Muhammad Puri, MD, MPH

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Numb and confused
Mr. L, age 17, is admitted to the hospital after ingesting 24 diphenhydramine 25-mg tablets in 3 hours as a possible suicide attempt. His parents witnessed him behaving strangely and brought him to the hospital. They state that their son was visibly agitated and acting inap­propriately. He was seen talking to birds, trees, and the walls of the house.

Mr. L says he is upset because he broke up with his girlfriend a week earlier after she asked if they could “take a break.” He says that he took the diphenhydramine because he wanted to “get numb” to deal with the emotional stress caused by the break-up.

After the break-up, Mr. L experienced middle-to-late insomnia and was unable to get more than 3 or 4 hours of sleep a night. He reports significant fatigue, depressed mood, anhedonia, impaired concentration, and psy­chomotor retardation. He denies homicidal ide­ation or auditory and visual hallucinations.

As an aside, Mr. L reports that, for the past year, he had difficulties with gender identity, sometimes thinking that he might be better off if he had been born a girl and that he felt uncomfortable in a male body.

Which treatment option would you choose for Mr. L’s substance abuse?
   a) refer him to a 12-step program
   b) begin supportive measures
   c) administer activated charcoal
   d) prescribe a benzodiazepine to control agitation

The authors’ observations
As youths gain increasing access to medical and pharmaceutical knowledge through the Internet and other sources, it appears that adolescent drug abuse has, in part, shifted toward more easily attain­able over-the-counter (OTC) medications. Diphenhydramine, a first-generation anti­histamine, can be abused for its effects on the CNS, such as disturbed coordination, irritability, paresthesia, blurred vision, and depression. Effects of diphenhydramine are increased by the presence of alcohol, monoamine oxidase inhibitors, diazepam, hypnotics, sedatives, tranquilizers, and other CNS depressants. In 2011, diphen­hydramine abuse was involved in 19,012 emergency room visits, of which 9,301 were for drug-related suicide attempts.¹

Diphenhydramine is an inverse agonist of the histamine H1 receptor.² It is a mem­ber of the ethanolamine subclass of antihis­taminergic agents.³ By reversing the effects of histamine on capillaries, diphenhydramine can reduce the intensity of allergic symptoms. Diphenhydramine also crosses the blood–brain barrier and antagonizes H1 receptors centrally.

Used as a common sleep aid and allergy medication, the drug works primarily as an H1 receptor partial agonist, but also is a strong competitive antagonist at musca­rinic acetylcholine receptors.4 It is abused for its sedative effects and its capacity to cause delirium and hallucinations.5 Diphenhydramine can have a stimula­tory effect in children and young adults, instead of the sedating properties seen in adults.6 Such misuse is concerning because diphenhydramine overdose can lead to delirium, confusion, and halluci­nations, tachycardia, seizures, mydria­sis, xerostomia, urinary retention, ileus, anhidrosis, and hyperthermia. In severe cases it has been associated with cardiac arrhythmias, rhabdomyolysis, status epi­lepticus, and death.4,6 Neurologic symp­toms of diphenhydramine overdose are listed in Table 1.

HISTORY Polysubstance abuse
Mr. L has a 2-year history of major depressive disorder and a history of Cannabis abuse with physiological dependence; Robitussin (base active ingredient, guaifenesin) and hydroco­done abuse with physiological dependence; 3,4-methylenedioxymethamphetamine (MDMA) abuse; and diphenhydramine abuse. He also has a history of gender dysphoria, although he reports that these feelings have become less severe over the past year.

Mr. L attends bi-weekly appointments with an outpatient psychiatrist and report­edly adheres to his medication regimen: fluoxetine, 40 mg/d, and risperidone, 1 mg at bedtime. He denies previous suicidal ide­ation, suicide attempts, homicidal ideation, or homicidal attempts. He reports no history of physical, sexual, or emotional abuse. He gets good grades in school and has no outstanding academic problems.

Mr. L began using Cannabis at age 14; his last use was 3 weeks before admission. He is guarded about his use of Robitussin, hydroco­done, and MDMA. However, Mr. L reports that he has researched diphenhydramine on the internet and believes that he can safely take up to 1,200 mg without overdosing. He reports normally taking 450 mg of diphenhydramine daily. Mr. L reports difficulty urinating after using diphenhydramine but no other physical complaints.

Mr. L lives with his father and stepmother and has a history of one psychiatric hospital­ization at a different facility 2 months ago, fol­lowed by outpatient therapy. He obtained his Graduate Equivalency Diploma (GED) and plans to attend college.

At age 5, Mr. L emigrated from Turkey to the United States with his parents. His mother returned to Turkey when he was age 6 and has had no contact with her son since. Whenever Mr. L visits Turkey with his father, the patient refuses to see her, as per collaterals. He gets along well with his stepmother, who is his maternal aunt. Mr. L has been bullied at school and reportedly has few friends.

On mental status examination, Mr. L has an appropriate appearance and appears to be his stated age. He shows good eye con­tact and is cooperative. Muscle tone and gait are within normal limits. He has no abnormal movements. Speech, thought processes, and associations are normal. He denies auditory hallucinations, visual hallucinations, suicidal ideation (although he presented with a prob­able suicide attempt), or homicidal ideation. No delusions are elicited.

Mr. L shows poor judgment about his drug use and situation. He demonstrates limited insight, because he says his only goal is to get out of the hospital. He is alert, awake, and oriented to person, place, and time. He shows no memory or knowledge impairment. He appears euthymic with an inappropriate and constricted affect. On neurologic exam, he had mild tremors in his hands. The authors’ observationsTreatment for diphenhydramine over­dose should begin quickly to prevent life-threatening effects and reduce the risk for mortality. The toxin can be removed from the patient’s GI tract with activated char­coal or gastric lavage if the patient presents within 1 hour of ingesting the substance. Administering IV fluids will prevent dehy­dration. Cardiac functioning is monitored and benzodiazepines could be adminis­tered to manage seizures.

Key elements of a toxicologic physical examination include:
   • eyes: pupillary size, symmetry, and response to light (vertical or horizontal nystagmus)
   • oropharynx: moist or dry mucous membranes, presence or absence of the gag reflex, distinctive odors
   • abdomen: presence or absence and quality of bowel sounds
   • skin: warm and dry, warm and sweaty, or cool
   • neurologic: level of consciousness and mental status, presence of tremors, seizures, or other movement disorders, presence or absence and quality of deep tendon reflexes.⁷

If a child or adolescent patient cannot communicate how much of a drug he (she) has ingested, questions to ask parents or other informants include:
   • Was the medication purchased recently, and if so was the bottle or box full before the patient took the pills?
   • If the medication was not new, how many pills were in the bottle before the patient got to it?
   • If the medication was prescribed, how many pills were originally prescribed, when was the medication prescribed, and how many pills were already taken prior to the patient getting to the bottle?
   • How many pills were left in the bottle?
   • How many pills were seen around the area where the patient was found?
   • How many pills were found in the patient’s mouth?⁷

Recommendations
It is well known that OTC medication abuse is a growing medical problem (Table 2). Antihistamines, including diphenhydramine, are readily available to minors and adults. Because of the powerful sedating effects of antihistamines, many adolescent health practitioners give them to patients who have insomnia as a sleep aid.⁸ As in our case, antihistamines are used recreationally for their hallucinogenic effects, at dosages of 300 to 700 mg.⁹ Severe symptoms of toxicity, such as delirium and psychosis, seizures, and coma, occur at dosages ≥1,000 mg.⁹

Bottom Line
Abuse of over-the-counter (OTC) drugs, such as diphenhydramine, among youths is a growing problem. Remember to question adolescents who appear intoxicated or to have overdosed not only about abuse of alcohol and illicit substances but also of common—and easily and legally accessible—OTC drugs.

Related Resources
• Carr BC. Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr. 2006;18(2):184-188.
• Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009;23(1):101-105.

Drug Brand Names
Diazepam • Valium                      Hydrocodone • Vicodin
Diphenhydramine • Benadryl        Risperidone • Risperdal
Fluoxetine • Prozac

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.