone and with alcohol, on cog- launched a sustained-release form (Ambien its adverse effects. nitive and psychomotor function.. J Clin Psychiatry. CR) in the USA in October 2005 yet the 1995 Jul;56(7):309-18.

(800) 592-1399 Spring 2010 THE FORENSIC EXAMINER® 31 21. Kleber H (1994) Assessment and Treatment 40. Ingram IM, Timbury GC (1960): Side effects of and other benzodiazepines. J Clin Psychiatry. 1993 Planning for Cocaine-Abusing Methadone-Main- librium (letter). Lancet 2:766, and see also: Hall Oct;54 Suppl:49-61; discussion 62-3. tained Patients: Treatment Improvement Protocol RCW, Joffe JR (1972), Aberrant response to diaz- 58. Cherek DR, Steinberg JL, Kelly TH. Effects of (TIP) Series 10 » Appendix E - Multidrug Abuse epam: a new syndrome. Am J Psychiatry 129:738- diazepam on human laboratory aggression: corre- Patterns 742, and see also: Ryan HF, Merrill FB, Scott GE, lations with alcohol effects and hostility measures. 22. Backmund M, Meyer K, Henkel C, Soyka M, et al (1968): Increase in suicidal thoughts and ten- NIDA Res Monogr. 1987;76:95-101. Reimer J, Schütz CG. (2005) Co-consumption of dencies, association with diazepam therapy. JAMA 59. Bond AJ, Curran HV, Bruce MS, Sullivan GO and benzodiazepines in heroin users, methadone-sub- 203:1137-1139, Shine P (1995) Behavioral aggression in panic dis- stituted and codeine-substituted patients. J Addict 41. Pompidou Group (2001) Proceedings of the Con- order after eight weeks’ treatment with alprazolam, Dis. 2005;24(4):17-29. tribution to the Sensible Use of Benzodiazepines: J. Affective Disorders 35:117-123 23. Rapeli P, Fabritius C, Kalska H and Alho H Meeting Organised by the Co-operation Group to 60. Brown CR. (1978) The use of benzodiazepines (2009) Memory function in ioiod dependent pa- Combat Drug Abuse and Illicit Trafficking in Drugs in prison populations. J Clin Psychiatry. 1978 tients treated with methadone or buprenorphine (Pompidou Group), Strasbourg (France), 29-30 Mar;39(3):219-22. along with benzodiazepines: longitudinal change January 2001, council of Europe (Pubs) 61. Balter MB, Manheimer DI, Mellinger GD, Uhlen- in comparison to normal individuals. Substance 42. Strahan A, Rosenthal J, Kaswan M & Winston huth EH (1984) A cross-national comparison of Abuse Treatment, Prevention and Policy, 4(6):1- A (1985) Three case reports of acute paroxysmal anti-anxiety/sedative drug use. Curr Med Res Opin. 15 DOI: 1186/1747-597X-4-6 excitement associated with alprazolam treatment, 8 Suppl 4:5-20 24. Lintzeris N, Mitchell TB, Bond A, Nestor L, Am. J. Psychiatry 142:859-861 62. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Strang J (2006) Interactions on mixing diazepam 43. Hill KP, Oberstar JV Dunn ER (2004) Zolpidem- (2005) An evaluation of persisting cognitive effects with methadone or buprenorphine in maintenance induced delirium with mania in an elderly woman, after withdrawal from long-term benzodiazepine patients. J. Clin. Psychopharmacol. 26:274-283 Psychosomatics 45(1):88-89 use. J Int Neuropsychol Soc. May;11(3):281-9. 25. Bashir A & Swartz C (2002), Alprazolam-induced 44. Ingram JM & Timbury GC (1960) Side effects of 63. Sakol MS, Power KG. (1988) The effects of long- panic disorder., J. Am Board Fam. Prac. 15(1):69-72 Librium, Lancet 2:766 term benzodiazepine treatment and graded with- 26. Weissman DE and Haddox JD. Opioid pseudoad- 45. DiMascio A & Shader RI (1970) Behavioral Tox- drawal on psychometric performance. Psychophar- diction. Pain 1989 36:363-366. Sees KL and Clark icity in: Psychotropic Drug Side Effects, Shader RI macology (Berl). 1988;95(1):135-8. HW. Opioid use in the treatment of chronic pain: & DiMascio A (eds) Williams & Wilkins (pubs), 64. Rickels K, Lucki I, Schweizer E, García-España assessment of addiction. J Pain Symptom Manage Baltimore, pp124-131 F, Case WG(1999) Psychomotor performance of 1993; 8:257-264. 46. Bladin PF (1973) The use of clonazepam as an long-term benzodiazepine users before, during, and 27. Fishbain DA (2003) Chronic Opioid Treatment, Ad- anticonvulsant, Med. J. Aust. 1:683-688 after benzodiazepine discontinuation. , J Clin Psy- diction and Pseudo-Addiction in Patients With Chron- 47. Gardos G, DiMascio A, Salzman C & Shrader chopharmacol. 1999 Apr;19(2):107-13. ic Pain , Psychiatric Times. Vol. 20 No. 2; 1-5 RI (1968) Differential actions of chlordiazepoxide 65. Salzman C, Fisher J, Nobel K & Glassman 28. IASP (1993) Nursing Curriculum http:// and oxazepam on hostility. Arch. Gen. Psychiat., R(1992), Cognitive improvement following benzo- www.iasp-pain.org/AM/Template. 18:757-760 diazepine discontinuation in elderly nursing home cfm?Section=Nursing&Template=/CM/HTMLD- 48. Gardos G (1980) Disinhibition of behavior by an- residents. Int. J. Geriatric Psychiatry isplay.cfm&ContentID=2320 tianxiety drugs, Psychosomatics 21(12):1025-1026 66. Barker MJ, Grenwood KM, Jacxkson M and 29. Hazilip TM & Ewing JA (1958) Meprobamate ha- 49. Hall RC, Zisook S. (1981) Paradoxical reactions Crowe SF (2004), Persistence of cognitive effects bituation. N. Eng. J. Med 258:1181-1186 to benzodiazepines. , Br J Clin Pharmacol. 1981;11 after withdrawal from long-term benzodiazepine 30. Mundy A (2009) Alert of MD abuse of Jackson Suppl 1:99S-104S use: a meta-analysis, Arch. Gen. Neuropsychol- drug, Wall Street Journal 6 August 2009, page A1 50. Covi I & Lipman RS (1977) Diazepam induced ogy 19:437-454 31. Daderman AM & Lidberg L (1999)Flunitraze- hostility in depression, Presentation at: American 67. Business Wire (2006) Assessment of Current and pam (Rohypnol) abuse in combination with alco- Psychiatric Association Scientific Meeting, May Future Opportunities and Threats in the Insomnia hol causes premeditated grievous violence in male 1977, Toronto. Market in the US, EU and Japanese Pharmaceutical juvenile offenders, J. Am. Acad. Psychiatry Law 51. Gardner DL & Cowdry RW (1985) Alprazolam- Markets, Business Wire, 2 March 2006 27(1):83-99 Induced Dyscontrol in Borderline Personality Dis- 68. Rupprecht, R, Rammes G, Eser D et al (2009) 32. Pahud J, Forrester A, Gamulin Z et al (1988) Post- order, Am J Psychiatry 1985; 142: 98-100 Translocator Protein (18 kD) as Target for Anxi- operative sedation with zolpidem, midazolam and 52. Dåderman AM, Lidberg L.(1999) Flunitraze- olytics Without Benzodiazepine-Like Side Effects, placebo: a randomized double-blind comparison, pam (Rohypnol) abuse in combination with al- Science 326; 490-493 Anesthesiology 69:555 cohol causes premeditated, grievous violence in 69. Baselt R (2008) Disposition of Toxic Drugs and 33. Kumar R, Mac DS, Gabrielli WF & Goodwin male juvenile offenders. J Am Acad Psychiatry Law. Chemicals in Man, 8th Edition, Biomedical Pub- DW (1987), Anxiolytics and memory: a compari- 1999;27(1):83-99. lications (pub), Foster City CA son of lorazepam and alprazolam, J. Clin. Psychia- 53. Karch FE (1979) Rage reactions associated with clo- try 48(4):158-160 razepate dipotassium, Ann. Int. Med. 91:61-62 34. Morris HH 3rd, Estes ML. (1987) Traveler’s am- 54. Rosenfeld WE, Beniac TE, Lippmann SM, Loe- Acknowledgment: nesia. Transient global amnesia secondary to triaz- wenson RB (1987), Adverse behavioral response The helpful editorial assistance and con- olam. JAMA. 1987 Aug 21;258(7):945-6. and see to clonazepam as a function of Verbal IQ- Perfor- structive advice of forensic psychologist Tom also: Editorial (1988) You don’t have to be a neuro- mance IQ discrepancy, Epilepsy Res. 1:347-356 n scientist to forget everything with triazolam--but it 55. Fiset L, Milgrom P, Beirne R, Roy-Berne P (1992) Schacht PsyD is gratefully acknowledged helps. JAMA. 1988 Jan 15;259(3):350-2. Disinhibition of behaviors with midazolam: report 35. Harazin J & Berigan TR (1999) Case Report: of a case. J. Oral. Maxilofacial Surg. 50:645-649 Earn CE Credit Zolpidem tartrate in somnambulism, Military Med- 56. Rodrigo CR (1991) Flumazenil reverses paradoxical To earn CE credit, complete the exam for this icine 164:669-670 reaction with midazolam, Anesth. Prog. 38:65-68 article on page 60 or complete the exam on- 36. Terrell HB (1988) Behavioral dyscontrol associated 57. Cole JO, Kando JC. (1993) Adverse behavior- line at www.acfei.com (select “Online CE”). with combined use of alprazolam and ethanol.. Am al events reported in patients taking alprazolam J Psychiatry. Oct;145(10):1313. 37. Yang W, Dollear M, Muthukrishnan SR (2005), ABOUT THE AUTHOR One rare side effect of zolpidem- sleepwalking: a case report, Arch Phys. Med. Rehabil. 86:1265- Jonathan J. Lipman, PhD, is a neuropharmacologist and president of 1266 Neuroscience Consulting Inc., a forensic, industrial, and research agency 38. BBC (2003) http://news.bbc.co.uk/1/hi/ providing pharmacological consultation services. Dr. Lipman also serves as health/1913066.stm and see also: http://news. associate clinical professor of psychiatry and behavioral science at the Quillen bbc.co.uk/1/hi/uk/1885684.stm retrieved online College of Medicine at East Tennessee State University. 15 May 09 39. Baraclough BM (1976) Barbiturate prescribing: psychiatrist’s views, Br. Med. J. 2:928-929

32 THE FORENSIC EXAMINER® Spring 2010 www.acfei.com