CHAPTER 6

Understanding Stimulants and Their Role in Chronic Fatigue Syndrome

Julie is a 36-year-old mother of two with a long history of seeking mental health treatment. She was a restless child prone to temper tantrums, and in fifth grade, she was too anxious to go to school for two months and refused to leave her mother’s side. “I always felt overwhelmed and could not focus on learning,” she explained. In middle school, Julie started to gain weight and became depressed. She attempted suicide at age 17, after which she sought counseling and medications.

Julie was accepted at a state university but had a disastrous first semester away from home. “My grades were terrible, and I didn’t know what to do with my freedom,” she recalled. “I drank too much and slept with too many guys. On one hand I had really bad self-esteem, and on the other hand, I discovered I had a lot of power over people, which I had never known I had before. I was so confused.”

Julie ultimately completed her bachelor’s degree, but it took almost six years. Afterward, she had no trouble finding a job. “I interviewed well and would always get hired but became bored easily and did not perform well on the job.” Over the next few years, Julie went through nearly a dozen jobs. With her parents’ guidance, she tried to get out of her self-defeating rut. She started a master’s program but dropped out after a semester. She moved from Detroit to Chicago, immediately floundered, and had to move home within the year. Julie met her husband around this time; he was a recovering alcoholic who struggled with mood swings. They had two young children in three years.

After the birth of her first child, Julie gained 50 pounds, and after her second pregnancy, she was 80 pounds heavier than when she graduated high school. “I always had a problem relationship with food. It got worse when I was home with my children and started to binge-eat at night after the house settled down. I ate thousands of calories at a time, three or four times a week, and couldn’t stop. I felt nothing but shame.”

Julie also noticed that her fatigue intensified, and she spent every free moment in bed. “My husband and I essentially became roommates. He appreciated I was taking care of the kids, and I was content he was keeping us afloat.” Eventually their strained marriage broke, and Julie and her husband divorced. “When I went back to work, I realized I was too fatigued to accomplish anything. It was just like after college when I went through so many jobs. My eating was out of control, and my family demanded I get help.” Julie was relieved when the psychiatrist diagnosed her with binge-eating disorder (BED). She was placed on Vyvanse, a medication approved for this condition, and within the week, the frequency of her binge episodes decreased dramatically. “I also realized that I had had a lot more energy on the medication; I started to do better at work and was more effective with my kids,” she said.

When Julie came to our clinic, she was panicked. “My insurance does not cover Vyvanse. This medicine has helped me with my chronic fatigue and binge eating, and I am doing better than ever.” Our clinic drafted an appeal letter to Julie’s insurance company, and after several exchanges, the company finally agreed to pay for the brand medication.

This chapter is about stimulants, including amphetamines, methylphenidate, and “wakefulness” drugs such as modafinil, that may help people with CFS. Keep in mind that the FDA has approved Vyvanse for ADHD and separately for BED. However, as of this writing, no medication has been approved for CFS. The RCS (Chapter 5) demonstrates that patients with CFS responded well to Vyvanse across a number of symptom domains. Unfortunately, Vyvanse is not available to everyone nor effective for everyone. Consequently, other medications that are stimulants or that are from a similar class should be considered. This chapter outlines stimulant medications that have been approved by the FDA to treat ADHD, BED, and some sleep disorders, and they may prove useful for CFS, as we found they did in our study described in Chapter 5.

There are three primary categories of prescribed stimulants: amphetamines, methylphenidate medications (which includes Ritalin and related medications),¹ and several different wakefulness-promoting drugs. Medications in this last category are non-amphetamine-like stimulant medications, the prototype being modafinil (Provigil). Throughout this chapter, I focus on medications that are good candidates for further research in the treatment of CFS. Note that physicians may prescribe medications off-label, which means not for their specific approved purpose.

At the onset, it important for readers to distinguish these safe and carefully studied medications from illegal stimulants such as cocaine or illegally manufactured methamphetamine. Cocaine and methamphetamine are dangerous, life-destroying drugs; they catapult the brain into a fevered and unhealthy state of euphoria and create an intense craving for more and more of the offending substance. Cocaine and methamphetamine play no role in therapeutic medicine and are rightly considered drugs of abuse.

Legal stimulant medications do not flood the brain; rather, they are taken up gradually into the central nervous system and do not cause euphoria. The chapter outlines prescribed stimulant medications and contrasts their lower risk for abuse and misuse compared to street stimulants and other drugs such as opioids and sedatives.

Considering Amphetamines

Amphetamines have been available to consumers for many years. In World War II, soldiers were given amphetamines such as Benzedrine to help them stay awake in combat conditions.2 After the war, the drugs were prescribed for a surprising number of medical conditions, including the following:

•Alcoholism

•Allergies

•Asthma

•Menstrual problems

•Morphine addition

•Schizophrenia

•Seasickness³

It is no longer accepted that stimulants are effective for any of these conditions, but in the postwar era, it emerged that amphetamines were effective for children with hyperactivity. This category of medications is still used today, primarily to treat impaired concentration and focus in children, adolescents, and adults with ADHD. A few of the stimulant medications are used to treat narcolepsy; and, as mentioned, LDX (Vyvanse) is approved for BED.

An Accidental Discovery: Amphetamine Improved Behavior in Hyperactive Children

Charles Bradley was the first psychiatrist to publish research about the use of amphetamines with children. In 1937, Dr. Bradley was the director of the Emma Pendleton Bradley Home, a youth facility in Providence, Rhode Island. Upon admission to the hospital, many of the young patients were given a routine spinal tap, and this procedure led to persistent headaches. Desperate to find a solution for these headaches, Bradley tested many different medications but found the most interesting results when he administered the amphetamine Benzedrine.

We do not know if the children’s headaches remitted with the amphetamine, but Bradley discovered that his patients’ behavior and academic performance improved markedly subsequent to receiving the drug. When Bradley took the children off the Benzedrine, their behavior quickly reverted to previous low-functioning levels.1 Until that time, it had been held that brain damage was the reason for severe hyperactive behavior. Later generations of physicians were dubious about the brain damage theory, and in 1972, physician Virginia Douglas at McGill University coined the phrase “attention deficit disorder,” which is now called attention deficit/hyperactivity disorder (ADHD).² Although the debates about the causes and treatments of ADHD rage on, no one disputes that Bradley stumbled on one of the most important findings of 20th century psychiatry.

Notes

1.Christine Adamec, Understanding Drugs: Amphetamines & Methamphetamine. New York: Chelsea House, 2011.

2.Ibid.

Amphetamines May Improve Symptoms of Chronic Fatigue Syndrome

Treatments for CFS remain elusive, likely because most doctors cannot agree on the underlying cause. The current trend in chronic fatigue research is to explore the relationship between fatigue and inflammation. Much energy is being focused on imaging the brains of individuals with CFS and finding precise methods to measure inflammatory changes in the brain. Very little current work is being conducted on therapeutics and few treatment ideas for CFS are emerging on the horizon.

I organized a small but carefully executed clinical trial using the medication, Vyvanse. The details of the study are outlined in Chapter 5. The salient findings were positive: Vyvanse decreased fatigue and chronic pain and was also useful in lowering generalized anxiety.

Although the study revolved around Vyvanse, I believe that other stimulant medications also may be helpful. I want to emphasize that to date the FDA has not approved stimulants to treat CFS. It is my hope, however, that larger-scale studies will soon be undertaken to validate the use of stimulants in treating CFS.

Benefits and Risks of Amphetamines

When amphetamines are taken to relieve ADHD, many studies have shown the benefits of these drugs in helping individuals perform more effectively in their personal, work, and family arenas. Of course, as with many centrally acting medications, an amphetamine should be initially prescribed at a low dosage and then titrated upward, as needed.

Benefits of Amphetamines

In my study, Vyvanse was evaluated in patients with CFS. Relative to a placebo-treated group, the Vyvanse group demonstrated significant improvement in fatigue and pain. Interestingly, the participants taking Vyvanse also noticed a decline in their generalized anxiety. There is reason to believe that these benefits extend to other amphetamines. Vyvanse has the unique features of a prodrug, meaning that the drug is converted to an active medication once it transfers from the gut into the bloodstream. This prodrug mechanism allows for a long-acting effect. Other brand-name amphetamines offer different properties, such as a longer duration of action. Amphetamine medications are also available in less expensive generic formulations. Examples include generic versions of Adderall and Adderall XR, referred to as mixed amphetamine salts. (Table 6.1 lists the major amphetamines that are available as of this writing, as well as formulations of methylphenidate and other medications.)

Risks/Disadvantages of Amphetamines

There are some clear limitations regarding the use of amphetamines. Patients who have heart conditions, hypertension, heart failure, or rhythm disturbances should avoid these drugs. Amphetamine decreases appetite, and patients with low weight may not tolerate this side effect. Individuals with known hypersensitivity to amphetamines should pursue another treatment option. Of course, the medications are not always helpful; treatment it is a trial-and-error process, guided by the skill and experience of the physician.

Amphetamines are not indicated for people with hyperthyroidism or women who are pregnant. Women who are breastfeeding should avoid amphetamines as the drug can be present in their breast milk, and the impact on infants, while probably minimal, is unclear.

Common Side Effects of Amphetamines

Not everyone experiences side effects with amphetamines, but some effects commonly appear. Side effects typically decrease over time and include the following:

•Headache

•Weight loss

•Nosebleed

•Diarrhea

•Nausea

•Nervousness

•Dry mouth

•Changes in sex drive

•Painful urination

•Painful menstruation4

Severe side effects should be reported to the physician urgently and include:

•Paranoia

•Hallucinations

•Seizures

•Delusions (fixed false beliefs)

•Rash

•Mania

•Hives

•Unexplained wounds on the fingers and toes

•Swelling of the face, throat, tongue, eyes, or lips⁵

No Quantifiable Measurements with Psychiatric Medications

One disadvantage of any psychiatric drug—and this includes antidepressants, antianxiety medications, and stimulants—is that there are no easily quantifiable measurements to determine that yes, this is the proper medication or adequate dose of the medication. A finger stick will measure the blood sugar level in a patient with type 1 diabetes. The level is either normal, below normal, or above normal, and this information guides the physician to prescribe the correct dose of insulin. In contrast, psychiatrists prescribing behavioral medications must rely on patients to report whether and how their symptoms have changed. Fortunately, research studies employ standardized rating scales for fatigue, anxiety, and pain, and there are scales available for routine visits to the doctor that help inform decision making.

Dexamphetamine and Chronic Fatigue Syndrome

In a small study that predated our project, Australian researchers studied 20 patients with CFS. Ten subjects were assigned to a dexamphetamine treatment group, and the other half were given a placebo. The FSS was obtained at baseline and at the end of the study to compare differences that resulted from treatment. The medication group took one 5 mg tablet twice daily at 8:00 a.m. and again at 2:00 p.m. If there was no satisfactory therapeutic response after a week, the researchers increased the medication to 10 mg twice a day. After another week, if needed, the medication was increased to 15 mg. As it turned out, seven subjects stabilized at 10 mg twice daily (a total of 20 mg), and three of the subjects took three tablets or a dosage of 15 mg per day. The researchers found that nine of the medication subjects improved on the Fatigue Severity Scale, compared to four of the subjects taking the placebo. This was a statistically significant difference, indicating that the dexamphetamine did improve the fatigue of the study subjects.6

The researchers concluded:

The use of dexamphetamine for chronic fatigue syndrome has a considerable degree of biological plausibility. The ability of dexamphetamine to antagonize the effects of sleep deprivation and increase alertness is among the best known of its actions, and symptoms similar, at least superficially, to those of sleep deprivation are very common in patients with chronic fatigue syndrome. In particular, difficulty sustaining concentration and slow recovery from exertion are among the most disabling symptoms of chronic fatigue syndrome, and the capacity of dexamphetamine to facilitate prolonged concentration and to allow renewed exertion without prolonged rest are prominent aspects of its action.⁷

In a subsequent publication, the lead author, Dr. Leslie Olson, expressed concern that short-acting amphetamines carry a double-edged sword. They help cognitive symptoms, but as the dose wears off abruptly, the patient crashes hard, and the benefits are quickly overrun by this unpleasant side effect.8

Short-Acting or Long-Acting Amphetamines

Most experts agree that the duration of the effect of amphetamines affects the drug’s safety and utility. It is important to understand the difference between short-acting and long-acting medications. In general, a short-acting amphetamine takes effect in about 30 minutes and may last up to four or five hours before its effects wane. In contrast, a long-acting drug lasts for 10 to 12 hours or longer, and intermediate-acting medications have a duration of effect somewhere between the two extremes. The amphetamine with the longest action is Mydayis, an amphetamine approved for ADHD in 2017. Mydayis lasts for up to 16 hours, and many doctors were concerned that it would cause insomnia. Clinical studies proved otherwise—only 2 percent of patients discontinued Mydayis because of poor sleep onset, and 94 percent with insomnia reported that their insomnia caused them only mild to moderate irritation. Most of the insomnia problems associated with this long-acting stimulant resolved over time.⁹ (See Table 6.1 for more information.)

Considering the Various Types of Amphetamines

In this section, I provide information about the different types of amphetamines or amphetamine-like medications that are available in the United States. These drugs are listed in alphabetical order, as they also appear in Table 6.1. The amphetamine molecule can appear as dextro-amphetamine or its mirror image, levo-amphetamine. If the d-amphetamine and l-amphetamine are combined in equal proportions, it is called a racemic mixture. Many of the preparations on the market have varying proportions of d to l ratio, and this translates to slightly different clinical effects. Amphetamines ultimately affect the concentration of dopamine and norepinephrine, which are neurotransmitters jetting throughout the brain, particularly in the prefrontal region of the brain.

Adderall and Adderall XR

Adderall is the best-known amphetamine, introduced to market in the 1990s. This tablet consists of a ratio of three parts d-amphetamine to one part l-amphetamine. Adderall is a short-acting drug that is available in dosages of 5.0 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 30 mg. The generic versions of Adderall are referred to as a mixed amphetamine salt.

Adderall XR is an extended-release formulation that was developed several years after Adderall. Adderall XR is a capsule with two different-sized beads. The smaller bead is absorbed within minutes after swallowing, and the larger bead is absorbed four hours later. Adderall XR exerts benefit for about seven or eight hours. It is available generically and comes in dosages of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg.

Adzenys XR-ODT

Adzenys XR-ODT is a long-acting drug manufactured by Neos Therapeutics, and it has the same d to l proportions as Adderall. This medication is distinctive in that it dissolves in the mouth and is appealing to people who do not like to swallow pills or capsules. Adzenys XR-ODT is orange-flavored and comes in dosages of 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, and 18.8 mg.

Dexedrine and Dexedrine Extended-Release Spansules

Dexedrine is a short-acting amphetamine tablet consisting entirely of d amphetamine. Dexedrine extended-release spansules are an extended-release formulation that take an hour to become effective and last about six to eight hours. Dexedrine spansules are available in generic form in 5 mg, 10 mg, and 15 mg doses. All forms of dexedrine are generic medications.

Evekeo

Evekeo is a short-acting drug made by Arbor Pharmaceuticals. Evekeo is 50 percent d-amphetamine and 50 percent l-amphetamine. It is available in dosages of 5 mg, 10 mg, 15 mg, and 20 mg. Evekeo ODT is an orally dissolving preparation that is packaged in a convenient blister pack.

Mydayis

Mydayis is a long-acting medication designed to be taken in the morning. Mydayis was developed by Shire and is now owned by Takada. Mydayis is a triple-bead formulation with each bead consisting of the Adderall molecule. Like Adderall XR, the first bead releases immediately, followed by the second dose, which is released four hours later. Approximately eight hours after ingestion, the third bead is released, and this accounts for the 16-hour duration of action. Mydayis is available in capsule form in dosages of 12.5 mg, 25 mg, 37.5 mg, and 50 mg.

ProCentra

ProCentra is a sugar-free, bubble-gum-flavored fluid that is available from Independence Pharmaceuticals. This amphetamine is used primarily for children with ADHD but may be used by adults who are averse to swallowing capsules. As the liquid can be consumed quickly, the risk of diversion (illegally giving it to someone else) and overdose may be greater than in traditional capsule-based stimulants. Diverting amphetamines and other scheduled drugs to others is illegal.

Vyvanse

Vyvanse (LDX) was brought to market by Shire and is now manufactured by Takada. It is approved by the FDA as a treatment for both ADHD and BED. Vyvanse is a prodrug. This prodrug mechanism allows for a long-acting effect, and patients report benefit for 9 to 12 hours after taking the morning capsule. Vyvanse is available in dosages of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. In contrast to Adderall and Mydayis, Vyvanse is not racemic and contains only d-amphetamine. The consumption of acidic substances such as fruit juices may decrease the effectiveness of the drug. In contrast, agents that decrease acid may increase its effectiveness.10

Zenzedi

Zenzedi, made by Arbor Pharmaceuticals, is a short-acting drug that is available in doses of 2.5 mg, 5.0 mg, 7.5, mg, 10 mg, 15 mg, 20 mg, and 30 mg. Like Vyvanse, Zenzedi is purely d-amphetamine.

Amphetamines and Methylphenidate May Raise Blood Pressure Only Slightly

Because amphetamines and amphetamine-like medications are stimulants, they may increase blood pressure somewhat, although usually not to the level of hypertension. Hypertension is defined as a blood pressure with a systolic blood pressure of 130–139 mm HG or a diastolic pressure of greater than 80.¹ For example, a person who has a blood pressure of 135/80 has high blood pressure, whereas a person whose blood pressure if 115/70 has normal blood pressure.

In large studies of stimulants in adult populations the typical increase in blood pressure was 2 to 4 mg of mm Hg. The average pulse elevations were four to six beats per minute.² Each physician will have to determine if their patient can tolerate these modest changes. It is best to measure blood pressure and pulse before a patient starts taking stimulants and then again, a month later, to ensure that these vital signs are within the normal range.

Individuals already diagnosed with hypertension are not good candidates for stimulant medications.

Notes

1.American College of Cardiology, “2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults,” Journal of the American College of Cardiology (September 2017), https://www.acc.org/~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Guidelines/2017/Guidelines_Made_Simple_2017_HBP.pdf (accessed August 22, 2019).

2.Food and Drug Administration, “Vyvanse^TM (lisdexamfetamine dinmesylate),” February 2007, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021977lbl.pdf (accessed September 9, 2019).

Considering Methylphenidate Medications

Methylphenidate is the other stimulant that has been used for decades to treat children, adolescents, and adults with ADHD. It has also been used in adults with certain sleep disorders. Like amphetamine, methylphenidate affects the concentration of dopamine and norepinephrine in the brain, but its mechanism of action is less complex. Methylphenidate formulations are available in short-acting and long-acting formulations. (See Table 6.1.)

Benefits and Risks of Methylphenidate and Related Medications

The benefits and risks of methylphenidate medications essentially parallel the properties of prescribed amphetamines. When they work well, these drugs enhance concentration and focus and are effective at combating the hallmark symptom of CFS. In general, methylphenidate is less activating than amphetamine, and the class of methylphenidates may be less obvious candidates for formal study in CFS. There are numerous reports of misuse and abuse of methylphenidate, and clinicians should prescribe this medication with this risk in mind.

Methylphenidate and CFS

In a study of 60 patients with CFS, Blockmans and colleagues¹¹ found significantly decreased fatigue scores with methylphenidate. In this study, methylphenidate was given twice a day at a dose of 10 mg each (20 mg per day) over a one-year period. Subjects were randomly assigned to either the medication group (the study group) or the placebo group (the control group). The research team found that concentration problem levels in the medication group decreased significantly when compared to the control group.

The researchers were surprised to find that muscle pain also decreased in the methylphenidate group. They wrote, “An unexpected finding of our study was that muscle pain was scored significantly lower with methylphenidate than at baseline or with placebo.” In addition, the researchers noted that methylphenidate was not associated with increased sleep disturbances.12

Looking at Types of Methylphenidate Related Drugs

There are multiple different brands and formulations of methylphenidate, and I discuss them next.

Adhansia XR

Adhansia-XR is produced by Purdue Pharma and is available in dosages of 25 mg, 35 mg, 45 mg, 55 mg, 70 mg, and 85 mg. It is a long-acting drug taken once daily in the morning.

Aptensio XR

This drug, manufactured by Rhodes Pharmaceutical, is a long-acting capsule that is taken once daily in the morning. The following dosages are available: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg.

Concerta

This is a long-acting drug taken that is slowly release through an OROS osmotic technology. Concerta was the first long-acting methylphenidate and was brought to market by the ALZA Corporation and marketed by McNeil. Concerta is taken once daily in the morning and is available in the following strengths: 18 mg, 27 mg, 36 mg, and 54 mg.

Cotempla XR-ODT

Neos Therapeutics manufactures Cotempla XR-ODT, a rapidly dissolving form of methylphenidate. This long-acting medication is taken once in the morning and is available in the following dosages: 8.6 mg, 17.3 mg, and 25.9 mg.

Focalin/Dexmethylphenidate HCl Extended Release

Teva manufactures the generic form of what was formerly called Focalin. Dexmethylphenidate is the d isomer of methylphenidate, and it has slightly different clinical properties than the racemic mixture. Patients generally have a preference between the two different formulations and can decide after they try each separately. Short and long durations are available. The extended release version is taken once per day and is available in the following capsule dosages: 5 mg, 15, mg, 30 mg, and 40 mg.

Jornay PM

This long-acting methylphenidate drug is administered in the evening because its onset of action is delayed for 10 to 12 hours after ingestion. This novel engineering, approved by the FDA in 2018, was developed by Ironshore Pharmaceuticals. Jornay PM comes in capsules with multiple strengths ranging from 20 mg to 100 mg. Jornay PM is taken at 8:00 p.m. and becomes active upon awakening in the morning. Prior to the availability of Jornay PM, patients had to awaken, take their stimulant medication, and wait 30 to 60 minutes for the medication to take effect. This delayed-release technology is particularly helpful for patients who have trouble transitioning from sleep to wakefulness in the morning and benefit from the medication being present at therapeutic levels upon awakening.

Metadate CD

Metadate CD, manufactured by UCB Inc., is a long-acting capsule and consequently is taken once daily in the morning, usually before breakfast. It is also available as a generic drug manufactured by Teva. The capsules last about six hours and are available in the following dosages: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg.

Methylin and Methylin ER

Methylin comes in the form of chewable tablets, regular tablets, and a liquid solution. The extended-release tablets are available in a 20-mg dosage, and is a generic drug. The grape-flavored chewable tablets come in the following dosages: 2.5 mg, 5 mg, and 10 mg. These chewable tablets are short-acting. The chewable tablets are made by Shiongi Inc., which also makes the liquid form of the drug.

Quillichew ER/Quillivant XR

Quillichew ER is a chewable cherry tablet that is long-acting. It comes in dosages of 5 mg, 10 mg, and 15 mg and is related chemically to Quillivant, a long-acting liquid suspension. Both medications were brought to market by Pfizer and were designed for younger children who have trouble swallowing tablets or capsules. Pfizer has since exited the ADHD market and sold the medications to a smaller company. These medications are now owned by Tris Pharma.

Ritalin LA

Ritalin LA was made by Novartis Pharmaceuticals Corporation as a long-acting capsule. Teva now produces a generic form of Ritalin LA in capsules that are 10 mg, 20 mg, 30 mg, and 40 mg. Ritalin LA is a dual-bead capsule where 50 percent is released immediately and then 50 percent is released four hours after the capsule is swallowed. The medication has a similar duration of action to Concerta of about nine hours, but compared to Concerta, it achieves greater effectiveness early in the day.

Daytrana

Daytrana is the only transdermal methylphenidate on the market. It is manufactured by Noven. Daytrana is applied to the upper buttock in the morning and removed later in the day. The manufacturer suggests a nine-hour wear time, after which the patch can be removed. The clinical effects dissipate over the next hour, ensuring no interference at bedtime. Adolescents and adults who initiate sleep later at night wear the patch for longer periods to obtain performance later into the evening. When Daytrana was initially introduced, there were some problems with adherence to the skin. This has been largely resolved, but because the patch can cause local irritation, it is suggested that the application site be alternated each day.

Possible Side Effects of Methylphenidate and Derivatives

As with amphetamines and related drugs, methylphenidate and derivative medications may also cause some side effects. Some of these side effects may include the following:

•Headache

•Decreased appetite

•Dry mouth

•Stomach cramps

•Weight loss

•Grinding of the teeth (bruxism)

•Nervousness

•Decreased sexual desire

•Heavy perspiration

•Muscle tightness

If any of the following symptoms or signs occur, the patient should see a physician right away or seek emergency medical help:

•Seizures

•Frequent painful erections or an erection that lasts longer than four hours

•Pain, numbness, or sensitivity to temperature in the fingers and toes

•Paranoia

•Agitation

•Changes in vision or blurred vision

•Blistering or peeling skin

•Hives

•Chest pain

•Shortness of breath

•Hallucinations

•Delusions

Stimulants and Drug Schedules

Prescribed stimulants are also scheduled drugs, which means that they are controlled by the Drug Enforcement Administration (DEA). There are five schedules, ranging from I to V. Schedule I drugs are all illegal and include such drugs as heroin and illegally manufactured methamphetamine. Marijuana is also a Schedule I drug under the DEA’s schedules, although at least half the states in the United States have approved “medical marijuana,” and some states allow the recreational use of marijuana among adults ages 21 years and older.

Schedule II drugs are medications that the DEA has determined have a high risk of abuse, and nearly all opioids (except for cough syrup with codeine) lie within Schedule II. Other drugs that are scheduled include sedatives such as barbiturates, sleep medications, and other medications that have some level of risk associated with them. In addition, most stimulants also lie within Schedule II, although wakefulness drugs like modafinil lie within Schedule IV. Because of this scheduling, some people are reticent to take stimulants because they fear that they might get addicted. The reality is that most people who encounter drug dependency are addicted to illegal drugs or to prescribed opioids. Prescribed stimulants rarely cause clinical dependency. To be sure, street stimulants such as cocaine or methamphetamine are trafficked and abused, but these illegal drugs were never intended for any medicinal value.

Numerous clinical studies explore the distinction of abuse potential between opiates and stimulant medications. For example, in 2015, Cassidy and her colleagues surveyed 10,000 people ages 18–49 years on their nonmedical use of scheduled stimulant drugs, including Adderall, Adderall XR, Concerta, Ritalin, and Vyvanse. The researchers also considered the lifetime nonmedical use of pain medications, sedatives/tranquilizers, and sleep medications. They found that the lifetime nonmedical misuse or diversion of any of these scheduled prescription drugs was 35 percent, meaning that more than a third of the respondents admitted to these behaviors.13 This sounds rather disturbing, but continue reading.

These researchers discovered that the most commonly abused drugs were pain medications (25%), followed by sedatives/tranquilizers (16%), sleep medications (10%), and, last, prescription stimulants (8%). In addition, they found that those individuals who were the most likely to misuse prescribed stimulants were ages 18–25.¹⁴ Of note, many of the young people misusing the stimulants had symptoms that were consistent with attention deficit hyperactivity disorder (ADHD) diagnosis, and thus, it is likely that at least some of these individuals were self-medicating to improve their symptoms, rather than trying to obtain a mind-altering high. In fact, other researchers who have studied college students who misuse prescribed stimulants (the demographic group that is the most likely to misuse these drugs), the primary goal was to improve their school performance and grade point average. They might be surprised to learn that misusing the medication did not improve their grades.¹⁵

A 2005 study of 4,000 respondents ages 18 to 49 evaluated the nonmedical use of Ritalin, Dexedrine Adderall, Adderall XR, and Concerta. The past-year prevalence of these “ADHD stimulants” was 4.3 percent among individuals ages 18 to 25 years and 1.3 percent among those ages 26 to 49 years. The most common type of misuse was giving the prescribed drug to friends and family members.¹⁶

As most people with CFS are typically older than age 25, the risk for misuse appears minimal.

Wakefulness-Promoting Drugs

Modafinil (Provigil) is one of several wakefulness-promoting drugs used to treat CFS. Modafinil, a non-amphetamine-like drug, is indicated for narcolepsy, a disorder in which a person has little control over falling asleep. Modafinil is also approved for patients with excessive sleepiness associated with sleep apnea and shift work sleep disorder (SWSD) a condition characterized by insomnia and excessive sleepiness affecting people who have inconsistent sleep schedules. Nurses and truck drivers notoriously suffer from SWSD, and the medication allows these shift workers to stay awake when needed until they transition to a new sleep/wake cycle.

In addition to modafinil, other wakefulness-promoting drugs include armodafinil (Nuvigil) and Sunosi (solriamfetol). Unfortunately, data is limited as of this writing, and carefully controlled studies have not been conducted with nonstimulants in CFS patients. My clinical experience is that they are effective in CFS and need to be systematically compared to long-acting stimulants.

Fatigued, Sleepy, and Depressed Patients Improved with Modafinil

In a study published in 2006, it was noted that some depressed patients treated with fluoxetine (Prozac), an antidepressant, continued to be sleepy and fatigued. In the six-week study, 21 patients were supplemented with 100 mg to 200 mg of modafinil in the morning. Each subject was evaluated with the Fatigue Severity Scale, the Epworth Sleepiness Scale, and the Hamilton Rating Scale for Depression at the onset of the study and at the second and sixth weeks of the study.

The results were positive; in this fluoxetine + modafinil study, all the patients improved in sleepiness and fatigue, and most of the subjects (76%) also improved in depression scores.1 The take home message is clear. As many patients with chronic fatigue syndrome suffer from depression as well as sleepiness and fatigue, a trial of modafinil along with an antidepressant may be a consideration.

Note

1.Numan Konuk, et al., “Open-Label Study of Adjunct Modafinil for the Treatment of Patients with Fatigue, Sleepiness, and Major Depression Treated with Selective Serotonin Reuptake Inhibitors,” Advances in Therapy 23, n. 4 (July/August 2006): 646–654.

Key Benefits and Risks of Wakefulness Drugs

Wakefulness drugs offer potential benefits to individuals with CFS. Wakefulness medications received Schedule IV classification from the DEA, meaning that this class of medication is less likely to be misused and diverted than Schedule II stimulant medications. The lower tiered scheduling offers other benefits as well. When a Schedule II drug is prescribed, the patient must obtain a new, separate prescription every month. In contrast, the medical provider can authorize multiple refills of Schedule IV medications. Another advantage is that doctors are less apprehensive about prescribing Schedule IV medications. Doctors are being scrutinized by state regulators about their use of controlled medication, and many states now issue a regular report card enumerating how many controlled substances a doctor wrote in the past three months. To avoid any appearance of impropriety, many providers are more comfortable prescribing nonstimulants, even if they do not feel these medications are safer or more effective than stimulant medications.

Wakefulness drugs may cause nausea, headache, anxiety, and difficulty with sleeping.

Modafinil and Chronic Fatigue Syndrome Recovery

Wakefulness medications have been studied to a very limited extent in CFS. In a case study of an afflicted 33-year-old man, Turkington and colleagues described Mr. C, who at age 19 complained to his physician of fatigue, poor sleep, and pain. He initially required complete bed rest, and over the next decade, he had periods of response and relapse. Eleven years later, Mr. C was in a wheelchair and could barely care for his basic needs. He was then treated with modafinil and clonazepam (an antianxiety medication) at a therapeutic dose. Upon receiving the medications, Mr. C reported significant improvement in his energy levels and noted sustained benefit from treatment. Dr. Turkington notes that the patient was sick for 13 years before he was finally diagnosed with CFS and treated for the condition.17 As a practicing psychiatrist, I too have witnessed a significant number of patients who, like Mr. C, who have responded favorably to modafinil. More studies of wakefulness-promoting medication in the treatment of CFS would be welcome.

More on Modafinil

Modafinil (Provigil) is a “wakefulness” drug. It is owned by Cephalon Inc. and is available in tablets in dosages of 100 mg and 200 mg. Armodafinil is the generic form of modafinil, and it is also owned by Cephalon.

Sunosi

Jazz Pharmaceuticals owns Sunosi. This wakefulness drug, approved by the FDA in 2019, is available in tablet form in dosages of 37.5 mg, 75 mg, and 150 mg. It is a dual reuptake inhibitor drug, and it acts to increase the release of both dopamine and norepinephrine. It has not been formally studied in CFS.

Table 6.1 Medications That May Be Further Explored to Treat CFS

Name	Short-acting	Long-acting
Amphetamines and Amphetamine Derivatives, Brand Name (Generic Name)
Adderall	√
Adderall XR		√
Adzenys XR-ODT		√
Aptensio XR		√
Dexedrine	√
Dexedrine spansules		√
Evekeo	√
Mydayis		√
ProCentra (dextroamphetamine sulfate)	√
Vyvanse (lisdexamfetamine)		√
Zenzedi (dextrianogetanube sulfate)	√
Methylphenidate and Derivatives
Adhansia XR		√
Concerta		√
Cotempla XR-ODT		√
Dexmethylphenidate HCl XR		√
Jornay PM		√
Metadate CD		√
Methylin	√
Methylin ER		√
Quillichew ER		√
Quillivant XR		√
ProCentra	√
Ritalin	√
Ritalin LA		√
Wakefulness Medications
Modafinil		√
Sunosi		√

This chapter has covered a number of medications that may help individuals with CFS, taking account both the risks and the benefits. In the next four chapters, I explore major features of CFS, including fatigue, chronic pain, brain fog, and sleep issues and offer suggestions on how to deal with these very troublesome symptoms.

Notes

1.N. G. Bradley and O’Brien, Angela, “Beyond ADHD and Narcolepsy: Psychostimulants in General Psychiatry,” Advances in Psychiatric Treatment 15 (2009): 297–305.

2.Norman Ohler, Blitzed: Drugs in Nazi Germany. New York: Penguin Press, 2017.

3.Christine Adamec, Understanding Drugs: Amphetamines & Methamphetamine. New York: Chelsea House, 2011.

4.National Institutes of Health, “Amphetamine,” MedlinePlus, April 15, 2019, https://medlineplus.gov/druginfo/meds/a616004.html (accessed August 23, 2019).

5.Ibid.

6.L.G. Olson, Ambrogetti, A., and Sutherland, D.C., “A Pilot Randomized Controlled Trial of Dexamphetamine in Patients with Chronic Fatigue Syndrome,” Psychosomatics 44, n. 1 (January–February 2003): 38–43.

7.Ibid., page 42.

8.Leslie Olson, “The Difference: Nootropic vs. Amphetamines,” PharmaQuality, May 15, 2017. https://pharmaquality.com/2017/05/15/the-difference-nootropic-vs-amphetamines/ (accessed September 6, 2019).

9.Jeffrey R. Strawn and Picard, Lara S. “Triple-Bead Mixed Amphetamine Salt for ADHD,” Current Psychiatry 16, n. 8 (August 2017): 33–37.

10.Stephen M. Stahl, Stahl’s Essential Psychopharmacology Prescriber’s Guide. Sixth Edition. Cambridge, UK: Cambridge University Press, 2017.

11.Daniel Blockmans, et al., “Does Methylphenidate Reduce the Symptoms of Chronic Fatigue Syndrome?” American Journal of Medicine 119 (2006): 167e23–167e30.

12.Ibid.

13.Theresa Cassidy, et al., “Nonmedical Use and Diversion of ADHD Stimulants among U.S. Adults Ages 18–49: A National Internet Survey,” Journal of Attention Disorders 19, n. 7 (2015): 630–640.

14.Ibid.

15.Amelia M. Arria, et al., “Do College Students Improve Their Grades by Using Prescription Stimulants Nonmedically?” Addictive Behavior 65 (February 2017): 245–249.

16.Scott P. Novak, et al., “The Nonmedical Use of Prescription ADHD Medications: Results from a National Panel,” Substance Abuse Treatment, Prevention, and Policy, October 2007, https://substanceabusepolicy.biomedcentral.com/track/pdf/10.1186/1747-597X-2-32 (accessed August 13, 2019).

17.Douglas Turkington, et al., “Recovery from Chronic Fatigue Syndrome with Modafinil,” Human Psychopharmacology Clinical and Experimental 19 (2004): 63–64.