Pii: s0149-7634(01)00038-0

Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 Mechanisms and abuse liability of the anti-histamine dimenhydrinate Alison G. Halperta, Mary C. Olmsteada, Richard J. Beningera,b,* aDepartment of Psychology, Queen's University, Kingston, Ont., Canada K7L 3N6 bDepartment of Psychiatry, Queen's University, Kingston, Ont., Canada K7L 3N6 Received 5 June 2001; revised 24 September 2001; accepted 25 September 2001 The over-the-counter anti-emetic dimenhydrinate (DMH) (Gravol or Dramamine) has been reported to be abused for non-medicinal purposes. Street drug users abuse DMH for the acute effects of euphoric sensations and hallucinations, while psychiatric patients abuse DMH for its anxiolytic or anti-cholinergic effects. DMH is an H1 histamine receptor antagonist, but it interacts either directly or indirectly with other neurotransimitter systems, including those using acetylcholine, serotonin, norepinephrine, dopamine, opioids or adenosine. Animal behavioural studies, such as self-administration, conditioned place preference, drug discrimination, and modulation of operant responding, show that anti-histamines have abuse potential. Further support comes from reports of acute and chronic abuse of DMH by humans.
Collectively, results con®rm the abuse liability of DMH. q 2002 Published by Elsevier Science Ltd.
Keywords: Dimenhydrinate; Diphenhydramine; 8-Chlorotheophylline; Drug abuse; Histamine; Anti-histamine; Review Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 2. Behavioural and neurochemical effects of dimenhydrinate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 2.1. Dimenhydrinate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 2.2. Diphenhydramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 2.3. 8-Chlorotheophylline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3. Evidence for abuse liability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.3. Case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.4. Neurochemistry of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 tripelennamine, a concoction known on the street as `T's and Blues'. This drug combination creates a `rush' that is Over-the-counter (OTC) drugs are not always used for indistinguishable from heroin [45]. Users of hallucinogens, their intended purposes. Thus, anti-histamines may be such as lysergic acid diethylamide (LSD), or marijuana will administered for their reinforcing rather than their analphy- substitute these drugs with large doses of OTC anti- lactic effects. For example, heroin addicts will mix the histamines to achieve euphoric tactile, visual or auditory narcotic analgesic pentazocine with the anti-histamine sensations [4,26]. These examples show that anti-histamines In recent years, a number of case study reports indicate * Corresponding author. Address: Department of Psychology, QueenõÂs that dimenhydrinate (DMH), an OTC anti-histamine with University, Kingston, Ont., Canada K7L 3N6. Tel.: 11-613-533-2486; the trade name Gravol or Dramamine, has abuse potential.
E-mail address: beninger@psyc.queensu.ca (R.J. Beninger).
DMH is composed of the anti-histaminergic agent 0149-7634/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
A.G. Halpert et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 diphenhydramine (DP), sold under the trade name Benadryl, that while DMH could alter vestibular functioning, neither plus the methylxanthine, 8-chlorotheophylline, in equimolar DP nor 8-chlorotheophylline had the same effect [20].
ratios [18,20]. At recommended doses DMH is used most commonly as an anti-emetic, an effect that is attributed generally to it's antagonism at the H1 receptor [23,55].
Both acute and chronic abuse of DMH have been reported.
DP, often identi®ed as the active component of DMH In 1997, a series of case studies described DMH abuse by [27], is a competitive antagonist at the H1 histamine receptor adolescents who administered the drug for its hallucino- [1]. Histamine exists in both the peripheral and central genic and euphoric properties [41]. In large doses (more nervous systems (CNS). In the CNS, it in¯uences neuroen- than four times the recommended dose), DMH produces a docrine system functions, ingestive behaviour, thermoregu- `high' characterised by hallucinations, excitement, incoor- lation, cardiovascular regulation, and arousal [5,39]. The dination, and disorientation [2,4,9,18,26]. These cases of neurotransmitter also affects motor activity in both humans DMH abuse have been reported in individuals with a history and laboratory animals. For example, histamine injections into the lateral ventricles of rats produced a biphasic motor Individuals with a history of a psychiatric disorder, such response: decreased activity in the ®rst 20 min after the as schizophrenia [2], depression, substance abuse, and injection, followed by a period of hyperactivity. Pretreat- personality disorders [9,18,35] may repeatedly administer ment with an H1 receptor antagonist blocked both effects DMH. In such cases, tolerance to the acute subjective effects [24]. On the other hand, the anti-histamine DP has been of the drug and symptoms of drug withdrawal can occur.
reported to induce motor excitation in monkeys [14].
Chronic consumption of DMH may be dif®cult to identify Whether these differences in motor activation are related because symptoms of the dependence resemble the symp- to drug dose, route of administration, species, or some toms of some psychiatric disorders such as major depression other experimental variable is not clear at present, and further studies are needed in this respect.
Many researchers suggest that DP, the anti-histaminergic There is little disagreement that recommended doses of component of DMH, is responsible for the reinforcing effect OTC anti-histamines, known to block the H1 receptor, of the drug [27]. This anti-histamine in¯uences neurotrans- decrease activity levels in humans. For example, partici- mitter systems either directly, by acting on receptors or pants self-report signi®cantly greater feelings of sleepiness transporters, or indirectly, by modulating their in¯uence.
after administration of DP than after placebo administration The neurotransmitter systems that have been implicated in the behavioural effects of DMH include those using dopa- Anti-histamines also have been reported to act like mine [53], acetylcholine [9], serotonin [8], norepinephrine anti-depressants in laboratory tests [39] or to have anxiolytic [22] and opioids [51]. The neural mechanisms underlying effects in psychiatric patients [18]. This suggests that the the abuse potential of DMH are not yet established, pharmacological effects of these agents may not be limited however, and evidence for the abuse potential of DMH in to the histamine system. Indeed, there is evidence that particular, and of anti-histamines in general, underscores the anti-histamines can interact with acetylcholine, serotonin, norepinephrine, dopamine, and opioid systems, and this may explain their effects on depression and anxiety.
Acetylcholine: Histamine and acetylcholine have a 2. Behavioural and neurochemical effects of number of similar characteristics: the regional distribution of the two neurotransmitters within the CNS is similar; both increase intra-cellular levels of cyclic guanasine mono- phosphate in the post-synaptic neuron; the long-term de- sensitisation pro®les of histamine and acetylcholine The effectiveness of DMH as an anti-emetic was ®rst are comparable [39]. Furthermore, anti-histamine drug reported in 1949, when it was found to aid in the prevention administration produces effects that resemble those of of both seasickness [19] and airsickness [50]. The anti- anti-cholinergic drug administration, including thought emetic properties of DMH are thought to be produced by disorder, hallucinations, amnesia and delirium [9], as well antagonism of H1 histamine receptors in the vestibular as analgesia [39]. This may be due to an excitatory effect system [23,46,55]. For example, electrophysiological on ACh release that is modulated by H1 receptor activity [5].
studies have shown that both DMH and DP can suppress Other classic anti-cholinergic effects, such as mydriasis, that vestibular neuronal ®ring that is enhanced by angular or are seen after anti-histamine administration may be the linear acceleration motions [23]. This would suggest that result of blockade of the muscarinic cholinergic receptor the ability of DMH to reduce nausea is due to the DP [34]. In line with these notions, schizophrenic patients component of the drug. There may also be a synergistic may be particularly susceptible to DMH abuse because of effect with the addition of 8-chlorotheophylline [10]. A its ability to relieve the extrapyramidal symptoms that cold microcaloric test on normal human subjects found are caused by anti-psychotic drugs and that are sensitive A.G. Halpert et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 to anti-cholinergic treatment [2]. Taken together, this evi- inhibitory effect on neural ®ring, and 8-chlorotheophylline dence suggests that anti-histamines may directly affect cholin- likely produces excitation by blockade of these receptors.
ergic neurotransmission or that there may be a functional While 8-chlorotheophylline is generally not considered to overlap between the cholinergic and histaminergic systems.
be a contributor to the behavioural effects of DMH [23], Serotonin: Animal studies show that anti-histamine drugs psychomotor stimulant effects following administration of have the ability to block serotonin re-uptake [6], suggesting the methylxanthine have been reported in animal studies.
that they may possess anti-depressant properties [39]. In Snyder et al. [48] found a correlation between potencies of humans, 77% of reactive depressive patients showed an methylxanthines at competing for adenosine receptors and improvement in mood after chronic DP consumption, the subsequent locomotor stimulation. For example, adeno- though this ®nding was not consistent [21].
sine inhibits dopamine systems and reducing the in¯uence Norepinephrine: Potential anti-depressant effects of of adenosine via receptor blockade would lead to an anti-histamines also may be related to their ability to inhibit increase in dopamine neurotransmission and a consequent norepinephrine re-uptake [7]. Furthermore, the analgesic increase in motor activity. Antagonism at the adenosine A2 effects of anti-histamine drug administration may, at least receptor may be responsible for these stimulant effects of partially, be explained by its interaction with the norepi- methylxanthines [49]. It has been suggested that the amount nephrine system [42], because increases in norepinephrine of 8-chlorotheophylline in a standard DMH tablet may have no signi®cant stimulatory effect [7], however, the beha- Dopamine: Central administration of histamine increases vioural effects of high doses of this methylxanthine have the activity of the mesolimbic, but not the nigrostriatal, dopamine system as measured by post-mortem analysis of In conclusion, DMH interacts with a variety of neurotrans- dopamine metabolite levels, and this effect is blocked by H1, mitter systems, some of which are also in¯uenced by 8- but not H2, receptor antagonists [16]. On the other hand, chlorotheophylline. It is therefore likely that some of these peripheral administration of anti-histamines increases in interactions may account for its diverse behavioural effects.
vivo release of striatal dopamine, particularly in the nucleus accumbens [13], and inhibits striatal dopamine uptake [8].
Behavioural studies have found that administration of the D1-like dopamine receptor blocker SCH23390 abolishes the potentiating effect of anti-histamines on the conditioned place preference produced by the analgesic pentazocine [52,53]. This result implicates D1 receptor activity in the Animal experiments provide researchers with a method reinforcing actions of anti-histamines. This apparent discre- of assessing abuse liability of drugs in controlled settings.
pancy, that both histamine agonists and antagonists potenti- To our knowledge, DMH itself has not been examined in ate DA activity in the nucleus accumbens, may be related to these studies (except in our own recent and as yet unpub- in vivo versus ex vivo measurements and/or central versus lished work, see below), although a number of behavioural peripheral routes of administration. In any case, it is clear paradigms have been used to evaluate the reinforcing effect that histaminergic agents modulate dopaminergic activity.
of the components of DMH, i.e., the anti-histamine DP and Histamine±dopamine interactions may be related to the the methylxanthine 8-chlorotheophylline. These include abuse potential of DMH and these are discussed below.
drug self-administration, conditioned place preference, Opioid: To explain the reinforcing effects of the T's and drug discrimination, and modulation of operant responding Blues street drug (a combination of the narcotic pentazocine maintained by other reinforcers (Table 1).
and the anti-histamine tripelennamine), researchers have i. Self-administration: In line with some theories of drug examined the drug interactions at the opioid receptor addiction [40,58], the anti-histamines that have psychomo- level. For example, Su [51] reported that it may be the tor stimulant properties are likely to be self-administered high binding af®nity of tripelennamine at these receptors [14]. For example, DP, which produces motor excitation that is responsible for potentiating the opioid-induced in mice [6] and monkeys [14], will maintain self-injection psychotomimetic effects. This suggests that anti-histamines in baboons and squirrel monkeys when substituted for may directly stimulate opioid receptors.
cocaine [3,43]. Furthermore, both DP and another anti- histamine tripelennamine maintained rates of responding in a second-order ®xed-interval schedule of i.v. drug injec- tions similar to those maintained by cocaine and d-amphe- 8-Chlorotheophylline is a methylxathine drug related to tamine under identical conditions [3]. These effects of DP caffeine and theophylline. It produces a number of effects, may not be mediated solely through the histamine system: including nervousness, restlessness, insomnia, convulsions, H1 antagonists maintain self-administration at doses greater anxiety, headaches, and nausea [36,44]. The behavioural than those necessary to saturate H1 receptors [3]. Whatever effects of this agent are attributed primarily to its ability the mechanism of its action, DP clearly has rewarding to block adenosine receptors [49]. Adenosine has a general effects in self-administration paradigms.
A.G. Halpert et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 Animal studies of the behavioural effects of DMH, DP or theophylline DP or tripelennamine maintained self-administration rates similar to those seen with cocaine or d-amphetamine when substituted for cocaine in monkeys DP maintained responding when substituted for self-injected cocaine in baboons Potentiation of pentazocin-induced place preference by tripelennamine Potentiation of morphine-induced place preference by histamine antagonists Injection of chlorpheniramine into nucleus basalis magnocellularis induced place preference Injection of chlorpheniramine into nucleus accumbens induced place preference Dose-dependent DMH-induced place preference in rats Tripelleamine substituted for amphetamine in pigeons and monkeys Chloropheniramine but not DP substituted for cocaine in rats Theophylline was discriminated from saline; the behavioural effects were generalizable to caffeine DP increased both suppressed and non-suppressed responding for food Responding for food or shock termination showed a dose-dependent increase after H1 antagonist Lesions to histamine system increase rates of self-stimulation Theophylline increased schedule-controlled operant responding Reinforcing effects of theophylline seen in operant responding are greater than those of caffeine Methylxanthines produce dose-dependent increases in reinforcement threshold in intra-cranial self- ii. Conditioned place preference: Anti-histamines caffeine, another methylxanthine, is substituted for the theo- potentiate place preferences induced by the sigma receptor phylline [7]. The cue effect of theophylline experienced by ligand pentazocine [53] and by morphine [54]. While rats appears to be similar to the cue effect of caffeine. As a Suzuki et al. [53] reported that the anti-histamine tripelan- methylxanthine, 8-chlorotheophylline appears to have beha- namine (2.5 mg/kg) did not produce a conditioned place vioural effects similar to those of caffeine.
preference, rats that were given the anti-histamine chlorphe- iv. Modulation of operant responding: Anti-histamines, niramine directly into the nucleus basalis magnocellularis including DP, increase responding for food on a second [38] or into the nucleus accumbens [60] showed a signi®cant order schedule of reinforcement [3,28]. DP also increases preference for the drug-paired location. Recent as yet the responding of squirrel monkeys that is suppressed by unpublished research from our own laboratory reveals a an aversive stimulus [3]. Responding for food or shock dose-dependent preference for a compartment paired with termination showed a dose-dependent increase when H1 DMH (no effect with systemically administered 25 or antagonists were administered prior to the test [28,29].
40 mg/kg of DMH, but signi®cant preference with 50 and Results show that operant responding maintained by food 60 mg/kg). Further experiments are being performed to reward is modulated by DP and other anti-histamines.
determine the relative contributions of DP and Placing lesions in parts of the histamine system will 8-chlorotheophylline to this reinforcing effect. Results also enhance operant responding. Following destruction show that anti-histamines have rewarding effects in the of the rostroventral part of the tuberomammillary nucleus, a hypothalamic region that is a source of iii. Drug discrimination: Monkeys, but not pigeons, brain histamine, rates of self-stimulation increased.
trained to discriminate amphetamine from saline, will not Histamine may have an inhibitory roll in the neuronal generalize the cue effect of DP from amphetamine when the anti-histamine is substituted for the psyhocomotor stimu- Theophylline increases schedule-controlled responding lant. Another anti-histamine, tripellenamine, completely in operant conditioning experiments [49]. When McKim substituted for amphetamine in both species [14]. When [30] compared the effects of theophylline with caffeine on anti-histamines are substituted for cocaine in rats, chlorphe- the food-reinforced operant responding of mice, the niramine mimicks the cocaine stimulus, while DP produces response-rate enhancing effects of theophylline actually responses predominantly associated with the saline lever exceeded those of caf®ene. On the other hand, methyl- [47]. While DP appears discriminable from both cocaine xanthines, including 8-chlorotheophylline, produce dose- and amphetamine, not all anti-histamines follow this dependent increases in the reinforcement threshold in pattern. This may suggest that anti-histamines have a roll intra-cranial self-stimulation paradigms [31]. It is unclear in the neuronal reward system that is similar to the actions of whether the effects of anti-histamines and theophylline on psychomotor stimulants. Further studies are needed.
operant responding are due to an in¯uence on reinforcement Rats can be trained to discriminate theophylline from systems or simply a consequence of their actions on the saline. Furthermore, the responding is maintained when A.G. Halpert et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 some patients report taking up to 5000 mg of DMH per day, more than 12 times the recommended daily dose of i. DMH: While there are reports of anti-histamines having 400 mg [4]. During periods of abstinence, patients exhibit stimulant effects in animal subjects [14], DMH is described withdrawal symptoms including depressed affect, lethargy, as a depressant by human participants [27,33]. One sign of irritability, loss of appetite and amnesia. In more severe this action is lethargy reported by participants in self assess- cases of withdrawl, abusers experience agitation, hostility, ment reports [27]. At the recommended therapeutic dose clumsiness, and nausea [2,9]. Craving between doses also (100 mg), DMH increases ratings of drowsiness, sluggish- occurs [2]. A history of psychiatric problems is often ness, silence, and depression [57]. Participants in this study evident in individuals who chronically abuse DMH. Many also felt less energetic, effective, decisive, and con®dent.
of the reported case studies involve patients with clinical Thus, at recommended doses, DMH appears to produce diagnoses of schizophrenia [2], depression, panic attacks, psychomotor depressant effects in humans.
personality disorder or substance abuse [9,18,35].
ii. DP: A high dose of DP (400 mg) increased subjective DP may be recommended to patients with chronic ratings on scales associated with drug abuse, such as `drug illnesses to help alleviate some of the aversive effects of liking' and `willingness to take the drug again' in patients the illness. Dinndorf et al. [12] reported several cases of with a history of barbituate abuse [37]. At the same time, chronically ill children and adolescents exhibiting drug however, self-ratings of negative side effects of DP admin- seeking behaviour after extended exposure to DP. Psychia- istration, including `dif®culty concentrating', `light-headed/ tric patients, and in particular those with schizophrenia dizzy', and `bad effects', also increased. A later study receiving neuroleptic treatment, may self-administer DP reported that DP may serve as a reinforcer for individuals for its potential to reduce extrapyramidal symptoms caused with a history of sedative abuse; the participants rated the direct measures of drug reinforcement, such as `liking' and We know of no case studies describing abuse of `good effects', as well as the indirect measures of drug 8-chlorotheophylline, suggesting that the abuse potential reinforcement, such as desire to take the drug again, esti- of DMH is dependent on the anti-histamine component of mates of the amount of money the drug would be worth on the drug. On the other hand, the methylxanthine may inter- the street, and the amount of money participants would act synergistically with DP to produce a greater reinforcing personally be willing to pay for the drug, higher for DP effect, which could explain anecdotal evidence suggesting than for the placebo [32]. As in previous studies, DP use that patients have a tendency to abuse Gravol (DMH) also resulted in signi®cantly higher peak ratings of bad effects. These aversive side effects may deter potential abusers from using anti-histamines for a `high' [32].
Although the data are limited, the studies cited above suggest that DP may be more reinforcing than DMH in The abuse potential of DMH may be related to an humans. The problem with this interpretation is that DMH interaction with the dopamine system, which has been was administered in recommended doses, whereas the admi- implicated in the reinforcing value of most drugs of abuse nistered dose of DP was large enough to induce intoxication [15,25,40,59]. For example, the reinforcing effects of and aversive side effects. It is interesting to note that the amphetamine and cocaine depend critically on dopamine quantity of DMH required to deliver 400 mg of DP is release in the nucleus accumbens [59] and some anti-hista- approximately 750 mg which is the amount of DMH mines substitute for the psychomotor stimulants in the self- reported to induce intoxication. Further studies are needed administration paradigm [3,43]. Neurochemical evidence, to compare the subjective effects of DP to DMH.
such as the H1 antagonist-induced increase in dopamine levels in the nucleus accumbens [13], and the inhibition of re-uptake of dopamine in the striatum [8] support this notion. In addition, the dopamine D1 receptor blocker i. Acute intoxication: DMH intoxication occurs when an SCH 23390 abolishes the potentiating effect of anti-hista- individual ingests anywhere from 750 mg (15 tablets) to mines on the conditioned place preference produced by 1250 mg (25 tablets) on a single occasion [4,41]. At doses opioids [52,53]. Therefore, although DMH has a diverse close to 800 mg, patients reported hallucinations, pleasant range of physiological and behavioural effects, abuse poten- and euphoric tactile and visual sensations, and excitement tial of this drug may be related to the reinforcing effects [2,9,18]; at larger doses (i.e., 1250 mg), some patients produced by its interaction with the mesolimbic dopamine became confused and violent [7]. DMH intoxication can be seen when someone with a history of using illicit drugs, especially marijuana or LSD [25,40], wants a ii. Chronic use: When DMH is abused chronically, This review emphasizes the abuse potential of anti- tolerance to the subjective effects of the drug develops; histamines, and in particular DMH and DP; anti-histamines A.G. Halpert et al. / Neuroscience and Biobehavioral Reviews 26 (2002) 61±67 are reinforcing in animal paradigms, and humans report desirable subjective effects following the drugs' administra- tion. Animal studies describe the ability of anti-histamines, [1] Babe KS, Sera®in WE. Histamine, bradykinin, and their antagonists.
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