Chapter 8 Stimulants and Other Fast-Acting Drugs

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Chapter 8. Stimulants and Other Fast-Acting Drugs

INTRODUCTION

Like all other drug classifications in clinical psychopharmacology, the term stimulants covers a

range of drugs, with some overlapping actions, that may be useful in treating some disorders,

syndromes, or symptoms (Table 8–1). Here, as elsewhere, we lack a tidy one-to-one correlation of

drug efficacy and syndrome.

Table 8–1. Stimulants: names, formulations, and strengths

Generic name Brand name Formulations and strengths

D-amphetaminea

Dexedrine

Dexedrine Spansule

Tablets: 5, 10 mg

Spansules: 5, 10, 15 mg

amphetamine/dextroamphetamineb Adderall

Adderall XR

Tablets: 5, 7.5, 10, 12.5, 15, 20, 30 mg

Capsules: 5, 10, 15, 20, 25, 30 mg

D-methamphetamine Desoxyn Tablet: 5 mg

methylphenidatea

Ritalin

Methylin

Ritalin SR

Ritalin LA

Metadate ER

Metadate CD

Concerta

Daytrana

Tablets: 5, 10, 20 mg

Tablets, chewable: 2.5, 5, 10 mg

Oral solution: 5 mg/5 mL, 10 mg/5 mL (500 mL)

Tablet: 20 mg

Capsules: 10, 20, 30, 40 mg

Tablets: 10, 20 mg

Capsules: 10, 20, 30 mg

Tablets: 18, 27, 36, 54 mg

Transdermal patch: 10, 15, 20, 30 mg/9 hoursc

dexmethylphenidate Focalin

Focalin XR

Tablets: 2.5, 5, 10 mg

Capsules: 5, 10, 20 mg

modafinil Provigil Tablets: 100, 200 mg

aAvailable in generic form.

bAvailable in generic except the extended-release form.

cDelivery rate of 1.1, 1.6, 2.2, and 3.3 mg/hour for the 10-, 15-, 20-, and 30-mg patches, respectively. In

vivo delivery rate is based on a wear period of 9 hours of pediatric patients ages 6–12 years.

The concept of stimulants began early with caffeine and then, probably, with ephedrine extracted

from a Chinese herbal remedy in the 1930s. Ephedrine was and still is a stimulant, causing euphoria

and sympathetic activation and alertness, even though it is mainly used in treating asthma and has

never been tested for efficacy in attention-deficit/hyperactivity disorder (ADHD), obesity, or, to our

knowledge, narcolepsy. From ephedrine, K. K. Chen synthesized a variant, amphetamine

(Benzedrine), which was, within 10 years, separated into its two stereoisomers, D-amphetamine

(Dexedrine) and L-amphetamine. The dextro isomer was much more potent and is almost the only

one used clinically today. It turned out to be effective in focusing attention and/or decreasing

maladaptive behaviors in children who would now be diagnosed as having ADHD; in reducing

sleepiness (i.e., in narcolepsy); and in reducing fatigue-induced decrements in behavior. It

decreases appetite and has been widely used as an antiobesity medication. For some years,

D-amphetamine was sold as a cold remedy, in an inhaler, to shrink swollen nasal membranes when

inhaled. It was also used in treating depression and related fatigue states, until the widespreadPrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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abuse of its analog D methamphetamine (speed) by self-injection in the 1960s led to legislation

scheduling most stimulants into Drug Enforcement Agency (DEA) Schedule II along with morphine

and the potent opiates. This decision was made despite the fact that almost all illicit

methamphetamine was made illegally and not diverted from drug companies, pharmacies, or

doctors.

As a result of the legislative scheduling, the use of stimulants in medicine decreased sharply, and

their use was sanctioned only for ADHD, narcolepsy, and obesity. Methylphenidate (Ritalin) was

marketed just before the law changed and has become much more widely used than

D-amphetamine for ADHD. In the last few years, Adderall, an “old” drug because it was effective in

treating obesity when all old drugs were assessed in the early 1960s, has recently been resurrected

as a treatment for ADHD (Horrigan and Barnhill 2000). Adderall contains three different salts of

D-amphetamine and one of L-amphetamine. So far, no studies are available comparing Adderall

with either D-amphetamine or methylphenidate in treating ADHD, but it seems likely to be about as

active as the total of its D-amphetamine salts in any of the situations in which D-amphetamine is

useful. Adderall is available in tablets of various strengths (see Table 8–1); its potency is probably

slightly less than the same dose of D-amphetamine, but its duration of action may be longer. It had

taken over a 33% market share by 2001 (Rosack 2001). A long-acting form of Adderall, Adderall

XR, lasts as long as 10 hours and is given at a dosage of 10–30 mg/day, with the dose taken in the

morning.

D-Methamphetamine is still available in immediate-release form by prescription as Desoxyn. Its

sustained-release form was believed by Wender to be superior in duration of action to either the

current Ritalin SR (available in a 20-mg dose) or the current Dexedrine Spansule. The last two have

a reputation for discharging their main dose of stimulant in the first hour or two and may not have

the prolonged effect their makers intended. Unfortunately, Abbott Laboratories recently stopped

distributing long-acting Desoxyn, so its possible benefits are irrelevant. (As of this writing, an

immediate-release form is still manufactured by Ovation Pharma.) Alternatively, it is possible that

the brain responds only to rising stimulant levels and that a prolonged, even elevation of blood

level over hours might lead to rapid loss of all behavioral effect. Newer and better long-acting

forms of methylphenidate and amphetamine are now available. One of these, Concerta, a

long-acting methylphenidate formulation that lasts 12 hours, was released in July 2000 and is

available in strengths of 18, 27, 36, and 54 mg. It appears to be truly long-acting.

A number of new stimulant dosing options have become available in the past few years, and

relevant studies of these agents were discussed by Dr. Lawrence Greenhill at the 2001 American

Academy of Child and Adolescent Psychiatry meeting as reported in Psychiatric News (Rosack

2001). Methylphenidate is available in its old, familiar immediate-release form, racemic dl

methylphenidate, with its effectiveness for ADHD symptoms lasting 3–4 hours, and

l-methylphenidate–sustained release (Ritalin SR), which has been available for several years and is

believed to be weaker, both in onset of action and possibly in duration of action, than

immediate-release Ritalin. Novartis, manufacturer of Ritalin and Ritalin SR, has developed Ritalin

LA (long acting), designed to release half of each dosage unit quickly and the other half slowly.

However, Novartis also has obtained pure d-methylphenidate (Focalin), which is twice as potent as

racemic Ritalin—2.5 mg of Focalin equals 5 mg of d,l-methylphenidate. The d isomer even appears

to be slightly—but statistically—more effective than twice the dose of d,l-methylphenidate.

To add options and perhaps confusion to the field, Celltech Pharmaceuticals has brought out a

long-acting methylphenidate (Metadate CD), which produces about 8 hours of effect, compared

with Concerta’s 12 hours of action. Both seem “better” in duration of action than Ritalin SR and,

presumably, Focalin. Further, another company has developed a transdermal methylphenidate

patch (Daytrana), which has recently become available.

Adderall XR also releases half its dosage of mixed amphetamine metabolites rapidly and the other

half slowly, both from little coated beads like those in a Dexedrine Spansule. These beads can be

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All these long-acting preparations cannot be smashed up without losing their prolonged action.

Concerta tablets, or their residua, can sometimes be seen in the taker’s feces.

The original idea behind all this ingenuity was to avoid the midday pill that may embarass

schoolchildren or complicate the lives of school nurses or that could be diverted to others. Also,

some youngsters with ADHD need continued medication effect to be able to do homework or other

evening activities well. These various forms allow the prescribing physician to adjust the drug

formulation to the needs and side effects of individual patients. If a patient has loss of appetite for

supper and insomnia, he or she may not need a 12-hour stimulant like Concerta.

One approach to all this is to determine the bid or tid dose of dl-methylphenidate or

D-amphetamine and then replace these multiple doses with the appropriate longer-acting

formulation.

Adderall was already believed to have a 5-hour duration of action in ADHD, and Adderall XR should

stretch this to possibly 10 hours.

Not all stimulants work in an identical way. Methylphenidate, D-amphetamine, and cocaine all

increase release of dopamine into the postsynaptic cleft. D-Amphetamine affects presynaptic

receptors as well, whereas methylphenidate does not. Pemoline (Cylert), which resembles

methylphenidate in its mechanism of action, was longer acting than D-amphetamine or

methylphenidate and was only in Schedule IV. However, it caused rare but lethal liver toxicity (see

below), which made it undesirable as a first-line drug, and has since been taken off the market.

Clinicians have had experience with D-amphetamine, methylphenidate, pemoline, and several

anorexiant drugs like phentermine for many years. It is clear that occasional patients will do very

well while taking one of these drugs but fail to respond to any of the others for no apparent reason.

The use of stimulants in psychiatric practice has been reviewed extensively elsewhere (Chiarello

and Cole 1987; Klein and Wender 1995; Satel and Nelson 1989; Wilens et al. 1995). It should also

be noted that in hospital pharmacies, stimulants have been made into suppositories for rectal

administration to patients unable to swallow pills.

Fenfluramine (Pondimin), which in 1997 was available for use in decreasing appetite, was

presumed to exert its effects through a serotonergic mechanism, but it was not a stimulant. In

1987 d-fenfluramine, one of its isomers, was introduced in the United States after having been

available in Europe for some time and was widely used alone or in combination with phentermine

(Ionamin) as “fen-phen” in obesity programs. d-Fenfluramine turned out to be associated with

changes in the heart valves and with occasionally fatal pulmonary hypertension and was withdrawn

from the U.S. market.

At about the same time, sibutramine (Meridia) was introduced for the treatment of mild to

moderate obesity. It was free of any evidence of abuse liability in premarketing studies but was

placed in Schedule IV anyway by the Food and Drug Administration (FDA) because other drugs

approved for the treatment of obesity were of abuse potential. Sibutramine started life as a

potential antidepressant; it blocks reuptake of norepinephrine, serotonin, and dopamine. However,

in its first two clinical trials in depression, the weight loss of the patients seemed even more

impressive than the effects on depression. Hence, we have an appetite-suppressing drug that is not

particularly stimulant-like in other respects.

Late in 1998 modafinil (Provigil) was marketed for the treatment of daytime sleepiness related to

narcolepsy. This drug had been in use in France for several years and had not been noted to be

abused. It was reported to “feel” like a stimulant in some human abuse liability trials but has

slower onset of action and longer duration of action than D-amphetamine. Further, it appears to

have no observable effect on any receptor or any biogenic amine in the brain. Radioactive modafinil

concentrates in the hypothalamus, whereas conventional stimulants do not. So we have yet another

“stimulant” that is not conventional. A number of studies have suggested that modafinil may help

lessen the fatigue and sleepiness associated with a variety of conditions, such as shift work andPrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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obstructive sleep apnea. In addition, preliminary work also suggests that modafinil may be

effective in the treatment of ADHD. Recent studies by our group and others suggest that a dosage

of 100–200 mg/day of modafinil added to a selective serotonin reuptake inhibitor (SSRI) helps

with fatigue and hypersomnia associated with depression.

The current dilemma is that ADHD and narcolepsy (and depression when it responds) may require

amphetamines as maintenance therapy for years or at least months, so that the DEA Schedule II

restriction that each prescription must be rewritten each month becomes a burden on both the

doctor and the patient.

As can be seen, this chapter on stimulant drugs covers drugs used for the core indications of the

older stimulants—ADHD, narcolepsy, and obesity—whether or not they have obvious stimulant

effects in man or animals. Monoamine oxidase inhibitors (MAOIs) could be included here, but drugs

whose major use is in treating depression are considered in Chapter 3 (“Antidepressants”) instead.

AMPHETAMINE ABUSE

D-Amphetamine and methylphenidate, but not magnesium pemoline or modafinil, are

spontaneously self-administered intravenously by laboratory animals and are well known to have

abuse liability in humans. An unpublished study by the second author showed pemoline, in single

doses of 75 mg and 150 mg, to have no euphoriant effects in casual recreational users. Sibutramine

is also without euphoriant effects (Cole et al. 1998).

One of the most abused stimulants to date is methamphetamine. This drug was used intravenously

in very high doses during the flower-child period of the 1960s, resulting in some individuals, known

as “speed freaks,” becoming heavily dependent. Such individuals usually took the medication in

relatively large doses in runs of a few days and then withdrew from the drug for a day or two,

experiencing a crash, before starting again. Patterns of oral abuse were less intense and dramatic

(Grinspoon and Hedblom 1975).

Methamphetamine abuse has reemerged in recent years. The original formulation, known as

“speed,” was the hydrochloride. Crystalline methamphetamine base, known as “ice,” has been

widely abused in Hawaii and California. It is chiefly smoked but is also used intravenously, the

preferred route during the 1960s. When smoked, it appears to give a rush (immediate pleasurable

feeling) similar to that of cocaine but with a longer duration of the euphoric state. This effect fits

with the known relative pharmacokinetics: methamphetamine is metabolized more slowly than

cocaine. In monkeys, cocaine is more abusable intravenously than is methamphetamine; monkeys

will work harder and longer to get cocaine and will continue self-administration for days without

stopping, until death occurs. In contrast, amphetamines are less reinforcing. It is too early to tell

whether smoked ice will be more or less of a problem than cocaine. Cho (1990) reviewed the

pharmacology of ice, but no studies and almost no other published reports on ice are available.

There is reasonable evidence that very high doses of D-amphetamine, generally higher than 80

mg/day and sometimes as high as 1,000–2,000 mg/day, can produce an acute psychosis that

generally resembles paranoid schizophrenia but can occasionally present with delirium and other

conventional signs of toxic drug psychosis. This condition is sometimes considered a model for

schizophrenia, or at least for acute paranoid psychosis. In addition, parenteral administration of

methylphenidate has been used as a test to predict risk of psychotic relapse in patients with

schizophrenia.

Magnesium pemoline was a little different from the other two drugs, having had a somewhat slower

onset and offset of action, and for a while was preferred in treating occasional patients who get

symptom relief for 3–4 hours from a single dose of methylphenidate or D-amphetamine but who

experienced an abrupt change in status as the drug wore off. For such patients, magnesium

pemoline may have been smoother and better tolerated. Unfortunately, the risk of serious liver

damage with magnesium pemoline use in both children and adults was increasingly judged to be

more serious (Young and Findling 1998), and the drug was eventually taken off the market.Print: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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Although modafinil is a Schedule IV drug, no evidence of an abuse potential has occurred in

postmarketing surveys since 1998. Since modafinil, unlike amphetamine, does not affect the

dopaminergic systems that mediate reward in the cortex, there is no physiological basis for abuse

or dependence. Rapid discontinuation of the drug has not been associated with withdrawal

symptoms.

USES OF STIMULANTS

Attention-Deficit/Hyperactivity Disorder

ADHD is the only condition other than narcolepsy and weight reduction for which stimulants are

currently approved by the FDA. In children, the syndrome is manifested by very short attention

span, overactivity, irritability, poor social relations, impulsivity, occasional angry or assaultive

behavior, poor school performance, and apparent inability to benefit from instruction or limit

setting. Some children with the syndrome have a parent with a history or current symptoms of a

similar condition. Occasional children with the syndrome have clear evidence of central nervous

system (CNS) damage at birth or subsequently; the majority of such patients, however, do not have

“hard” neurological signs of clearly diagnosable brain injury or abnormality.

In children with ADHD, any of the three drugs is likely to be clinically better than placebo in about

70%–80% of those treated; about 30% show a clear and highly impressive degree of clinical

improvement, and another 40% show some modulation of behavior that may be of some clinical

importance. Occasionally, children are made more active by these drugs. In the first weeks of

treatment, children often look drawn and even somewhat depressed and rarely show any

euphoriant effect from the medication. It is not clear that the drugs dramatically reduce activity

level. They probably act by improving attention span and organizing behavior more effectively.

Some degree of growth inhibition or weight loss has been reported occasionally in children, but

these are generally not major problems. (See Chapter 12: “Pharmacotherapy in Special Situations”

for further discussion of the use of stimulants in children.)

Huessey (1979), at the University of Vermont; Ratey et al. (1994) and Spencer et al. (1995) in

Boston; and Wender et al. (1985) at the University of Utah identified adults with symptoms

resembling those seen in children with ADHD and showed that such adults respond to stimulant

therapy. These drug responders are very likely to be remembered as hyperkinetic children by their

parents. Some individuals who have had clear clinical benefit from stimulants in childhood continue

to require and to benefit from stimulant medication well into adult life. Many children with ADHD,

however, seem to grow out of the major manifestations of the illness at some time in adolescence,

although they are often left with residual symptoms of impaired concentration or coping ability,

which may or may not be benefited by further stimulant administration. This issue is well discussed

by Klein and Wender (1995). Further, Ward et al. (1993) developed a useful self-report form for

use by adult patients suspected of having had ADHD behaviors in childhood.

The interesting and clinically useful aspect of stimulant therapy in treating either children or adults

with ADHD is that clinical effects are often clear and dramatic within a day or two of reaching the

appropriate dosage. Stimulant therapy, with this rapid clinical response, stands in dramatic

contrast to the more conventional antidepressants and antipsychotics, which often take days or

even weeks to achieve a satisfactory clinical result.

In clinical practice, adults with personality disorder, short attention span, restlessness,

hyperactivity, irritability, impulsivity, and related symptoms sometimes present with a history of

illicit drug abuse. In treating such individuals, a trial of a stimulant raises an ethical problem: when

it is clear that any stimulant will be abused, the drug cannot be used. Stimulants can be used in

patients with a history of drug abuse under the following circumstances:

The stimulant drug has clearly been used to improve functioning rather than to get high (produce

euphoria).

1.  
2. A good therapeutic alliance is available.
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4. Other approaches have failed.
5. The patient’s problems are seriously interfering with his or her life functioning.

Some children and adults with ADHD respond to bupropion, venlafaxine, or desipramine, which can

be used with patients who might abuse a stimulant. Clonidine, atomoxetine, and guanfacine may

also be alternatives for patients who cannot use stimulants. Emerging data suggest that the

nonstimulant modafinil also may be useful in the treatment of ADHD.

The utility of stimulant therapy in treating substance abusers with a clear history of ADHD,

including individuals addicted to cocaine (Schubiner et al. 1995), has been documented in open

trials, as has the lack of utility of stimulant therapy in treating cocaine users without ADHD during

the early post–cocaine withdrawal period; methylphenidate facilitates return to cocaine use in such

patients. There is now a smattering of studies of the use of various antidepressants (desipramine,

phenelzine, bupropion, SSRIs, selegiline, and venlafaxine) in treating patients with ADHD, both

childhood and adult varieties. Desipramine and bupropion are the best-documented drugs for this

purpose. Most controlled studies have been positive. Some clinicians believe that, in children at

least, desipramine tends to lose its effectiveness over time. With all these drugs, it is best to start

with low dosages (e.g., 10 mg/day of desipramine, 75 mg/day of bupropion sustained-release [SR]

formulation) on the presumption that some ADHD patients will be likely to respond to low doses

and show undesirable side effects at higher dosages.

The issue of the existence of ADHD (or attention-deficit disorder without hyperactivity) in adults

has received more attention in the last few years. Ratey et al. (1994), in a clinical report, described

patients with these conditions and their responses to various medications, and Spencer et al.

(1995) reported positive results in a placebo-controlled trial of methylphenidate in treating adult

ADHD patients at Massachusetts General Hospital. The superior effectiveness of stimulants,

compared with psychosocial treatment, for childhood ADHD received strong support from a

federally sponsored multicenter study (Jensen et al. 2001). Further, the breadth of stimulant effect

in conduct disorder in children was strongly supported by the results of a study by Klein et al.

(1997).

Atomoxetine is a pure norepinephrine reuptake blocker that is FDA approved for the treatment of

ADHD in children and adults. It appears to have no abuse liability potential and has been shown to

be significantly more effective than placebo in children and adolescents as well as in adults with

the disorder. In a small study in adults, Spencer et al. (1998) reported that the drug was

significantly more effective than placebo. The average dosage was 76 mg/day. Subsequently,

several positive trials in adults have been reported (Michelson et al. 2003). Similarly, the drug has

been reported to be effective in a large study in children and adolescents (Michelson et al. 2002)

(see Chapter 12: “Pharmacotherapy in Special Situations”). Atomoxetine appears to be more

effective in improving attention than in controlling hyperactivity. Relative to the effects of

stimulants, the effects of atomoxetine on ADHD are also more gradual. Stimulants tend to show

more rapid benefits.

The adult daily dose is 40–100 mg; in children, the daily dose is approximately 1.2 mg/kg and

should not exceed 1.4 mg/kg, or 100 mg, whichever is less. Primary side effects appear to be, in

children, loss of appetite and gastrointestinal upset and, in adults, gastrointestinal upset,

orthostatic blood pressure effects, and insomnia. In contrast to the older stimulants, the dosage of

atomoxetine has to be increased slowly to avoid somatic side effects.

Depression

In the early literature on the use of amphetamines in psychiatry, there were a number of case

reports of individuals presenting with the full syndrome of endogenous depression who responded

dramatically to racemic amphetamine. A few double-blind trials completed since the early 1970s

showed some evidence of clinical efficacy of stimulants in depressed outpatients. Findings from

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Given the ill repute into which stimulants have fallen, it has probably not been reasonable to

conduct further trials of stimulants in patients with first-onset, non-treatment-resistant depression.

However, in patients with a chronic treatment-resistant depression who have failed to respond to a

range of standard antidepressants, stimulants occasionally provide excellent symptomatic relief

and often enable patients to function adequately for prolonged periods without side effects or any

indication that the drug is being abused or misused. Some of these patients have clear-cut

endogenous symptoms, others appear to have atypical depressions, and still others have major

symptoms of fatigue or neurasthenia. A survey of stimulant prescribing patterns in a sample of

Massachusetts psychiatrists (Cole et al. 1993), as well as a more recent Canadian survey of

psychiatrists (Beck et al. 1999), confirmed that these heterogeneous indications still apply to

current clinical practice.

It is not possible to tell in advance which depressed patients will benefit from stimulant therapy.

Rickels et al. (1970) suggested some time ago that relatively heavy intake of coffee (four cups a

day or more) was a predictor of good clinical response, at least to magnesium pemoline. In

contrast, patients who are intolerant of caffeine sometimes cannot tolerate stimulants.

However, experience at McLean Hospital, in an informal study of 30 patients who had done well

while taking prescribed stimulants for more than 2 years, suggests that some depressed patients

with excellent response to stimulants dislike or avoid caffeine-containing beverages. Only three of

the patients in the study had histories suggestive of childhood ADHD, but many had a significant

“thought disorder” (i.e., difficulty in organizing their thoughts and in functioning effectively at

work or school). Almost all had significant depression, and several had bulimia. All but three had

had persistent benefit from stimulants for a period ranging from 2 to 30 years.

The cases of the three patients with poor outcomes can be summarized as follows: one took

stimulants at very high doses for 20 years, initially to lose weight, but instead he gained weight

massively, finally requiring a gut bypass operation. His career was probably adversely affected, and

a family disaster, with resulting major depression, led to his referral to McLean from another state.

One professional with clear ADHD symptoms from childhood who succeeded academically without

stimulant therapy ended up taking methylphenidate 80–120 mg/day, which, paradoxically, caused

fatigue and inability to function professionally. The third, after having had a favorable response for

a decade, began to experience marital stress and developed paranoid hypomania alternating with

depression. Each retrial of a stimulant to relieve her chronic depression led to hospitalization, with

the patient in a paranoid excitement.

The poor outcomes in these three cases must be balanced against the substantial symptom relief

and improved role functioning in all the other patients seen in consultation. Many were followed for

up to 15 years with continuing benefit (Cole et al. 1993).

Stimulants also have a place in the crisis management of individuals whose functioning is impaired

by depression and whose life situation would deteriorate rapidly if they were not able to resume

functioning within a few days. In such situations, a trial of methylphenidate, D-amphetamine, or

Adderall is worth initiating to attempt to get a patient through a crisis when failure to function

might result in getting fired from a job or flunking out of college. In such situations, weaker

semistimulants such as bupropion are unlikely to work rapidly enough to be useful. Pemoline used

to be the ideal first stimulant to try, but liver problems make it an undesirable choice. In the future,

modafinil, assigned to Schedule IV and therefore refillable, may prove useful. For now,

D-amphetamine in its generic form costs less and is a bit more likely to be effective than

methylphenidate. One might begin with D-amphetamine 5 mg in the morning and increase the

dosage by 5 mg every morning until the patient either feels better or feels unpleasantly stimulated.

The patient should check in daily during this process. If the morning dose helps, a second, equal

dose 4–6 hours later should be added. If the D-amphetamine has an unpleasant effect, it should be

stopped and methylphenidate 10 mg (5 mg in elderly or hypertensive patients) should be tried

instead. Adderall, the mixture of amphetamine salts, at an initial dose of 10 mg can also be tried.

Dosages up to 20 or 30 mg/day of D-amphetamine or twice that amount of methylphenidate alsoPrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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can be used to see whether a response occurs.

The major problem in recommending stimulant therapy to other psychiatrists for a specific patient

is the likelihood that the patient will be left taking an ineffective dosage (e.g., initial dose 5–10 mg

once or twice a day) for a couple of weeks, until the drug is stopped for lack of efficacy. Using a

stimulant in adult psychiatric patients requires close—almost daily—monitoring, at least by

telephone, so that the treating psychiatrist can determine whether the drug at the dosage given

had any effect. In the absence of any effect, positive or negative, the dosage should be steadily

increased until something happens—up to 40 mg/day of D-amphetamine or 80 mg/day of

methylphenidate. This dosing method is infrequently used, perhaps because of fear of the abuse

potential of the drug (uncommon in psychiatric patients) or because psychiatrists are so

accustomed to using drugs that take 7–30 days to act that they do not change their prescribing

behavior when using unfamiliar but rapid-acting drugs like D-amphetamine.

Some patients show an initial excellent response to a stimulant medication and then develop rapid

tolerance and all effect is lost, whereas others continue to benefit from the same low dose of the

stimulant for months or even years. Still other patients feel anxious, agitated, and unpleasantly

“wired” while taking some or all stimulants. If the drug is to be stopped, it can be either tapered or

stopped abruptly. Some rebound depression may occur (see Chapter 11: “Pharmacotherapy for

Substance Use Disorders”). Patients with a history of pronounced mood disturbances may require

hospitalization.

D-Amphetamine is available in 5-mg, 10-mg, and 15-mg Spansule (slow-release) formulations.

Methamphetamine (Desoxyn) is available in a 5-mg tablet. Adderall is available in 5-mg, 7.5-mg,

10-mg, 12.5-mg, 15-mg, 20-mg, and 30-mg tablets, about equivalent in efficacy to that dose of

dextroamphetamine.

Methylphenidate is available in a 20-mg SR formulation. Better, really longer-acting preparations of

several stimulants have recently been marketed or are now under development (see discussion

earlier in chapter). One of these, Concerta, is available in 18-mg, 27-mg, 36-mg, and 54-mg

12-hour SR tablets. Several years ago, the increasingly common use of methylphenidate was a

concern to many in the community, and there has been considerable debate as to whether it is

being overused. The debate has subsided in the past few years.

Some depressed patients prefer taking ordinary tablets of D-amphetamine or methylphenidate and

may take the entire daily dose at once on arising, even if 30–60 mg/day is being given. Such

patients feel no rush or high but are relieved of depression for at least 24 hours. Others take single

fast-release tablets several times a day, taking another as the effect of the first dose wears off.

Some dislike this on-off effect and prefer to use SR preparations.

After decades in which only single-dosage forms of D-amphetamine and methylphenidate were

available, there are now several forms of methylphenidate with different lengths and forms of

sustained release. Several appear designed to avoid the necessity for the child with ADHD to take a

second dose of stimulant around noon, which entails involving the school and making the child’s

“problem” obvious to teachers or classmates. The most recent variant, the “patch,” bypasses the

oral route and uses a “bandaid”-like approach. It is too early to tell if this or other available

formulations are better or worse than other established formulations. We suggest that ordinary

immediate-release pills be used initially and that the dose and the formulation be adjusted to

improve drug response (e.g., ability to study after school) or avoid side effects (i.e., anorexia or

initial insomnia).

Phenylpropanolamine was marketed as an over-the-counter antiobesity pill in 37.5-mg and 75-mg

strengths, usually in a SR preparation. We have seen occasional patients with either depression or

ADHD who had found phenylpropanolamine helpful in the way a standard stimulant sometimes is.

However, most patients and most recreational users of drugs find the subjective effects of

pseudoephedrine or phenylpropanolamine mildly unpleasant. When phenylpropanolamine was

abused in “triple-threat” illicit pills containing ephedrine and caffeine as well, it is likely that thePrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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ephedrine or the combination accounted for the pills’ amphetamine-like properties.

Phenylpropanolamine alone may reduce appetite and increase pulse and blood pressure a little, but

it is not a useful stimulant. It should be noted that the drug marketed in Europe as

phenylpropanolamine is a different stereoisomer and probably has amphetamine-like stimulant

effects.

In November 2000, the FDA issued a public health advisory concerning phenylpropanolamine in

over-the-counter and prescription drug products. There was growing evidence that

phenylpropanolamine increases the risk of hemorrhagic stroke in women and, perhaps, in men

(though the risk appears to be lower in men). The advisory committee recommended that drug

companies discontinue marketing drug products containing phenylpropanolamine. Then in

December 2005, the FDA stated their position in a bulletin: “The Food and Drug Administration

(FDA) is taking steps to remove phenylpropanolamine . . . from all drug products and request that

all drug companies discontinue drug products containing phenylpropanolamine.” Currently, drug

products (OTC or prescription) do not contain phenylpropanolamine (see the FDA’s information

page on phenylpropanolamine (www.fda.gov/cder/drug/infopage/ppa).

Acquired Immunodeficiency Syndrome

Patients with AIDS often have a mixture of depression, fatigue, and difficulty initiating activities,

perhaps a form of akinesia (see Chapter 12: “Pharmacotherapy in Special Situations”). Such

patients may have CNS complications of AIDS, including shrinking of the basal ganglia. Standard

tricyclic antidepressants (TCAs) may or may not be poorly tolerated, but one fears that they may

cause increased memory problems or delirium. Methylphenidate appears to be widely used in

treating such patients, with excellent results, though little has been written about this use. Patients

can begin taking low dosages (e.g., 5 mg bid), titrated to a level relieving symptoms without

causing side effects. The dose may need to be increased gradually as the disease progresses. Local

experts in Boston give us the impression that methylphenidate in treating AIDS-related depression,

inertia, and confusion resembles L-dopa in treating parkinsonism—a replacement therapy needed

because of changes in the brain. This idea is, of course, purely speculative.

Other stimulants have not, to our knowledge, been tried in AIDS patients, but there is no obvious

reason why D-amphetamine, D-methamphetamine, or Adderall should not be tried. Some children

with ADHD do better on one than on another, and stimulant-responsive depressed patients often

have clearly better responses to one of these drugs than to the others, for no known reason.

Appetite suppressants, such as phenmetrazine, phentermine, and Biphetamine, sometimes work as

antidepressants in individual patients. There is preliminary evidence that modafinil helps relieve

depression when added to an SSRI (Monza et al. 2000); similar cases have been seen at McLean

Hospital. Sibutramine, an appetite suppressant at 5–15 mg/day, was originally developed to be an

antidepressant; it would not be surprising if it also was useful in treating “ordinary” depression as

well as anhedonia in patients with AIDS. There is, however, some evidence that standard

antidepressants, both TCAs and SSRIs, are useful in treating depressive disorders in patients

testing positive for HIV, with or without overt AIDS, and are well tolerated (Markowitz et al. 1994).

Stimulants may have unique abilities to improve energy or cognitive functioning of AIDS patients,

but all studies in this important area are uncontrolled and the findings are relatively impressionistic

(Angrist et al. 1992).

Other Medical Conditions

A growing series of case reports has documented the usefulness of stimulants in treating patients

on the medical wards of general hospitals. These patients have various combinations of debilitating

depression and fatigue that make them unable to cooperate in necessary treatments, and they lose

weight rapidly. In this situation, standard antidepressants simply do not have a fast enough onset

of action. Stimulants do, probably about 50% of the time, have a fast enough onset of effects. For

this indication, therefore, they are being used more commonly and appear to be safe (Wallace et al.Print: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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1995).

DRUG COMBINATIONS

Methylphenidate and D-amphetamine both interact with imipramine in laboratory animals to

potentiate response to electrical stimulation of pleasure centers. Part of this potentiation is

pharmacokinetic, in the sense that the stimulant and the TCA interfere with each other’s

metabolism, causing higher blood levels of each. This property was sometimes used clinically, when

methylphenidate was prescribed early in TCA therapy to hasten response. If a patient improved

with methylphenidate plus imipramine, it was impossible to know whether the clinical response

was due to 1) the methylphenidate alone, 2) a longer period taking imipramine, 3) the elevation of

imipramine blood level caused by methylphenidate, or 4) a true combined effect of the two drugs.

Generally, we do not recommend this combination approach (see Chapter 9: “Augmentation

Strategies in Treatment-Resistant Disorders”). Stimulants have been used to counteract anergia

secondary to SSRI therapy in depression. Here, the plasma levels of the SSRI may be increased.

Intuitively, it should be considered clinically dangerous to combine a stimulant with an MAOI,

because the addition of a stimulant might precipitate a hypertensive crisis. However, we know of a

few patients who have, on their own responsibility, added magnesium pemoline, methylphenidate,

or D-amphetamine to reverse MAOI-induced sedation or lack of clinical response, with alleged good

subjective effects and no apparent effect on blood pressure. Other such patients have been

described in the literature. We have seen hypertensive crises when phenylpropanolamine or

pseudoephedrine was added to an MAOI, but so far we have not encountered any such crises with

stimulant-MAOI combinations. Stimulant-MAOI combinations are not recommended in general

practice; however, the combination has been used cautiously to counteract MAOI-induced

hypotension (see Chapter 3: “Antidepressants”) and, by us, to reverse MAOI-induced daytime

sedation, so far without adverse effects.

PSYCHOSIS

The older literature, from the 1930s and 1940s, on the use of racemic amphetamine,

D-amphetamine, and methylphenidate in treating patients with what was then called chronic

schizophrenia reported mixed results: some patients improved on a stimulant given alone, some

showed no change, and some worsened. However, more recent studies of single doses of

intravenous methylphenidate showed that this drug increases psychosis in drug-free acutely ill

patients with mania or schizophrenia but has only a mild stimulant effect when such patients are in

remission. Studies by Angrist et al. (1980) and Robinson et al. (1991) demonstrated that

chronically ill schizophrenic outpatients who showed increased psychosis after a single dose of a

stimulant were much more likely to relapse into a psychotic exacerbation than were patients who

showed no worsening on stimulant administration. Other work by Lieberman et al. (1994) also

supports the finding that an exacerbation of psychosis to a single dose of methylphenidate may

predict higher relapse risk in stable patients whose antipsychotic dose is reduced or discontinued.

This type of research has become extremely controversial in recent years because of ethical

concerns about worsening patients’ conditions.

Another “stimulant,” fenfluramine in its racemic form, was used in the past to raise TCA blood

levels and to lower blood serotonin in autism. It has been shown to have weak antimanic effects.

Unfortunately, the release of its d-isomer in the United States for obesity was followed by intensive

use in combination with phentermine (so-called fen-phen). A number of patients developed

pulmonary hypertension with serious consequences, and both forms of the drug, the earlier dl form

and d-fenfluramine, were withdrawn from clinical use in the United States.

STIMULANT USE VERSUS ABUSE

We have occasionally seen patients who had taken prescribed stimulants for years, with claimed

excellent relief from depression, fatigue, or disorganized behavior, and had had the drug withdrawn

by a physician concerned about drug abuse. Such patients then often failed to respond to a variety

of more conventional TCAs and were dysphoric and unable to function adequately for years. WhenPrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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the stimulant was represcribed, these patients often did quite well again for prolonged periods. It

may be very hard to tell whether such individuals (who rarely have histories suggestive of ADHD)

really have a uniquely stimulant-responsive disorder or whether they have somehow become

dependent on stimulants. In either case, if they cope well and feel well only when taking

stimulants, take low to moderate dosages as prescribed, and do not develop tolerance, the

stimulant should be continued. If the physician feels uncomfortable about prescribing stimulants

for such patients, consultation with a clinical psychopharmacologist may provide helpful clinical

and ethical support.

More difficult permutations of the problem exist, of course. What about a patient who recalls

D-amphetamine as making him feel “better,” but not better enough to actually complete graduate

courses or even to motivate him to pay the bill of the psychiatrist who was prescribing the pills?

What about a patient for whom a host of antidepressants have failed but who refuses to try an

MAOI because of the restricted diet and risks? Should she be forced to fail on an MAOI before a

stimulant is tried or retried? What about a marginally employed, distant, mildly paranoid young

man with severe ear pain of an undiagnosable nature who buys illicit stimulants to relieve the pain?

The stimulants do not help him function, and they do not make him more paranoid—they only make

him feel better. What about the chronically very depressed woman who feels better only when

taking 200 mg of methylphenidate a day? We feel more comfortable prescribing stimulants when

they either obviously improve functioning or, at least, relieve incapacitating distress. We would not

force a patient to try an MAOI if he or she has already improved while taking a stimulant in the

past, but these are personal judgments.

In summary, we suspect that the useful, rapidly acting stimulant drugs are underused in American

adult psychiatric practice. They do not always work or even help, but when they do, they can be

very effective. It is still unclear whether bupropion, which resembles the stimulants in some

respects, or other new drugs, which do not (see Chapter 3: “Antidepressants”), will provide safer,

less abusable drugs that will help those psychiatric patients who now respond only to standard

stimulants.

OTHER FAST-ACTING DRUGS

Psychopharmacology mainly concerns itself with complex drugs shown to be relatively useful in

depression, mania, psychosis, and, more recently, dementia—drugs with complicated mechanisms

of action taking days to weeks to get full clinical effect.

Two hundred years ago the pharmacopoeia used in asylums was much more limited and quite

different. Opiates have been a mainstay of treatment for violent or agitated patients for centuries.

By the late 1800s sedatives—barbiturates, chloral hydrate, and paraldehyde—came into use to

manage excitement. Marijuana was reported (in a letter to the editor of the British Medical Journal

in the late nineteenth century) to be useful in reducing nighttime agitated wandering. Apomorphine

and hyoscine were used in combination to “snow” patients being transported from Bellevue’s

psychiatric facility in Manhattan to the several surrounding state hospitals.

Then several biological therapies (electroconvulsive and pentylenetetrazol convulsive treatment,

continuous sleep therapy, insulin coma therapy, and psychosurgery) were introduced, each on the

basis of initially striking rapid clinical improvement in a few of patients. These therapies were

dramatically more effective but had problems.

To our knowledge stimulants—caffeine, theophylline, cocaine—did not become part of asylum

therapies, though one suspects that Freud was not the only psychiatrist to explore the subjective

effects of cocaine.

By the 1930s the stage was set for LSD-25 which rapidly “invaded” the mind of a Swiss

pharmacologist who had unknowingly absorbed the miniscule amount of lysergic acid diethylamide

needed to get a striking psychedelic experience. At the same time ephedrine was found in China

where it was known as a ma huang and permuted into d-amphetamine. The later was tried in

children being treated at the Bradley Home in Rhode Island, allegedly to reduce headache causedPrint: Chapter 8. Stimulants and Other Fast-Acting Drugs http://www.psychiatryonline.com/popup.aspx?aID=238094&print=yes…

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by radiological brain studies. Anyway dl-amphetamine had a striking immediate good behavioral

effect—one that was easily replicated in smaller, blinded studies (Cole 1969).

Most recently, tetrahydrocannabinol (Marinol, 5-mg tablets) has been available for use in the

nausea and vomiting associated with cancer treatments. We know of a handful of noncancer

patients with severe anxiety, nausea, and weight loss who have responded well to Marinol when

standard methods have failed. Moreover, a patient with painful, incapacitating dystonia has had

significant relief of spasms for 3 months on 5-mg delta-tetrahydrocannabinol three times a day.

The stimulants are widely used examples of this broadening group of drugs. They do a particularly

good job of illustrating shifts in attitudes to drug classes over time from anathema to, more

recently, quite wide acceptance of the diagnoses of ADHD in both children and adults and even the

rebirth of older drugs like Adderall and Ritalin into a variety of formulations.

Finally, the study of hallucinogens as treatment approaches appears to have been finally made

possible by changes in procedures and attitudes at the U.S. Food and Drug Administration (FDA)

and by the gradual increase in evidence that regular users of peyote in the Southwest United States

and of another hallucinogen in Brazil are not appreciably harmed by this use. Furthermore,

perusual of the World Wide Web shows that a number of Web users claim that a single dose of

psilocybin is enough to stop a highly painful run of cluster headaches in its tracks.

All these treatments share, to some degree, rapid action and in some ways are related to other

drugs taken socially such as opiates, cocaine, and alcohol. Even alcohol has been prescribed in

psychiatry. In the 1970s there was an elderly agitated professional man with a 6-month stay at

McLean who was regularly prescribed two martinis two nights a week to reduce his anxiety over

going off grounds to have dinner with his wife. We have heard of alcohol by stomach tube having

been used to handle hysterical paralyses (or catatonia) successfully before the newer barbiturates

or benzodizepines became readily available.

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