a treatment algorithm for attention deficit hyperactivity disorder in cocaine-dependent adults: a...

Substance Abuse, Vol. 20, No. 1, 1999

A Treatment Algorithm for Attention DeficitHyperactivity Disorder in Cocaine-Dependent Adults:A One-Year Private Practice Study with Long-ActingStimulants, Fluoxetine, and Bupropion

Ricardo Castaneda, M.D.,1,2 Norman Sussman, M.D.,1 Robert Levy, M.D.,1 andManuel Trujillo, M.D.1

A subgroup of adults in private treatment for cocaine dependence in remissionreported a therapeutic effect from cocaine during the initial phases of cocaine addictionand, also, met DSM-IV criteria for ADHD. We report evidence that study subjectsprobably medicated their ADHD symptoms with cocaine and describe a 1-yeartreatment algorithm featuring long-acting stimulants that was effective in the manage-ment of their ADHD and cocaine dependence. Nineteen stable patients in full remis-sion from all substance dependence were entered into an open label, prospective,treatment trial for ADHD. The treatment schedule consisted of the progressive intro-duction—and discontinuation of ineffective medication—of each of several medica-tions in the following order: fluoxetine, bupropion, pemoline, sustained-release meth-ylphenidate, dextroamphetamine spansules, and methamphetamine gradumets.Treatment of ADHD was successful. Several treatment regimens, especially thoseincluding long-acting stimulants, alone or in combination with other agents, werehighly effective. All but 1 of the 19 subjects had a fully effective response for atleast 1 full year. Mean UTAH scale scores were 7.4 before any medications wereadministered and 1.6 at the end of the study. Treatment proved successful in sup-pressing ADHD symptoms, with minimal cocaine slips or side effects.

INTRODUCTION

We identified a subgroup of adult cocaine dependent patients in private outpa-tient treatment who reportedly experienced a positive therapeutic effect from co-caine during the initial phases of their cocaine addiction. Cocaine induced remark-

1Department of Psychiatry, Bellevue Hospital/New York University School of Medicine.2To whom correspondence should be addressed at New York University Medical Center, 550 FirstAvenue, New York, New York 10016.

KEY WORDS: attention deficit hyperactivity disorder; cocaine dependence; treatment.

590889-7077/99/0300-0059$16.00/1 C1999 Association for Medical Education and Research in Substance Abuse

able calm and relaxation. It also stabilized their mood, improved their ability tothink, and increased their capacity to engage in productive activity. This observationcontradicted our own empirical studies of cocaine abuse, which generally foundthat most cocaine addicts experienced worsening of associated psychiatric symptomswhile abusing cocaine (1-3).

One possible explanation for the apparent disparity of patient reactions isthat those who experienced positive or paradoxical effects from cocaine also hadattention deficit/hyperactivity disorder (ADHD) (4). Indeed, the clinical pictureincluded hyperactivity, disorganization, impulsivity, emotionality, unstable person-ality, fidgetiness, and inability to relax. Subsequently, neuropsychological testing,diagnostic interviews, and conferences with family members confirmed that all ofthese individuals met strict DSM-IV criteria for ADHD in adults (5).

There have been additional anecdotal reports that describe a subgroup ofcocaine addicts with ADHD who exhibited paradoxical reactions to cocaine suchas increased focusing, a less euphoric response, and somnolence (6, 7). We reportbelow additional evidence that our subgroup of cocaine addicts probably medicatedtheir ADHD symptoms with an available stimulant, cocaine, and describe a treat-ment algorithm that was effective in the management of their ADHD and cocaineabuse. The rationale for medication selection, as well as the order of medicationadministration and dosages in the treatment algorithm, is described under Method.Although their own effectiveness in this population has not been reported, weadministered long-acting stimulants in light of the proven efficacy of short-actingpreparations of methylphenidate and amphetamines for ADHD (8-14). We se-lected, also, pemoline (4) and two antidepressants with activating effects, fluoxetine(15) and bupropion (16), all of which have been reported to benefit ADD symptoms.

METHOD

This was an outpatient, open-label, prospective, 1-year-long study of 19 privatepatients in treatment for cocaine dependence in remission.

Inclusion Criteria. The population studied consisted of self-paying patientswho were seen in weekly or biweekly private treatment and agreed to participatein the study. All patients met both, DSM-IV criteria for cocaine dependence inremission, and narrow DSM-IV criteria for adult attention deficit hyperactivitydisorder. All subjects also were positive for at least six out of the eight diagnosticUTAH Criteria for Adult ADHD (Table I)(17). Patients were psychiatrically stableand free of any other substance abuse at time of inclusion in the study. Althougha history of psychotic disorders constituted exclusionary criteria, affective illness,or anxiety disorders in full remission, and Axis II disorders (including strong ASPDtraits) did not. With the exception of two bipolar patients maintained on valproicacid and one patient on various treatments for erectile dysfunction (prostaglandininjections, yohimbine, 2 days/week), we did not include any other patient who wason any active psychopharmacological treatment.

Demographics. Most were affluent and belonged in the middle or highersocioeconomic range. There were only two women among the 19 subjects. Only

60 Castaneda, Sussman, Levy, and Trujillo

Long-Acting Stimulants for ADHD in Cocaine Addicts 61

Table I. The Utah Criteria for Identifying Symptoms of ADHD in Adults

I. Childhood characteristicsA history consistent with ADHD. The following are our diagnostic criteria for ADD inchildhood.A. Narrow criteria (DSM-IV)

That the individual meet DSM-IV criteria for ADHD in childhoodB. Broad criteria

Both characteristics 1 and 2 and at least one characteristic from 3 through 61. Hyperactivity: More active than other children, unable to sit still, figetiness, restlessness, al-

ways on the go, talking excessively2. Attention deficits: Sometimes described as having a "short attention span," distractibility,

unable to finish school work3. Behavior problems in school4. Impulsivity5. Overexcitability6. Temper outbursts

C. Parents' Rating Scale (Conners Abbreviated Rating Scale)Although not necessary for diagnosis, a score of 12 or greater places the patient in the 95thpercentile of childhood "hyperactivity."

II. Adult characteristicsA. Motor hyperactivity: Manifested by restlessness; inability to relax; "nervousness" (meaning in-

ability to settle down — not anticipatory anxiety); inability to persist in sedentary activities (forexample, watching movies, TV, reading the newspaper); always on the go, dysphoric when in-active

B. Attention deficits: Manifested by an inability to keep one's mind on conversations; by distracti-bility (incapacity to filter out extraneous stimuli); by difficulty keeping one's mind on readingmaterials or tasks ("mind frequently somewhere else"); frequent "forgetfulness"; by often los-ing or misplacing things; forgetting appointments, plans, car keys, purse, and so on

C. Affective lability: Usually described as antedating adolescence and, in some instances, as farback as the patient can remember; manifested by definite shifts from a normal mood to de-pression or mild euphoria or — more often — excitement; depression described as being"down," "bored," or discontented"; anhedonia not present; mood shifts usually last hours to,at most, a few days and are present without significant physiologic concomitants; mood shiftsmay occur spontaneously or be reactive

D. Hot temper, explosive, short-lived outbursts: A hot temper, "short fuse," or "low boilingpoint" outburst, usually followed by quick calming down. Subjects may report having tran-sient loss of control and be frightened by their own behavior; easily provoked or constant irri-tability; temper problems interfere with personal relationships

E. Emotional overreactivity: Cannot take ordinary stress in stride and react excessively or inap-propriately with depression, confusion, uncertainty, anxiety, or anger; emotional responses in-terfere with appropriate problem solving; experience repeated crises in dealing with routinelife stresses; describe themselves as easily "hassled" or "stressed out"

F. Disorganization, inability to complete tasks: A lack of organization in performing on the job,running a household, or performing schoolwork; tasks are frequently not completed; the sub-ject switches from one task to another in haphazard fashion; disorganization in activities, prob-lem solving, organizing time; lack of "stick-to-it-iveness"

G. Impulsivity: Minor manifestations include talking before thinking things through; interruptingothers' conversations; impatience (for example, while driving); impulse buying. Major manifes-tations may be similar to those seen in mania and antisocial personality disorder and includepoor occupational performance; abrupt initiation or termination of relationships (multiple mar-riages, separations, divorces); excessive involvement in pleasurable activities without recogniz-ing risks of painful consequences (buying sprees, foolish business investments, reckless driv-ing). Subjects make quick and easy decisions without reflection, often based on insufficientinformation and to their disadvantage; inability to delay acting-out without experiencing dis-comfort

H. Associated features: Marital instability; academic and vocational success less than expected onthe basis of intelligence and education; alcohol or drug abuse; atypical responses to psy-chotropics; family histories of ADHD in childhood; antisocial personality disorder and Bri-quet's syndrome

one-third of them (6 out of 19) were not engaged in full-time employment at thetime of inception of the study and were instead financially dependent on theirfamilies. Age in the study sample ranged from 22 to 54 years, with a mean age of37 years. At the time of initial treatment for ADHD, 7, or 37%, were single and12, or 63%, were married. Fifteen subjects (79%) had completed high school, 8(42%) graduated from college, and 2 (10%) completed postgraduate education.Noteworthy is the fact that, without any exception, all of eight subjects who com-pleted college attributed their ability to engage in productive study to intermittentor frequent use of cocaine and/or amphetamines at that time.

Diagnosis of Attention Deficit Disorder. All patients met the narrow DSM-IV diagnostic criteria for ADHD (5). We intended to include patients in "partialremission" (i.e., adults who no longer had the full disorder), but in fact, all 19 subjectsmet the full diagnostic criteria and displayed at least 75% of the characteristics ofthe Utah Criteria for Adult ADHD (17). Additionally, confirmation of offspring'sADHD Childhood Characteristics in the Utah Criteria for Adult ADHD wasobtained on 15 patients during phone interviews with at least one of their parents.Based on their own retrospective reports all patients had met narrow DSM-IVcriteria for ADD/Hyperactivity disorder.

Diagnosis of Cocaine Dependence. Patients were in full or partial remission(DSM-IV) from cocaine dependence and other substance abuse (alcohol, opiates,sedative, marijuana, and ketamine). In fact, half of our patients had been abstinentfrom cocaine for over 1 year by the time they were initially diagnosed as havingADHD. A minimum of 6 months of stable abstinence from cocaine or any othersubstance previously abused was required prior to a treatment trial for ADHD.Only patients who had not experienced more than two "slips" within those 6 monthswere included. A "slip" constituted a period of cocaine use lasting no more than 2days, followed by consistent abstinence for over 1 month. Abstinence was monitoredclinically and corroborated with urinary drug screenings obtained weekly on 11, or57.9%, and biweekly on 8, or 42.1%, of the 19 patients throughout treatment.

The duration of remission from cocaine dependence (and other psychoactivedrugs) prior to ADHD treatment ranged between 6 and 26 months, with a meanduration of 13.9 months. Most patients (11, or 58%) were also in partial or fullremission from other psychoactive substances, including the following: alcohol, 6(or 31%); opiates, 3 (or 15%); marijuana, 2 (or 10%); benzodiazepine, 1 (or 5%);and ketamine, 1 (or 5%).

Prior to attaining remission most patients (10, or 52%) had experienced cocaineslips during treatment for their cocaine addiction (mean: 1.6 1- to 2-day slips).During ADHD treatment, only four patients, or 21%, used cocaine. Two of thesepatients had two 1-day slips each. The other two had a full-blown cocaine relapserequiring hospitalization and interruption of ADHD medications.

Other Psychiatric Diagnoses. Most patients had at least one associated psychi-atric diagnosis. These medication-free patients met criteria for a least one of thefollowing associated disorders: dyssomnia, tic disorders, social phobia, generalizedanxiety disorder, dissociative disorder NOS, male erectile disorder, eating disorderNOS, partner relational problem, and occupational problem.

Medical Issues. All patients were cleared for medication treatment by theirown private physician within 5 months prior to initial administration of any drugs.


Subsequent laboratory evaluations were obtained within 6 to 9 months after initia-tion of the study, including basic hematology (CBC) and a chemical profile (SMA12). Except for mild preexisting hyperlipidemias, no other significant laboratoryabnormalities were found.

Treatment Algorithm for ADHD

Algorithm Design. Generally, algorithms are constructed with the medica-tions most likely to succeed at the beginning. We introduced antidepressants earlierinstead of stimulants however, because it seemed prudent to us to evaluate thefirst potential benefits of antidepressants in addicted ADHD subjects. Thus, weintroduced medications within the algorithm in an order inversely proportionalto their expected degree of stimulating properties. We ranked medications andadministered them in the following order: fluoxetine, bupropion, pemoline, andlong-acting stimulants. We introduced the cheapest long-acting stimulant—methylphenidate—first, and Desoxyn gradumets, the most expensive one, last.

The most important aspect of the treatment algorithm is the use of long-actingstimulants, as opposed to short-acting psychostimulants. Although there have beenreports of treatment of ADHD in cocaine addicts with methylphenidate (18) andpemoline (4), our initial experience with a variety of "stimulant" antidepressants,sedatives, and amphetamine-like drugs was not positive. We had learned earliernot to administer short-acting amphetamines or methylphenidate since they hadinduced substance abuse behaviors in three of four patients during the first 2 daysof administration. They also produced a "cocaine high"-Mike feeling (19). We choseinstead slow-release versions of the same compounds and found them to be effectiveand not associated, even over periods of several months, with any of the "addictive"behaviors or responses seen with their short-acting counterparts.

Initial Dosing. We determined initial medication dosages based on theamount expected to possibly induce activation/stimulation in normal subjects. Start-ing dosages were as follows: fluoxetine, 20 mg; bupropion, 100 mg; pemoline, 37.5mg; methylphenidate, 20 mg; dextroamphetamine, 10 mg; and methamphetamine,15 mg.

The treatment schedule consisted of the progressive introduction of each ofseveral medications in the following order: fluoxetine (Prozac), bupropion (Wellbu-trin), pemoline (Cylert), methylphenidate (Ritalin-SR), dextroamphetamine span-sules (Dexedrine capsules), and methamphetamine (Desoxyn Gradumet). Since wedid not seek antidepressant effects but only activation/stimulation, we discontinuedmedications after 2 weeks when no beneficial effect on ADD symptoms was attaineddespite doubling of the initial dose.

Evaluation Parameters of Treatment Efficacy. UTAH scores were obtainedat least weekly and within 2 days following any treatment modification. Input frompatients' significant others was also obtained at least weekly. A treatment regimenwas considered "fully effective" if it suppressed 80% of the initial ADHD symptoms(UTAH Criteria for Adult ADHD) (17) for at least 1 full year.

Protocol of Medication Administration. Each medication was added to thetreatment protocol as follows.


(1) Only one medication was introduced or added at a time. Medications weresupplied 1 week at a time.

(2) Any medication that did not suppress or greatly improve at least two itemson the Adult UTAH scale ("partially effective") within 5 days of initialadministration and doubling of the initial dose was immediately discon-tinued.

(3) Each of these at least partially effective medications was continued for 3weeks prior to the introduction of a subsequent agent. If the medicationwas no longer effective after 2 weeks despite doubling of the dose for 2or 3 days, it was then discontinued. If it continued to suppress or greatlyimprove at least 80% of all items identified at the inception of treatmenton the Adult UTAH scale ("fully effective"), no subsequent medicationswere added. Increments of daily medications were administered in di-vided doses.

(4) If a prior medication was only partially effective, a subsequent medicationwas added. If the new medication was also at least partially effective—i.e.,it suppressed at least two additional items in the UTAH scale for at least2 weeks—it was added to the treatment regimen. Fully effective treatmentregimens precluded the addition of any new medications.

(5) Fully effective treatment regimens that stopped working despite doublingof medications dosages (i.e., they were not even partially effective) werediscontinued and a subsequent agent was introduced, usually 1 week later.Fully effective treatments which became partially effective were enhancedwith the introduction of a subsequent agent, also within 1 or 2 weeks ofnoticing the reduction in clinical effect. In actuality, only one patient waskept on more than two concurrent agents for more than 12 weeks.

(6) When no single treatment regimen remained fully effective for more than36 weeks at a time, all previously fully effective treatment regimens werealternated on a rotational basis, usually with only a 2- to 5-day washoutperiod. (Again, in actuality, only one patient required more than twotreatment regimens to be alternated in his rotational treatment program.He, in fact, is a "rapid metabolizer" who does not require any washoutperiods between these two treatment regimens).

(7) Patients with medical problems and histories of drug reactions and thoseon medications that represented a contraindication for administration offluoxetine, bupropion, pemoline, amphetamines, or methylphenidate wereexcluded. Only one exception was made with one patient with a historyof allergy to fluoxetine and lack of response to bupropion, who was starteddirectly on pemoline.

(8) Cocaine use during the course of treatment resulted in immediate interrup-tion of medication for ADHD. Treatment with the last regimen was re-sumed one week after a slip (maximum of two-day duration).

Seventeen of the 19 patients were accompanied by one or more relatives and/orfriends to at least two sessions per month. This practice, which was an integral partof the addiction treatment, also helped in patient assessment and verification ofcompliance with the treatment algorithm.


RESULTS

Efficacy

Treatment proved effective in suppressing most ADHD symptoms. Of thevarious effective treatment regimens resulting from the algorithm, however, twowere consistently most successful. The most effective treatment regimen consistedof monotherapy with a long-acting stimulant. The other one included one long-acting stimulant in combination with an antidepressant or pemoline.

Most drugs were at least partially effective for various periods of time. Atreatment regimen was considered "fully effective" if it suppressed almost 80% ofthe initial ADHD symptoms (UTAH Criteria for Adult ADHD) (17) for at least1 full year. The mean UTAH scale before any medications were administered was7.4. All but 1 of the 19 subjects studied eventually had a fully effective response(Table II). At the end of this 1-year treatment, the mean UTAH score was 1.6.

Medication Dosages

For the most part, medication dosages were fairly uniform among patients,whether the medications were used alone or in combination with other drugs.Increments in dosages rarely exceeded double that of the initial dose (Table II).The high-test dosage range was associated with administration methylphenidate,which was always begun at 20 mg/day but was increased in all patients. We allowedoccasional flexibility with starting doses, as in two patients who were started on 40mg/day of Ritalin-SR (divided doses) because of their history of adequate responseat this dosage in the past. When used in nine treatment regimens, lasting between12 and 52 weeks, methylphenidate was administered as follows: four patients (44%)received 40 mg/day; two patients (22%) received 60 mg/day; and one patient wasplaced on each of the following—80,100, and 120 mg/day. (Interestingly, the patienton 100 mg/day showed a consistent suppression of 90% of his ADHD symptomson the same single-drug treatment for 1.5 years until the medication abruptly ceasedto be effective. Attempts at that time to regain symptom reduction with large dosesof dextroamphetamine and methamphetamine were completely unsuccessful andall medications were interrupted. Reinstatement of methylphenidate after a 3-month drug-free period resulted in fully effective treatment of over 36 weeks again.(The patient remained symptom-free at the time of preparation of our manuscriptseveral months later.)

Dextroamphetamine was always started at 10 mg/day but needed to be in-creased to 60 mg/day in all three patients who attained fully effective treatmentfor 36 to 52 weeks.

Methamphetamine at 15 mg/day was fully effective for more than 2 weeks inonly one of four patients. This patient had more symptom suppression (1 in theUTAH scale) during the first 12 weeks on 5 mg Desoxyn than during two subsequentdosage increments, to 10 and 15 mg/day, which produced a UTAH score of 2, for36 and 52 weeks, respectively.

Pemoline was begun at 37.5 /day but was increased to 37.5 mg b.i.d. in all but


one of seven patients. The one patient kept on 37.5 mg/day also took fluoxetine(20 mg/day) and attained a consistent 60% reduction (UTAH score of 2) of hismoderate ADD symptomatology (he had the lowest initial UTAH score among allsubjects, 6).

Increments on the initial dosage did not increase the effectiveness of fluoxetineand bupropion. These drugs were started at 20 mg/day and 100 mg b.i.d., respectively.With only one exception, neither drug was fully effective alone for more than 12consecutive weeks. Used in combination, however, fluoxetine clearly assisted otherdrug regimens including pemoline, methylphenidate, and dextroamphetamine toinduce high levels of symptom suppression for 1 whole year as described below.

Effectiveness of the Different Treatment Regimens Administered (Table II)

Treatment Regimens fully effective for 36 to 52 weeks. Fifteen patients (79%)were kept on a fully effective treatment regimen for between 36 and 52 weeks. Asingle-drug regimen was effective among 12 patients (63%): methylphenidate—6patients (32%); fluoxetine—2 patients (10%); and pemoline, dextroamphetamine,and methamphetamine—1 patient each (5%). Five patients, or 26%, required atwo-drug regimen which included fluoxetine and another one of the following drugs:pemoline, two patients (10%); bupropion, one patient (5%); and methylphenidate,one patient (5%). One patient (5%) was placed on two different treatment regimenswhich were alternated every 38 weeks.

Treatment Regimens Fully Effective for 12 to 36 Weeks. Four patients (20%)never attained full symptom suppression on any treatment regimen for more than36 consecutive weeks. However, they all were eventually treated effectively on twodifferent treatment regimens, with each regimen alternating every 12 to 35 weeks.The five alternating treatment schedules included the following drug combinations:Patient 1—fluoxetine, methylphenidate, and pemoline alternating with fluoxetine,pemoline, and dextroamphetamine; Patient 2—methylphenidate and fluoxetine al-ternating with bupropion and Patients 3 and 4—pemoline alternating with methyl-phenidate.

Treatment Fully Effective for Less than 12 Weeks. Five treatment regimenswere effective only for periods of 2 to 4 weeks or 4 to 12 weeks. They includedthe following medications: fluoxetine and bupropion, dextroamphetamine, and pem-oline. Significantly, all of these short-lived drug schedules were eventually replacedby longer-lasting ones described before.

Treatment Nonresponse. Only one patient, a 22-year-old single female, failedto respond to treatment for ADHD. The only medication that produced sometemporary relief was clonazepam at a very low dosage, 0.5 mg daily. She experienceda cocaine relapse and required hospitalization. A second patient, a married 29-year-old businessman, also relapsed, but did it at a time when he had successfullyattained 100% ADHD symptom relief on two drugs, pemoline and methylphenidate,each one alternating every 24 weeks. As mentioned above, fluoxetine and bupropionwere only rarely fully effective when used alone for more than 12 weeks.

Most patients (14, or 74%) were administered at least two treatment regimensthat proved ineffective during the study trial. The mean number of failed treatment


attempts was three for the entire sample. Only 5, or 26%, attained fully effectivetreatment lasting at least 12 weeks with fluoxetine, the drug generally administeredfirst, usually in combination with other drugs, especially methylphenidate, but alsobupropion, pemoline, and dextroamphetamine.

Adverse Effects

Medications were taken with meals and adverse side effects were rare andmild. Three patients experienced mild appetite loss on fluoxetine, methylphenidate,and dextroamphetamine, and one patient experienced moderate agitation and anxi-ety with bupropion, which responded quickly to administration of clonazepam andinterruption of the antidepressant. He responded well to pemoline and subsequentlyto methylphenidate, without any adverse effects. Another patient experienced mildinsomnia, which subsided upon a 50% reduction of his daily pemoline use (18.25mg/day).

There was no evidence of any abusive/addictive use of any stimulant medicationand no elevations of hepatic transaminases were observed during biannual labora-tory follow-up.

DISCUSSION

We studied the efficacy of a treatment algorithm including long-acting stimu-lants and antidepressants in managing ADHD among stable, adult patients inremission from cocaine dependence. Although treatment regimens in the algorithmthat included long-acting stimulants were far more frequently effective than mono-therapy with fluoxetine or bupropion, other treatment combinations also weresuccessful in suppressing ADHD symptoms without jeopardizing sobriety. Boththe degree and the duration of efficacy of long-acting stimulants in this populationcompare favorably to the results from the five controlled and three open-labelstudies of short-acting stimulants in other adult samples (8-14).

There was a 25% prevalence of ADHD among our moderate-sized populationof generally well-functioning sober adult cocaine addicts. This number is consistentwith other reports that cite a 17 to 40% prevalence of ADHD among differentcocaine-dependent populations (6, 20). Regarding the efficacy of the treatmentalgorithm, it is noteworthy that while most patients eventually attained a very highlevel of clinical improvement of their ADHD symptoms on only one drug—mostlya long-acting stimulant—a third of them (37%) required drug combinations oralternating treatment regimens. And, although most drugs were found to be clini-cally effective for various periods of time, the duration and extent of their clinicaleffectiveness varied among different patients. Nonetheless, one or more "fullyeffective" treatment regimens (suppressing 80% of initial ADHD symptoms for 1full year) were eventually found for all but 1 among the 19 subjects studied. Thisdiversity in clinical response to a similar schedule of drug regimens supports thenotion that ADHD is a multi-syndromic entity comprising several neurobiologicsubtypes (21). Alternatively, the unpredictability of treatment response among our

68 Castaneda, Sussman, Levy, and Trajillo

subjects could also be explained by differences in the rate at which individualsmetabolize and/or develop tolerance to stimulant drugs.

The most obvious connection between any therapeutic effect of cocaine andthose drugs that alleviate ADHD symptoms is the overlap of their effects onthe monoamine neurotransmitters. The current understanding of how medicationsaffect these neurotransmitter systems is consistent with the observed outcome inour study population.

The neurotransmitters commonly cited as being involved in the pathophysiol-ogy of ADHD are dopamine, norepinephrine, and serotonin (22). The mainstay oftreatment has been short-acting preparations of methylphenidate or amphetamines,which have their main effects on these neurotransmitters. Like these psychostimu-lants. cocaine can produce an enhancement of cortical cathecolamine activity. It isthis temporary amelioration of intrinsic dopamine deficiency in the frontal lobesof most adults with ADHD that has been linked to the therapeutic effects of thesedrugs (4, 22).

It is important to note that the general applicability of our findings is limiteddue to several study limitations, such as the lack of a placebo control group and thesmall number of subjects relative to the large number of treatments administered.Lacking an internal control group and another treatment algorithm for comparison,for example, hinders the assessment of the usefulness of fluoxetine and bupropion—which were seldom effective alone. Nevertheless, the high degree of effectivenessof long-acting stimulants for ADHD symptoms in this population is apparent.This is also important because of social and regulatory concerns about any use ofpsychostimulants, which have generated a generally negative view of the administra-tion of these agents to any person with a substance abuse problem. The prescriptionof these agents to "drug addicts" could be interpreted as perpetuating or "priming"the use of cocaine and draw the attention of governmental agencies. A recentlypublished double-blind placebo controlled study of methylphenidate as a "replace-ment" medication in cocaine-dependent subjects who continued to use cocainesuggests that concern about these potential liabilities is unwarranted (23). Thosein that study had neither child nor adult ADHD according to DSM-1V criteria.They had no psychiatric diagnosis other than cocaine dependence. Methylphenidatedid not reduce cocaine intake, but it did not increase cocaine use or cause untowardeffect. According to the investigators, that study appears to contradict the theorythat stimulants "prime" further cocaine use. Given our highly positive experiencewith long-acting stimulants, however, we recommend these compounds over shorter-acting preparations for treatment of ADHD among addicted individuals. Positivefindings from our own study, however, should not be generalized to cocaine abuserswithout ADHD. Whether long-acting stimulants—which have very little addictivepotential—may be substituted for cocaine for a significant period of time, however,warrants investigation. Maintenance treatment with stimulants for cocaine addictsmay be a worthwhile area of clinical research (23).

It is reasonable to conclude that some ADHD patients may initially derivesymptom suppression from the use of cocaine, but the eventual development ofdrug dependence worsens their overall level of functioning. This is particularlyapparent among those patients who reportedly found cocaine/amphetamine use a


necessary practice throughout college. A history of an atypical, if not "paradoxical,"response to cocaine use was a common denominator for all patients in this study.This type of response may be an indication of underlying ADHD and warrantsspecific clinical assessment among addicted (4) and non-addicted individuals.Whether any individual with ADHD may be able to continue using cocaine forself-medicinal purposes is unlikely but has not been investigated.

Although it seems likely that long-acting stimulants also should be highlyeffective among ADHD patients without a history of cocaine dependence, this wasnot established in this study. However, based on our experience with this treatmentalgorithm, we have found it very effective in our clinical practice to begin treatmentof addicted and nonaddicted ADHD patients directly with long-acting stimulants.

CONCLUSION

When initiating the study, we did not expect to achieve such a high degree ofADHD symptom suppression with a single-drug treatment regimen on all patients.Others have demonstrated a need for multiple-agent therapy for ADHD in nonad-dicted patients (4, 22). With this knowledge, as well as observations from ourown initial treatment trials, we developed a treatment algorithm that includedprogressive administration (and discontinuation of any ineffective medication) offluoxetine (15), bupropion (16), pemoline (4), and slow-release preparations ofmethylphenidate, dextroamphetamine, and methamphetamine. We hoped to attaina drug regimen that suppressed 80% of a patient's initial ADHD symptoms for atleast 1 full year, a response that we considered "fully effective" when using theUTAH Criteria for Adult ADHD scale (17). Those treatment regimens in thealgorithm which included long-acting stimulants, alone or in combination withfluoxetine or bupropion, were consistently effective, without significant side effects.As described above, we found this treatment strategy to be highly effective insuppressing ADHD symptoms with minimal cocaine slips or relapses.

The utility of this algorithm in other cocaine-addicted individuals must beconsidered in the context of the generally high level of functioning of the studysubjects. They were sober, most of them for over 1 year. This permitted credibleassessment of ADHD and other psychiatric symptoms as well as evaluation of theirpharmacological response. Diagnosis is likely to be less reliable and treatment morerisky and unpredictable among less advantaged addicted individuals. Furthermore,most of the study subjects were self-supporting, and all were within the middleor higher socioeconomic range and had stable financial and social supports. Notinsignificantly, all could afford the highly expensive long-acting amphetamine prepa-rations. Restricted access to specialists and inability to afford expensive medicationsby individuals with ADHD may prevent the application of this treatment modelin the clinical setting. The highly encouraging results of the study, however, warrantresearch evaluation of the treatment algorithm in both nonaddicted and addictedindividuals with ADHD.


ACKNOWLEDGMENTS

This project was supported in part by BRSG SO7 RR05399-28 awarded bythe Medical Research Support Grant Program, Division of Research Resources,National Institute of Health (Dr. Castaneda). The study was done at New YorkUniversity Medical Center, New York.

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