JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
`Volume 4, Number 4, 1994
`Mary Ann Liebert, Inc., Publishers
`Pp. 217-223
`
`Opinion Piece
`
`The Story of Four Salts
`
`CHARLES W. POPPER, M.D.
`
`Since June 1994, a newly named product for attention-deficit/hyperactivity disorder (ADHD) has been
`promoted through journal advertisings exhibit booths at professional meetings, and mass mailings to physi-
`cians. Marketed as Adderall, this mixture of dextroamphetamine and racemic amphetamine (d,l-ampheta-
`mine) salts is advertised as a long-lasting amphetamine which "may eliminate the need for 'in-school' ad-
`ministration." Some protest has arisen, partially driven by concern that the Food and Drug Administration
`(FDA) would grant manufacturing rights or "longer duration" advertising rights to a combination product
`without data on safety, efficacy, pharmacokinetics, and duration of effects in adults or children.
`Though few child psychiatrists or pediatricians were aware of its existence, this four-salt amphetamine
`combination has carried FDA labeling as a treatment of ADHD for almost 25 years. However, the reasons
`for approval appear to be more historical than pharmacological.
`In the 1950's and 1960's, a variety of amphetamine resins and salts were present in numerous combina-
`tion products, which often included a hodge-podge of other compounds such as methaqualone, reserpine,
`or vitamins. One such product was initially marketed as Obetrol. Advertised for the treatment of obesity
`since 1960, the original formulation contained methamphetamine and amphetamine. In 1970, the FDA con-
`ducted a class review of all amphetamine-containing products. Several products were discontinued.
`Methamphetamine was judged ineffective for treating obesity, and its removal was required from all com-
`mercially manufactured diet pills. Obetrol was then reformulated to contain its current ingredients: d-am-
`phetamine sulfate, d,l-amphetamine sulfate, d,l-amphetamine aspartate, and d-amphetamine saccharate. The
`10-mg pills contain 2.5 mg of each component, and the 20-mg pills contain 5 mg of each. Since the active
`ingredients were all amphetamines, the FDA considered Obetrol to be a "single entity" product. Newly stan-
`dardized language for package inserts for all amphetamines permitted the indications to include ADHD and
`narcolepsy (Federal Register 1970). Thus, the inclusion of ADHD in the Obetrol package insert was based
`on the FDA blanket policy for amphetamines, not on safety or efficacy studies of this four-salt formula-
`tion.
`Obetrol was used widely in the 1970's as a treatment for obesity, and its marketing for ADHD was left
`fallow. Sometime over the intervening years, it seems that original documentation about this product has
`disappeared. After the transfer of ownership to a different pharmaceutical house in 1994, the formulation
`was re-named as Adderall, and its promotion for treating ADHD has become vigorous.
`Adderall is not the only mixture of amphetamines currently on the market. Biphetamine, a mixture of d-
`and d,l-amphetamine delivered from a cationic exchange resin complex, also carries FDA-approved label-
`ing for ADHD. According to its package insert, the delivery system for Biphetamine gives it a "slightly
`lower, later, and flatter peak and a slightly higher blood level
`. maintained over a period of 16 hours.
`The clinical significance of these differences is not known." If it were not priced so expensively, one might
`wonder whether Biphetamine could become competitive as a once-daily stimulant treatment.
`
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`OPINION PIECE
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`The only other amphetamine product that I could find in the 1994 Physician's Desk Reference (PDR) is
`benzphetamine hydrochloride (Didrex), which is advertised only for treating obesity. ADHD is not listed
`as an indication for benzphetamine. According to its package insert, "Pharmacokinetic data in humans are
`not available." Benzedrine, a racemic mixture of d- and 1-amphetamine sulfate that was once a common
`treatment for ADHD, is no longer marketed.
`In addition, a large series of nonamphetamine (or not-quite-amphetamine) central nervous system stim-
`ulants and sympathomimetics are commercially marketed. Some of these agents might be efficacious in
`treating ADHD, and their pharmacokinetic and safety profile (if known in humans) might conceivably al-
`low once-daily treatments. Also, these agents might carry hidden dangers, in addition to the well-known
`ones.
`The difference between Adderall and these other agents is that Adderall is being actively marketed for
`ADHD, rather than merely passively lingering in the depths of the PDR. With fame comes scrutiny.
`Does Adderall really have a longer duration of action than other stimulants? Without efficacy data, du-
`ration of therapeutic effect cannot be defined. According to Roger Griggs, President of Richwood
`Pharmaceutical Company, the present manufacturer of this product, no scientific data are available to the
`company to support the claim that Adderall may have a longer duration of action.
`Instead, the company has distributed an unpublished report recently written by Dr. Ronald Jones, a de-
`velopmental pediatrician. In this retrospective review of his experience in clinical practice, Dr. Jones de-
`scribes his impressions of Adderall in. 88 patients and compares them to his observations of sustained-
`release methylphenidate in other patients. Therapeutic and side effects of the two preparations were
`reported to be generally comparable. The paper claims to have "shown [Adderall] to be safe and effec-
`tive," but there were no placebos, controls, standardized scales, or statistical analysis, and the data pre-
`sented were very limited. Without presenting relevant data, the paper states that "In our clinical experi-
`ence, we felt that Adderall's duration of effect was slightly longer than standard methylphenidate." A
`morning dosage was said to last through the school day, but two-thirds of the Adderall patients "were
`given a second dose of a short-acting stimulant after school." An unreported number of patients were
`also on antidepressant and neuroleptic agents. Only 33 patients took Adderall alone. A statement sug-
`gests that the salts have "varying dissolution rates," but no documentation was cited. Only five refer-
`ences were cited, including one outdated 1977 reference. The main side effects were anorexia and in-
`somnia. Rebound irritability as well as moodiness, nervousness, frequent crying, emotional lability, violent
`temper, and paranoia were also noted. Long-term safety was mentioned: "Three of our patients used
`Adderall in excess of seven years with no significant side effects nor toxicity reported." Dr. Jones made
`some important and appropriate cautionary statements: "In no way should this retrospective evaluation
`be interpreted as scientifically valid or a predictor of expected clinical outcome," and "The clinical sig-
`nificance of the combination over other single-entity products is yet to be determined." This unpublished
`report is the only written document that the manufacturing company is currently able to offer concern-
`ing the use of Adderall in children with ADHD.
`However, some independent observers believe that claim of longer duration is valid. I have spoken with
`nationally prominent clinician-researchers in child and adolescent psychopharmacology who, based on un-
`controlled treatments in their clinical practices, estimate that the effects of Adderall may last for 6-9 hours
`in children and perhaps longer in adults. Of course, pharmaceutical advertising must be supported by sci-
`entifically collected data rather than by personal testimony.
`Does Adderall have a more gradual onset and offset of clinical action? Again, without data, this ques-
`tion cannot be addressed scientifically. Among the noted clinician-researchers who have used Adderall in
`clinical practice settings, the onset and offset of drug action were viewed as more gradual than with dex-
`troamphetamine (Dexedrine) or methylphenidate (Ritalin). If true, the more gradual onset might specula-
`tively reduce the euphoric effect and the risk of substance abuse. If the offset were more gradual, there
`might be less rebound phenomena (above-baseline hyperactivity or tic frequency after the medication wears
`off). In fact, these physicians state that, in their experience, the problems with rebound hyperactivity are
`mild with Adderall.
`Does Adderall have a more "smooth " clinical action during the day ? If its duration of action were longer,
`Adderall might give fewer daytime "ups and downs" typically associated with the repeated short-term dos-
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`OPINION PIECE
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`ing strategy with dextroamphetamine and methylphenidate. Again, the clinicians'
`testimonials suggested
`that Adderall appeared relatively free of these "ups and downs."
`Do d- and l-amphetamine have different properties? Speculatively, some of the properties claimed for
`Adderall might be related to different physiological actions of d- and l-amphetamine. In fact, both isomers
`are biologically active and have somewhat different pharmacological properties.
`In early reports on treatment of behavior disorders with racemic d,l-amphetamine or with dextroam-
`phetamine, Bradley (1950) and Laufer and Denhoff (1957) observed that most children responded well to
`either formulation, but that some children did better on one drug or the other.
`More rigorous studies were reported by Arnold and colleagues (1972, 1973, 1976). A randomized dou-
`ble-blind placebo-controlled crossover comparison of the d- and the 1-isomers was conducted with 31 chil-
`dren with minimal brain dysfunction (Arnold et al. 1976), replicating the findings of a prior nonrandom-
`ized study in 11 children (Arnold et al. 1972). Seven milligrams of levoamphetamine succinate were
`compared to 5 mg of dextroamphetamine sulfate to correct for differences in molecular weight. Both the
`d- and 1-isomers were found active, about equally efficacious, and more effective than placebo, but typi-
`cally one agent was notably more effective than the other for individual children. Generally, d-ampheta-
`mine appeared nonsignificantly more effective than the 1-isomer, but almost two-thirds of the children im-
`proved with the 1-isomer. The 1-isomer appeared slightly more effective in "unsocialized-aggressive" children
`(though not statistically significant), whereas the d-isomer was slightly better for "overanxious" hyperac-
`tive children. Both isomers produced, similar amounts of insomnia and weight loss (greater than placebo),
`and there were few other problems; blood pressure increases were minimal. Interestingly, two children who
`appeared to show a clinical deterioration on the d-isomer actually appeared to improve with the 1-isomer,
`and some children with anorexia on the d-isomer did well on the 1-isomer. Overall, 28% of the drug-re-
`sponders preferred the 1-isomer. This study supports the notion that l-amphetamine may be therapeutically
`beneficial in ADHD, at least in some children.
`Other data suggest that d- and l-amphetamine may have some different physiological and behavioral ef-
`fects. The 1-isomer may induce less euphoric effect than the d-isomer (Alles 1939, Yokel and Pickens 1974),
`which is consistent with the (undemonstrated) claim of reduced abuse potential with Adderall. Similarly,
`the two isomers appeared to have unequal effects on different components of behavior in Corson's animal
`model of hyperactivity in dogs (Arnold et al. 1973).
`The neurochemical effects of the d- and 1-isomers have been quite difficult to identify (or at least repli-
`cate), perhaps because of the complexity of their properties. The metabolism of amphetamine itself is known
`to be subject to stereospecific effects, with ß-hydroxylation more quickly with the d-isomer (Goldstein and
`Anagnoste 1965) and enzymatic deamination proceeding more quickly with the I-isomer. The d-isomer
`might be more quickly (Benakis and Thomasset 1970) or fully (Goldstein and Anagnoste 1965) taken up
`into the brain (as well as the heart and liver), has a lower LD50 in mice (Moore 1963), and is more potent
`in reducing reserpine-induced effects on rat behavior (Rech 1964). Over the course of many years, findings
`on the differential effects of the two isomers on dopamine and norepinephrine neurotransmission have re-
`mained contradictory and inconclusive (e.g., Taylor and Snyder 1970, Harris and Baldessarini 1973, Asghar
`and De Souza 1989). Further, the clinical implications of the neuropharmacological findings in animals can
`only guardedly be interpreted, since the metabolism of amphetamine varies considerably between species.
`Thus, there are several mechanisms by which the d- and I-isomer might have clinically different effects.
`However, I have found no reproducible data to indicate that the d- and 1-isomers are different in the tim-
`ing or duration of their clinical effects.
`Why were these particular salts selectedfor this formulation? There does not appear to be any literature
`that compares the effects of different salts of d-amphetamine or l-amphetamine, and the manufacturer of
`Adderall does not have any such information. The pharmaceutical company believes that these salts were se-
`lected to produce a longer duration of action. The development work for this formulation was presumably
`conducted in the 1950s and is now no longer available to the company. The company is forthright in saying
`that it is not certain why these particular salts were selected or by whom the research might have conducted.
`If the assumption is made that the formulation provides a more extended duration of action, then several
`mechanisms might be imagined. For instance, the four salts might have slightly differing rates of dissolu-
`tion; however, the solubility characteristics of these salts are not known, at least to the manufacturer (and
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`I could not locate this information in standard references). It is difficult to imagine that differences in dis-
`solution would be clinically significant. Alternatively, the dissociation of these salts once in solution might
`proceed at different rates. These salts would be expected to dissociate freely in solution. Perhaps there is
`an unknown interaction between the salts or the isomers. More plausibly, the free d- and 1-isomers of am-
`phetamine might be absorbed or metabolized differently. Conceivably, different rates of absorption or me-
`tabolism of the four components might yield a spectrum of faster and slower clearances, which might pro-
`vide a spread of clinical action over an extended period; but then it would seem unlikely that a very "smooth"
`effect would be observed over time. Thus, based on available information, it is not clear what mechanisms
`would provide theoretical support for the suggestion that the allegedly longer duration might be tied to the
`use of these particular salts.
`Conjecturally, the explanation might relate to chemical rather than pharmacological properties of the salts.
`The amount of free amphetamine base that is released from an amphetamine salt will vary. Since the mo-
`lecular mass of each salt differs, and the number of amphetamine molecules present in a salt may differ,
`pills containing equal milligram quantities of the salts do not yield equal quantities of free amphetamine in
`solution. Thus, it is possible that some of the salts simply release more amphetamine molecules into the
`body than the sulfate salts found in other amphetamine products. That is, Adderall may deliver extra am-
`phetamine molecules into the child without being obvious about it. This could explain a longer duration of
`increase in side effects (which the clinician-
`action,
`though it would probably also lead to a general
`researchers did not observe in their clinical practices).
`Scientifically, it would be very useful to know the effects of each salt separately. This might allow a sim-
`plification or improvement in the formulation. There is a strong disincentive to investigate the individual
`components of Adderall, at least for its own manufacturer, since any change in the ingredients of the prod-
`uct would require FDA approval.
`Is Adderall safe? This product introduces two new amphetamine salts that are not otherwise marketed.
`Although the two sulfate salts have been previously marketed in numerous products, the saccharate and as-
`partate salts are novel ingredients. The implications for safety and efficacy are not clear. The company has
`some data on the LD50 of some of the salts and the salt combination in rodents, but there appears to have
`been no rigorous testing of the safety or efficacy of these salts alone or in combination in animals or hu-
`mans, let alone in children.
`As previously noted, some clinician-researchers believe that Adderall produces less symptom rebound,
`and have speculated that abuse risks may be reduced. If true, these would be very important advantages,
`but again, hard data are needed before such claims can be heeded.
`How does Adderall stack up against its competition? The safety and efficacy of dextroamphetamine,
`methylphenidate, magnesium pemoline, tricyclic antidepressants, and even clonidine, are far better estab-
`lished than Adderall.
`The primary advantage of Adderall would be, if true, its long duration of action. Slow-release forms of
`dextroamphetamine and methylphenidate often do not provide a longer duration, and sometimes appear less
`effective than regular-release forms, presumably because the clinical effects of psychostimulants are not
`tightly correlated with stimulant blood levels. Pemoline (Cylert) can be administered once daily, but its risk
`of forming hepatotoxic metabolites requires periodic liver function testing. Heterocyclic antidepressants can
`be taken once or twice daily, but they have numerous side effects and relatively weak therapeutic effects
`on cognitive symptoms. Clonidine skin patches do not require daily administration, but they too have less
`benefit for cognitive than behavioral symptoms; also, the patch often causes allergic skin reactions or may
`not adhere reliably to sweaty skin. A beta blocker such as nadolol (Corgard) can be given once daily, but
`its efficacy has not been studied in children with ADHD. Methamphetamine (Desoxyn) appears to be effi-
`cacious and safe when used as prescribed,
`though it has not been scientifically studied in ADHD.
`Methamphetamine may have a longer clinical duration than dextroamphetamine or methylphenidate. Based
`on his experience in clinical practice, Wender (1993) estimates the clinical duration of methamphetamine
`for treating ADHD in adults to be in the range of 6-12 hours, comparable to the claims put forward for
`Adderall. However, the risks of abuse are significant, the stigma of using "speed" in children is a major
`barrier, and its cost is comparatively high. So there is still a market niche in the 1990s for a once-a-day
`psychostimulant to target the cognitive and behavioral components of ADHD.
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`Dextroamphetamine is a highly effective drug for ADHD (Dulcan 1990) and probably the best when cost
`is figured into the calculations. However, there have been periodic problems with the availability of dex-
`troamphetamine due to the yearly production quotas imposed by the FDA, since amphetamines were found
`to be manufactured in quantities "greatly in excess of demonstrated medical needs" (Federal Register 1970).
`Though active lobbying by Ch.A.D.D. and other lay organizations have recently won some concessions that
`could alleviate this problem, drug production quotas are not the only difficulty. Many pharmacies choose
`not to carry dextroamphetamine, allegedly because of its risk for theft and abuse (which are probably not
`greater than with methylphenidate) and its reputation (amphetamine has more of an "image" problem than
`methylphenidate). Paradoxically, it may sometimes be easier to find Adderall than dextroamphetamine in
`local pharmacies. Currently, though, Adderall is not yet present on the computer search systems of many
`pharmacies, which do not yet have easy access to it through their usual suppliers.
`Is Adderall cost-competitive? At present, Adderall is comparable in cost to generic methylphenidate, but
`more expensive than generic dextroamphetamine.
`If one assumes that the claims of longer duration are accurate, then it would be fair to compare Adderall
`to the longer-lasting preparations. In a survey of 25 pharmacies (Boston area, November 1994, consumers'
`price for 100 pills), I found that the costs of Dexedrine Spansules (630 for a 10 mg pill) and Adderall (590
`for 10 mg) were essentially the same. However, Adderall was markedly less expensive than sustained-re-
`($1.31 for 37.5 mg),
`lease methylphenidate (820 for 20 mg), Ritalin-SR ($1.11 for 20 mg), Cylert
`Biphetamine ($2.53 for 12.5 mg), or Desoxyn ($2.59 for 10 mg). By comparison, the costs of generic dex-
`troamphetamine (140 for 5 mg) and even Dexedrine (230 for 5 mg) were much lower.
`These prices are consistent with standard wholesale prices charged to pharmacies (The Red Book 1994):
`Dexedrine (380 for two 5 mg pills), Adderall (460 for 10 mg), Dexedrine Spansules (480 for 10 mg), Ritalin-
`SR (940 for 20 mg), and Cylert ($1.10 for 37.5 mg).
`Is there a problem with Adderall advertising? The 1970 FDA gave blanket clearance for amphetamines
`to be marketed and advertised, recognizing that some specific products did not have efficacy or safety stud-
`ies. Rather than being "grandfathered" in from the pre-KeFauver days, Adderall is the result of an estab-
`lished (though possibly outdated) policy of the FDA. It is certainly legal for a pharmaceutical house to ad-
`vertise an FDA-approved product.
`However, it is easy to see why many physicians were concerned about recent advertising for Adderall.
`Certain aspects of the advertising for Adderall could be viewed as potentially misleading. In a recent pro-
`motional piece, four references were cited in the usual manner of pharmaceutical advertising to highlight
`published studies on the medication. A statement about amphetamine half-life was supported by two cita-
`is "an integral
`tions to successive editions of the same publication. A referenced quotation that Adderall
`part of a total treatment program" is not accurate, and suggests that the four-salt amphetamine combination
`is essential to treatment; the source of the quote actually reads, "Amphetamine [is] an integral part of a to-
`tal treatment program." The statement, "Strategic dosing of Adderall may eliminate the need for 'in-school'
`administration," cannot be supported by available data. In a piece on comparative pricing, Adderall is com-
`to regular dextroamphetamine, which is less expensive than
`pared to regular methylphenidate but not
`Adderall. The advertising materials indicate that "clinical evaluation" is "underway" for Adderall, Ritalin,
`and Cylert, suggesting that the existence of research on these agents implies that the research databases on
`these treatments are comparable.
`The nature of this advertising, rightly or wrongly, casts a cloud over the four-salt combination itself.
`How does it all add up? An agent which is said to have novel good properties but no novel bad proper-
`ties must be taken with some suspicion until there is formal evidence. While it is possible that this salt com-
`bination constitutes a major advance, it is difficult to imagine why such a discovery would have laid dor-
`mant for years, was not pursued by other drug companies with other products, and now surfaces with
`important treatment implications.
`Discretion would seem to dictate that clinicians keep close to the main avenues of treatment, that the
`FDA clarify its position on this combination product, and that the company curtail its promotion until this
`product is shown to conform to current standards of scientific validation.
`The Richwood Pharmaceutical company is now funding some studies on Adderall. Some will wonder
`about the appropriateness of a pharmaceutical house making profits amidst this legal but quirky situation,
`221
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`but their approach is much more helpful than the position taken by many major pharmaceutical companies,
`which essentially amounts to "We don't endorse the use of our product in children, and we don't study its
`effects in children."
`It seems extremely unlikely that this four-salt product would be granted approval under the current-day
`standards of the FDA, at least not with the available level of documentation. Yet there are reasonable pol-
`icy questions about how to proceed with a product that may have passed muster historically and legally,
`but might now be an anachronism. Should the drug be allowed to maintain its current status? Should the
`company be required to update its research database? Should the FDA have a proactive program for re-
`viewing old formulations? The FDA has recently placed Adderall "under investigation," an action which
`does not, in itself, imply any wrong-doing whatsoever.
`Although serious questions may be raised about the rationale, pharmacology, and commercial promotion
`of this drug combination, physicians should be prepared to keep an open mind about the possibility that
`this four-salt combination might have some surprising qualities. It remains to be seen whether these will be
`good or bad surprises.
`the reluctance of pharmacies to carry dex-
`In view of the production limits on dextroamphetamine,
`troamphetamine and the alleged clinical advantages (longer duration, once-daily administration, less re-
`bound, less abusability), Adderall may someday become a useful alternative treatment of ADHD. For now,
`in the absence of any demonstrated advantages, the difficulty of ra-
`clinicians are likely to be thoughtful
`tionalizing why this combination of salts was originally selected, and especially the unavailability of effi-
`cacy data in ADHD, safety in children or adults, pharmacokinetic studies, and knowledge of basic chemi-
`cal properties.
`A larger and more general question is whether there are long-acting psychostimulant preparations that
`have not been adequately explored for their potential in treating ADHD. In addition to methamphetamine
`(Desoxyn) and resin-release amphetamine (Biphetamine), which already carry FDA labeling for ADHD,
`the pharmacological world is filled with other amphetamines (like benzphetamine) and "me-too" CNS stim-
`ulants that are already commercially available. Clinicians would be well advised to steer clear of experi-
`menting with nonstandard and often inadequately tested CNS stimulants in children, but this is fertile ground
`for enterprising pharmaceutical companies and controlled clinical research.
`
`ACKNOWLEDGMENT
`I would like to thank Mr. Roger Griggs, President of Richwood Pharmaceutical Company, for his coop-
`eration and openness, both in providing information about the product and in being clear when information
`was not available.
`
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`
`Address reprint requests to:
`Charles W. Popper, M.D.
`Harvard Medical School
`115 Mill Street
`Belmont, MA 02178-9106
`
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