Epidemiological studies show that, 4% to 5% of the general population have severe ADHD. Of this number, half have a comorbid substance use disorder. The aim of this article is to help physicians understand and manage this challenging combination of comorbidities.
Epidemiological studies show that, 4% to 5% of the general population have severe ADHD.1 Of this number, half have a comorbid substance use disorder, such as cigarette smoking.2 As it stands, few physicians feel comfortable diagnosing and managing ADHD in adults, and even fewer would contemplate treating an adult with ADHD who has an addiction.3,4 The aim of this article is to help physicians understand and man-age this challenging combination of comorbidities.
Establishing the number and severity of symptoms on the basis of a validated checklist is necessary but not sufficient. To establish a diagnosis, an open-ended question such as “What makes you think you might have ADHD?” elicits a clear history of lifelong impairment in multiple domains of the patient’s life. The primary domains are academic, social, and vocational, but one should also inquire about career advancement, parenting, health, intimate relationships, substance abuse, and legal concerns. A good second question might be, “What did it say in the comments section of you report cards?”
Assuming that doing well in elementary or high school rules out ADHD is one common pitfall. A vigilant parent can compensate so well for a child’s ADHD that the disorder does not manifest clinically until college, when the unstructured environment, lack of parental prompting, and the critical need for time management brings the dysfunction to the fore. Another pitfall is the assumption that the lack of hyperactivity precludes ADHD. This is how many young women with ADHD are missed. ADHD is just as likely in a child that quietly doodles and stares off into space as it is in the disruptive child who will not sit still and climbs on the furniture. Assuming that the lack of typical ADHD symptoms rules out the diagnosis is also a common pitfall. Patients can be focused and attentive while doing things they like or when under pressure, but yet be totally disorganized, scattered, chronically late, impatient, and always on the go.
In essence, the diagnosis of ADHD is not made on the basis of traits the patient does not have; the diagnosis of ADHD requires at least 6 symptoms of distractibility/executive dysfunction or hyperactivity/impulsivity, but not both. Finally, because younger patients may be somewhat in denial and adult patients may have difficulty in remembering the past, the most reliable diagnosis of ADHD is made with longitudinal information, that is, corroborated by a parent, older sibling, or partner.
Where neurobiology and diagnosis intersect
Each of the brain’s numerous circuits has a primary neurotransmitter that turns it on and secondary neurotransmitters that fine-tune the circuit. While ADHD and addiction are distinct disorders, the diagnosis can be difficult because they often share the under-function of one or more of the dopaminergic circuits.5
Rather than struggling with ADHD as an atheoretical grab bag of symptoms, a more cohesive conceptualization of ADHD is to deconstruct it neurobiologically into 4 symptom clusters. Each of these is hypothesized to derive from the underfunction of a different dopaminergic circuit, which loops from one part of the cortex, through the striatum and thalamus, and then back to the cortex.
• Poor selective attention: difficulty in focusing, listening, reading; difficulty in sticking to task, thoughts always wandering, losing and forgetting things; underfunction of the dorsal anterior cingulate cortex– lower striatum-thalamus loop.
• Poor sustained attention: difficulty in organizing, planning, problem solving, managing time; lack of foresight to potential consequences; lack of hindsight; inability to learn from mistakes; difficulty in choosing between com-peting priorities; underfunction of the dorso-lateral-prefrontal cortex–upper striatum-thalamus loop.
• Poor motor control: fidgeting, being physically restless, difficulty in sitting for prolonged meals, meetings, movies; underfunction of the prefrontal motor cortex–lateral striatum-thalamus loop.
• Poor impulse control: acting before thinking, talking before thinking, interrupting, intruding, being impatient; underfunction of the orbitofrontal cortex–lower striatum-thalamus loop.
Tuning the dopamine circuits
Dopaminergic circuits are tuned by noradrenaline, acetylcholine, glutamate, serotonin, and Î³-aminobutyric acid (GABA). While dopamine isolates the signal to which one should pay attention, noradrenaline amplifies the volume of the signal.5 Acetylcholine, acting through nicotinic receptors, also increases the strength of the dopamine signal. Acetylcholine receptor (nAChR) genes are associated with the age of initiation of substance abuse and early subjective responses to alcohol and nicotine.6
Serotonin (5-HT) can either increase or decrease dopamine neurotransmission depending on which receptors it is working through. 5-HT2A receptors have a stimulating effect on dopamine neuronal activity in the ventral tegmental area. 5-HT2C receptors have an inhibitory effect on dopamine neurotransmission.7 Glutamate is an excitatory neurotransmitter that interacts with the N-methyl-D-aspartate receptor to overcome background inhibition and elicit neuronal activity. Glutamatergic projections stimulate mesocorticolimbic dopaminergic neurons-a process thought to be associated with the euphoria of drug seeking. This process has been shown to correlate with “drug liking” and psychological dependence.8
GABA is an inhibitory neurotransmitter. It opens a channel in the membrane through which negatively charged chloride ions can enter the cell. This influx makes the cell less likely to be excited by incoming stimuli. Inhibition is important for keeping the excitation in check and resetting the circuit.5 GABA-ergic projections decrease dopaminergic transmission and are associated with decreased drug liking and decreased craving.9
Addiction and reward circuitry
Humans have evolved an unconscious awareness of the need to pay attention to certain important events. These include threats, competition, sex needs, socialization, and sustenance. Salient events trigger dopamine neurotransmission, which stimulates parts of the brain that allow us to increase vigilance; inhibit unnecessary movement; and focus, filter, take in, process, and store information. They also stimulate the experience of reward.
Experiencing a natural high from normal stimuli (eg, hugging your children, listening to music, mountain biking) is the marker of a healthy reward circuit. Reward circuit underfunction has been described in the literature and named, “reward deficiency syndrome.”10 People with reward deficiency do not experience pleasure from normal stimuli. There is no one particular personality type in people with reward deficiency. Some will live in quiet desperation; others will compensate with stimulus-seeking behaviors that offer more intense but natural highs. Stimulus seeking can manifest quite broadly by any behavior that consistently increases thrill, risk, opposition, drama, and/or chaos. Others will use substances. It is worth emphasizing that reward deficiency syndrome increases the likelihood of “using” to cope. It does not equate with addiction. Addiction requires the added criteria of being unable to control the reward seeking, despite evidence of harm.
Substances of abuse
Most of today’s street drugs started off as naturally occurring substances that our ancestors found by accident. Refining of those substances created the first illicit drugs. All addictive drugs strongly stimulate dopamine neurotransmission,11 through which they stimulate the reward circuit as well as learning, memory, and behavioral circuits.12 People vulnerable to addiction will experience these drugs as highly pleasurable.13 This perception can lead to a spiral of poor choices and negative consequences.
Increased vulnerability to addiction
When adolescents with a vulnerability to addiction experiment with drugs or alcohol, they may stumble on a substance so rewarding that it effectively reverses their dysphoria. Depending on the degree of genetic, experiential, and physiological vulnerability, this experience can drive recurrent use, misuse, abuse, or in some cases, full-blown addiction.14
The more powerfully and rapidly a drug stimulates dopamine neurotransmission, the more reward/euphoria it creates and by extension, the more addictive it is. When smoked, crystal methamphetamine can multiply dopamine neurotransmission 150 times. When snorted, cocaine can multiply transmission 35 times. Even eating chocolate can double the rate.15
Comorbid addiction disorder and ADHD is frequent. The high heritability of ADHD and addiction seen in twin and adoption studies suggests that there are common genes between the two. Other studies suggest that there may be numerous genetic insults that increase vulnerability to ADHD and addiction. No single gene has been shown to make more than a small contribution.16
A number of studies have found that the risk of ADHD is higher in persons who both carry genetic variants and have been exposed to an environmental risk factor (eg, prenatal maternal smoking, alcohol consumption, psychosocial adversity).17-19
Functional MRI studies show reduced frontostriatal circuit activity in both ADHD and substance use disorder,20 specifically in the dorsal ACC-a part of the brain that monitors behavior, suppresses emotional feelings (eg, cravings), and chooses among competing priorities. This reduction in activity worsens with chronic drug use.21
Current data suggest that these genetic, environmental, and drug-induced insults combine to create an area of impaired dopamine neurotransmission. This combination is associated with diminished perception of reward, worsening cognition, and impaired behavioral inhibition. This makes life seem boring, worsens the ability to recognize future negative consequences, and diminishes the ability to say “no” to an enticing distraction. This explains how a severely addicted person’s ability to choose among competing priorities degenerates to the point where he chooses to use drugs rather than pay the rent or buy food.
Treatment of ADHD in the face of addiction
In the absence of comorbidity, treatment of patients with ADHD is relatively straightforward and can be highly rewarding. The most effective medications (largest effect size) are the psychostimulants (methylphenidate, dexamphetamine, and variations thereof).22 Of the stimulants, the safest and least open to abuse are the long-acting stimulants.23 These medications reduce the speed and degree of dopamine neurotransmission compared with shorter-acting stimulants; they therefore do not produce euphoria, drug liking, or withdrawal effects on discontinuation and, as such, are not considered to be addictive.24
Nonstimulants such as extended-release bupropion and atomoxetine are second-line medications. They are less effective than stimulants (ie, have a smaller effect size), but they can be highly useful when stimulants are contraindicated.25 Older drugs such as desipramine can be effective in certain situations but are considered third-line agents because of the higher risk of adverse effects.26
Nonpharmacological treatments, while generally less effective than stimulant medication, nicely complement drug treatment and can increase the overall effectiveness of treatment significantly.27 In adults, psychosocial treatment includes lifestyle and workstyle coaching, parenting advice and coping strategies, organization skills building, counseling for non-ADHD comorbidity, exercise programs, nutritional supplements, diet management, and stress management techniques. All patients benefit from education and from having their physicians advocate on their behalf.
Studies have shown that ADHD is associated with earlier onset of substance use, more severe addiction, and more difficulty in maintaining abstinence.28 Treatment of ADHD in children and adolescents seems to decrease the risk of subsequent addic-tion, but a number of recent studies suggest that decreasing risk likely requires long-term treatment-at least long enough to cover the period of increased vulnerability into early adulthood.29-31
Managing ADHD with stimulants in patients who are active substance abusers is not contraindicated and in fact has shown some promise. Stimulants may improve retention in addiction treatment, and in some cases, they may decrease harm from substance use.32,33 However, stimulants have not been particularly effective in decreasing drug use per se; this may be because the prevalence of comorbidities is high in ADHD and because treating ADHD with stimulants (especially short-acting stimulants) has its own inherent risks.23,34
While it can be difficult to make the diagnosis of ADHD in persons with an active substance use disorder, the 2 disorders can be reliably separated if one obtains a clear history from family and school reports of ADHD symptoms that preceded drug use and/or that persisted through periods of prolonged abstinence.35,36 The use of psychostimulants to manage ADHD in active stimulant users is contraindicated. Because of the high incidence of comorbid mood and impulse control disorders, the primary risk associated with using stimulants in this population is mood dysregulation. A secondary risk is that stimulant medication, at least initially, may cause a high that triggers increased drug use. This is particularly true of short-acting stimulants, which also pose the added risk of being prone to misuse, abuse, and diversion.23,37
These risks can be mitigated by a combination of patient education, contracting, and due diligence38:
• Assessing patients for a full range of comorbidity in the presence of a family member
• Starting medication at low doses and titrating slowly up to symptom remission, with close follow-up
• Educating patients about possible adverse effects and how to manage them
• Ensuring that patients avoid stimulant-containing foods, drinks, and medications
• Using nonstimulants in the first 4 months of recovery and prescribing extended-release stimulants whenever possible
Use of extended-release psychostimulants to manage ADHD is not contraindicated in patients with a past history of stimulant abuse (eg, cocaine, methamphetamine, MDMA) as long as they are 4 months stimulant-free. Stimulants may improve retention in addiction treatment, and in some cases, may decrease harm from substance use.32,33 However, stimulants have not been particularly effective in decreasing drug use per se; this may be because the prevalence of comorbidities is high in ADHD.34 There is a relatively high rate of treatment dropouts in this population, which suggests that these risk management strategies-while necessary-may not be sufficient.
Pretreating the patient with ADHD and comorbid substance abuse with a mood stabilizer before the addiction of a psychostimulant will increase the safety of this intervention significantly and may result in a number of other benefits, including increased positive outcomes and fewer adverse effects, relapses, and dropouts. Anecdotally, the addition of mood stabilizers appears to help reduce cravings, emotional volatility, and impulsivity.
Janice is a 26-year-old with ADHD. She began to use crystal methamphetamine as a teenager and reported that the drug gave her a sense of clarity and calmness that she had never known before. She ended up using “meth” day and night for 6 years.
Before she started to use drugs, she had a history of depression, obsession, and temper tantrums. In school, she was easily distracted and could not complete assignments. Despite her best efforts, she lost interest and dropped out of school at age 16. Janice has a maternal and paternal family history of ADHD, depression, and severe alcoholism.
On presentation, Janice complained of an inability to focus. She said she is easily distracted and has a problem completing tasks. She forgets instructions, loses things, and can’t pay attention, even when she tries. She has not used methamphetamines for 3 years.
Stimulant treatment that was adequate to treat Janice’s ADHD symptoms increased her obsessions and triggered paranoia. Withdrawal of the stimulant and treatment of her obsessions with an SSRI triggered hypomania. Subsequently, withdrawal of the SSRI and treatment with the glutamate-blocker lamotrigine stabilized her mood and allowed successful reintroduction of the SSRI as well as the stimulant. Within a few months, ADHD symptoms, obsessions, depression, and irritability had completely resolved.
Mood stabilizers can increase GABA (as with divalproate), decrease glutamate (as with lamotrigine), or do both (as with topiramate).5 Neurobiologically, increased glutamate mediates stimulation of dopamine transmission and decreases GABA- mediated inhibition of dopamine, which are responsible for relapse in cocaine use associated with cocaine cues.15 Thus, the benefits are mediated through the reversal of these risk factors.
In Janice’s case, it required the benefits of counseling, group support, lifestyle modification, and strategic polypharmacy aimed at her specific comorbidities. The combination of stimulants with an SSRI and a mood stabilizer seems to have produced results difficult to obtain with any one of the drugs alone.
1. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163:716-723.
2. Wilens TE. Attention deficit hyperactivity disorder and substance use disorders. Am J Psychiatry. 2006;163:2059-2063.
3. Chan E, Hopkins MR, Perrin JM, et al. Diagnostic practices for attention deficit hyperactivity disorder: a national survey of primary care physicians. Ambul Pediatr. 2005;5:201-208.
4. BCMA Policy Papers. Your Attention, Please: A Call to Improve Access to Care for ADHD Patients. British Columbia Medical Association; NOVEMBER 2009. http://www.bcma.org. Accessed October 2, 2009.
5. Stahl SM. Stahl’s Essential Psychopharmacology, Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambridge University Press; 2008:chaps 17, 19.
6. Schlaepfer IR, Hoft NR, Ehringer MA. The genetic components of alcohol and nicotine co-addiction: from genes to behavior. Curr Drug Abuse Rev. 2008;1:124-134.
7. Dremencov E, El Mansari M, Blier P. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci. 2009;34:223-239.
8. Uys JD, LaLumiere RT. Glutamate: the new fron-tier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets. 2008;7:482-491.
9. Xi ZX, Gardner EL. Hypothesis-driven medication discovery for the treatment of psychostimulant addiction. Curr Drug Abuse Rev. 2008;1:303-327.
10. Blum K, Braverman ER, Holder JM, et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000;32(suppl i-iv):1-112.
11. Newton TF, De La Garza R 2nd, Kalechstein AD, et al. Theories of addiction: methamphetamine users’ explanations for continuing drug use and relapse. Am J Addict. 2009;18:294-300.
12. Di Chiara G, Bassareo V, Fenu S, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;47(suppl 1):227-241.
13. Volkow ND, Fowler JS, Wang GJ, et al. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol. 2007;64:1575-1579.
14. Carboni E, Silvagni A, Rolando MT, Di Chiara G. Stimulation of in vivo dopamine transmission in the bed nucleus of stria terminalis by reinforcing drugs. J Neurosci. 2000;20:RC102.
15. Bassareo V, Di Chiara G. Modulation of feeding-induced activation of mesolimbic dopamine transmission by appetitive stimuli and its relation to motivational state. Eur J Neurosci. 1999;11:4389-4397.
16. Lesch KP, Timmesfeld N, Renner TJ, et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm. 2008;115: 1573-1585.
17. Becker K, El-Faddagh M, Schmidt MH, et al. Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms. J Pediatr. 2008;152:263-269.
18. Todd RD, Neuman RJ. Gene-environment interactions in the development of combined type ADHD: evidence for a synapse-based model. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:971-975.
19. Laucht M, Skowronek MH, Becker K, et al. Interacting effects of the dopamine transporter gene and psychosocial adversity on attention-deficit/hyperactivity disorder symptoms among 15-year-olds from a high-risk community sample. Arch Gen Psychiatry. 2007;64:585-590.
20. Goldstein RZ, Alia-Klein N, Tomasi D, et al. Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc Natl Acad Sci U S A. 2009;106:9453-9458.
21. Salo R, Nordahl TE, Natsuaki Y, et al. Attentional control and brain metabolite levels in methamphetamine abusers. Biol Psychiatry. 2007;61:1272-1280.
22. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11:625-639.
23. Kollins SH. A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders. Curr Med Res Opin. 2008;24:1345-1357.
24. Volkow ND, Wang GJ, Fowler JS, et al. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. J Pharmacol Exp Ther. 1999;291: 409-415.
25. Newcorn JH, Weiss M, Stein MA. The complexity of ADHD: diagnosis and treatment of the adult patient with comorbidities. CNS Spectr. 2007;12(8 suppl 12):1-16.
26. Slatkoff J, Greenfield B. Pharmacological treatment of attention-deficit/hyperactivity disorder in adults. Expert Opin Investig Drugs. 2006;15:649-667.
27. Molina BS, Hinshaw SP, Swanson JM, et al; MTA Cooperative Group. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009;48:484-500.
28. Wilens TE. The nature of the relationship between attention-deficit/hyperactivity disorder and substance use. J Clin Psychiatry. 2007;68(suppl 11):4-8.
29. Faraone SV, Wilens T. Does stimulant treatment lead to substance use disorders? J Clin Psychiatry. 2003;64(suppl 11):9-13.
30. Wilens TE, Adamson J, Monuteaux MC, et al. Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorder in adolescents. Arch Pediatr Adolesc Med. 2008;162: 916-921.
31. Biederman J, Monuteaux MC, Spencer T, et al. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry. 2008;165:597-603.
32. Levin FR, Evans SM, Vosburg SK, et al. Impact of attention-deficit hyperactivity disorder and other psychopathology on treatment retention among cocaine abusers in a therapeutic community. Addict Behav. 2004;29:1875-1882.
33. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol. 2002;10:286-294.
34. Levin FR, Bisaga A, Raby W, et al. Effects of major depressive disorder and attention-deficit/hyperactivity disorder on the outcome of treatment for cocaine dependence. J Subst Abuse Treat. 2008;34:80-89.
35. Levin FR. Diagnosing attention-deficit/hyperactivity disorder in patients with substance use disorders. J Clin Psychiatry. 2007;68(suppl 11):9-14.
36. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H. Glutamate transmission in addiction. Neuropharmacology. 2009;56(suppl 1):169-173.
37. Wingo AP, Ghaemi SN. Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients. Psychopharmacol Bull. 2008;41:37-47.
38. Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict. 2007;16(suppl 1):45-56.