A Simple Overview of Medications for ADHD

Medications used for ADHD do not treat the cause of ADHD but instead are instead used to manage the symptoms of ADHD. Medications used to treat ADHD can be split into two types: stimulant and non-stimulants. Stimulant medications for ADHD work by increasing activation in brain regions which are associated with attention skills, however as stimulants are swallowed and ingested, they are absorbed into the blood stream and can affect other parts of the body, having other, possibly undesirable side effects. It is very important when considering medication that you see a medical professional with a high level experience in administering and prescribing medication. Certain ADHD medications such as the stimulant are considered Schedule 8 (Drugs of Addiction).

Stimulant medications include Ritalin, dexamphetamine, Vyvanse, Concerta. Stimulant medications can come in short acting form where the effects occur rapidly after ingestion and last for a relatively short period of time, or they can come in long acting form where the effects lasts for a relatively longer period of time (however still typically less than 12 hours). In contrast, non-stimulant medications for ADHD include any medications that do not directly increase activation in brain regions. Non-stimulant medications include Strattera, Guanfacine, and Clonidine. Studies show that medications are generally effective in reducing ADHD symptoms however medications are associated with side effects including, but not limited to, dry mouth, decreased appetite, mood changes, jitteriness/tension, depression, weight loss, and vertigo. There is also some relatively new evidence that anti-depressant medications can be effective in reducing ADHD symptoms. Importantly however, because medications for ADHD treat the symptoms and not the cause, once there is no medication left in the body, the symptoms return. This can be clearly observed in the stimulant medications where symptoms return to pre-medication levels usually within 4-10 hours.

The Detailed Science of Medications for ADHD

ADHD Stimulant Medication Options in Australia

Stimulant medications for ADHD work by increasing brain activity in regions such as the prefrontal cortex which are crucial for executive functioning (Kolar and colleagues, 2008). There are two broad categories of stimulants, short acting and long acting. Short acting stimulants typically take effect within 30 – 45 minutes of ingestion and last around 3-6 hours (Yucel and colleagues, 2015). In contrast, long acting stimulants take effect within the same day of ingestion and last around 8-12 hours (Yucel and colleagues, 2015).

Short Acting Stimulants in Australia

1. Ritalin

Short-acting Ritalin contains the active ingredient methylphenidate which increases the levels of two excitatory neurotransmitters, norepinephrine and dopamine, by preventing their reuptake into neurons (Wilens, 2006). In doing so, it elevates brain signals and the functions associated with these neurotransmitters. Norepinephrine plays a vital role in regulating attention along with levels of alertness and stress, and assists in memory formation (Ranjbar-Slamloo and Fazlali, 2020). On the other hand, dopamine is involved in a wide range of functions including short term memory, attention span, organisation and strategy abilities, and responses to reward (Ranjbar-Slamloo & Fazlali, 2020). Thus, short-acting Ritalin works overall to improve attention.

The effects of short-acting Ritalin last up to around 4 hours, with brain studies showing that effects reach their peak around 1 hour after oral consumption (Colzato & Arntz, 2017). A key advantage of this medication is that it can be taken more flexibly on an as-needed basis and can be used to supplement other once-daily medications if necessary (Kolar and colleagues, 2008).

Efficacy

Much research has demonstrated the ability of Methylphenidate (Ritalin) to reduce ADHD symptoms however the overall effect is small and varies greatly according to dose (Santosh, 2011). For example, Kooji and colleagues conducted a study in 2004 comparing the impact of 0.98mg/kg/day dosage to placebo, a drug made of an inactive substance, on adults with ADHD. Results revealed that while more patients on Ritalin experienced a significant reduction of symptoms compared to those on the placebo (38% vs 7% respectively), this reduction was only a 30% improvement. In contrast, other studies find response rates of up to 75% but with much higher doses (Santosh, 2011).

The advantages of short-acting Ritalin include an improvement to concentration, attention, listening skills, control of actions and reduction of fidgeting. It also decreases impulsivity, hyperactive behaviour and improves focus. Arnsten and Dadly (2005) demonstrated that short acting Ritalin in clinical doses leads to an improvement in spatial working memory, set-shifting and other prefrontal cortex cognitive functions.

According to two stimulant studies by Spencer and colleagues positive effects of ADHD symptom reduction in adults was found. Within a previous study (Spencer, 1995), adult participants with ADHD were placed in a placebo, an inactive substance trial, or methylphenidate treatment group. ADHD symptoms, such as hyperactivity and inattentiveness actions, were reduced by 78% in the treatment group. In Spencer and colleagues’ (2005) subsequent study, the same effect of a 76% reduction in ADHD symptoms was also found.

Side Effects

A wealth of research demonstrates that taking short-acting Methylphenidate produces a range of adverse side effects (Santosh, 2011).  For example, a systematic review by Godfrey and colleagues (2009) revealed that participants who took methylphenidate reported: dry mouth (31% and 11% for methylphenidate and placebo, respectively), decreased appetite (27% vs 9%), mood changes (18% vs 2%), jitteriness/tension (22% vs 5%), depression (21% vs 9%), weight loss (11% vs 0%) and vertigo (12.5% vs 2%; Godfrey, 2009). Godfrey (2009) also reported that methylphenidate produced changes in cardiovascular measures. Specifically, patients taking short-term methylphenidate had significantly greater blood pressure and pulse rates at the end of the study than patients taking placebo (Godfrey, 2009).

The side effects of stimulant medication, such as short acting Ritalin, are dose-dependent, able to be managed by increasing or decreasing dosage of the medication or changing the time of consumption.

Short Acting Ritalin can also result in insomnia, due to a behavioural rebound occurring when the medication is wearing off the stimulant effects on the adults ADHD (Powers, 2000).

The side effects of using this medication firstly includes worsened symptoms of anxiety,
agitation, or other psychotic disorders that the individual may have. This medication can also
cause blurred vision or other changes to eyesight, headaches, trouble sleeping, irritability,
moodiness, nervousness and an increased blood and heart pressure. This medication can also
be habit-forming, meaning that when a high dosage of Ritalin is consumed, the quick rise of
dopamine within the brain can result in a euphoric state. It also can be habit-forming in that
after taking high dosages for a long period of time, an individual may experience withdrawal,
which includes the symptoms of fatigue, sleeping problems and depression. Thus, it is
recommended to reduce consumption slowly over time when recommended by your doctor.

The misuse of this medication can result in feelings of hostility and paranoia. Extremely high
dosages of this medication can result in shakiness, delusions, mood changes, hallucinations
and seizures. The misuse of this stimulant, by crushing pills and injecting it into the body can
cause blocked blood vessels. Misusing Ritalin also can lead to vomiting, abdominal pain and
diarrhoea and if misused over time, it can cause malnutrition and weight loss. An overdose of
this medication can lead to dangerously high blood pressure and irregular heartbeat.

The consumption of Ritalin can lead to a reduction of appetite, stomach aches and nausea.
It is important to note that if an individual is taking other prescribed medications, such as
Monoamine oxidase inhibitors anti-depressants, that this can lead to fatal outcomes when taken
simultaneously with Ritalin.

Long-Term Prognosis

Other long term effects of Ritalin is that it impacts the circulatory system. An individual’s fingers
and toes may become cold and painful, and your skin colouration may turn blue or red. The
use of Ritalin is also linked to Peripheral Vascular Disease, including Raynaud’s Disease.
This stimulant may also raise your body temperature, heart rate and blood pressure. For individuals with a previous blood-pressure or heart problems, this medication must be taken with caution as it can increase the risk of a heart attack.

2. Dexamphetamine

Dexamphetamine (dexedrine or DEX) is another short-acting medication that works to increase levels of dopamine and norepinephrine in the brain but does so through triggering greater release of each neurotransmitter (Kenny and colleagues, 2015). Dexedrine is absorbed quickly however effects only last 4-6 hours, therefore the medication often needs to be taken multiple times per day (Kolar and colleagues, 2008). Similar to short-acting Ritalin, Dexedrine is commonly prescribed as a supplementary medication or when patients request greater flexibility of their dosing (Kolar and colleagues, 2008).

Efficacy

Taylor and colleagues (2000) looked the efficacy of taking DEX on adults with ADHD. For this study, participants completed the ADHD-checklist before and after taking DEX for 2 weeks. They found that taking DEX significantly improved ADHD symptoms on a statistical level.  However, it failed to reduce these symptoms below the level used to predict clinically significant ADHD, suggesting that this medication may not be effective in reducing ADHD symptoms clinically (Taylor, 2000). Further research using clinically-approved ADHD diagnostic methods is needed to clarify this observation.

Dexamphetamine has been used for adults with ADHD in order to reduce their symptoms of ADHD. Within a study by Weiss and Heichtman (2005), showed that 85.7% of participants in the treatment control trial of receiving dexamphetamine showed an improvement in ADHD symptoms, such as hyperactivity and inattention.

Another study by Paterson et al (1999), randomly assigned ADHD adults in a 6-week excellent study where participants were either in the dexamphetamine or placebo group. According to self rating scale data, at 6 weeks, the dexamphetamine group had significantly lower symptom scores compared to the placebo group. The hyperactivity and inattentiveness score for the dexamphetamine group also decreased significantly. Clinicians found that 58% of the dexamphetamine groups were ‘much improved’ or ‘very much improved’. The clinicians also found that 78% of participants in this group experienced levels of benefits from the drug greater than the level of side effects.

Referring to a study completed by Bresnahan and colleagues (2006), an analysis of dexamphetamine-responsive adults with ADHD was completed. The results from this investigation demonstrated that following medication there was a significant reduction in slow brain wave activity for ADHD groups, similar to those of the control group. This shows that the slow brain wave activity of ADHD adults was normalised due to their responsiveness to this medication. Previous studies by Bresnahan and colleagues (1999), have shown adults with ADHD report slow wave activity (delta and theta), which is reflected in ADHD impulsive behaviours. Reductions in delta, absolute and relative theta, and total power were observed. However,  absolute and relative theta activity failed to fully normalize, which has been found in medication studies of children with ADHD (Clarke and colleagues, 2002). The failure to fully normalise ADHD adult levels may be related to the residual symptoms still evident in this group when they are on medication. Thus, further research must explore whether a greater degree of normalization corresponds to a greater level of behavioural response. The results of this study showed that reduction in slow wave activity following treatment with stimulant medications may be strongly associated with, and may perhaps underlie, the positive changes noted in the patient’s behaviour.

Within the study by Taylor and Russo (2000) the efficacy of Modafinil was compared to Dextroamphetamine for adults with ADHD. The results of this investigation showed that 48% of the participants had a favourable response to dextroamphetamine. Subjects were asked which of the drugs assisted the reduction of their ADHD symptoms the greatest, with 48% selecting dextroamphetamine, with 29% of these participants being of the inattentive ADHD subtype.

Side-Effects

Paterson and colleagues (1999) investigated the effects of short-acting DEX compared to placebo, an inactive substance.  Almost 30% of participants who received dexamphetamine reported adverse side effects (Paterson, 1999).  The most commonly reported side effects (relative to placebo) were: decreased appetite (36% vs. 13%), sleep disturbances (25% vs. 18%), palpitations (23% vs. 9%) dry mouth (30% vs. 16%), menstruation disturbances (11% vs. 0%) and libido decline (11% vs. 3%).

Within Taylor of Russo’s study (2000), the adverse effects of insomnia, irritability, muscle tension and appetite suppression were the most common, more prevalent in the dextroamphetamine treatment group compared to the modafinil group. The rebound effect for the participants taking dextroamphetamine lasted 30 minutes to an hour and occurred in the evening.

Long Acting Stimulants in Australia

1. Long Acting Ritalin

Ritalin LA is a stimulant that increases attention and decreases impulsiveness and hyperactivity in patients with ADHD. Ritalin LA is thought to work by regulating specific chemicals in the brain that affect behaviour. It helps to focus attention, shut out distraction and allows impulsive people to think before they act. If successful, it will enhance an inattentive person’s natural ability. Ritalin LA is available in long-acting capsules containing 10 mg, 20 mg, 30 mg, 40mg or 60 mg of methylphenidate hydrochloride as the active ingredient. In adults, the maximum recommended daily dose is 80 mg.

Efficacy

Medori and colleagues (2007) researched the effectiveness of long-acting (LA) methylphenidate in adults with ADHD. In this experiment, adults with ADHD were given either placebo or LA methylphenidate for five weeks.  The results showed that taking methylphenidate significantly reduced symptom severity.  However, this reduction failed to reach clinical significance. Therefore, this suggests that taking LA Methylphenidate does decrease symptom severity, but participants are still often displaying clinically significant levels of ADHD symptoms (Medori, 2007).

Side-Effects

Long-acting (LR) methylphenidate medications have also been widely reported to produce negative side effects (Rosler, 2009).  Specifically, Rosler & Fisher (2009) looked at the adverse effects of taking extended-release (ER) methylphenidate and reported that it produced: decreased appetite (in 38% of patients taking methylphenidate ER compared to 13% for placebo), sleep problems (25% vs 18%), dry mouth (30% vs 16%), palpitations (23% vs 9%), excessive thirst (24% vs 12%), menstrual problems (11% vs 0%) and reduced libido (11% vs 3%). Rosler and colleagues (2009) also reported that the heart rate of patients taking methylphenidate increased significantly over the testing weeks, compared to placebo.

2. Long Acting Dextroamphetamine

This form of Dextroamphetamine acts as a pro-drug which requires an enzymatic breakdown in red blood cells, in order to become the prominent active ingredient d-amphetamine and the amino acid lysine (Pennick, 2010). Long acting dextroamphetamine lasts up to 14 hours and clinical effects are observed 2 hours after consumption.

Efficacy

Within another study by Adler and colleagues (2008), a randomised trial of adults with ADHD found that the consumption of long acting dexamphetamine led to significantly significant improvements in ADHD for all doses (30-50mg). The percentage of improvements for each different dosage of long acting dexamphetamine was 57% for 30mg per day dosage, 62% for 50mg per day and 61% for 70mg per day. Within a 12-month follow up study, the statistically significant improvement found in the original study was maintained (Weisler, 2009).

Side-Effects

Spenser and colleagues (2006) investigated the effects of long-acting dexamphetamine in adults with ADHD.  The most commonly reported side-effects (compared to placebo) were: headaches (23% vs. 11%), decreased appetite (18% vs. 11%), dry mouth (16% vs. 4%) and jitteriness (12% vs. 2%).

Within the study by Adler and colleagues (2008), the adverse effects were mild and included dry mouth, decreased appetite and insomnia.

3. Vyvanse

Vyvanse, lisdexamfetamine dimesylate, is another ADHD Long Acting Stimulant which can be used to reduce symptoms of ADHD in adults. Vyvanse differs from Long Acting Dexamphetamine due rapid absorption of Vyvanse (lisdexamfetamine) in the gut after morning consumption which is then converted to dexamphetamine before it is active through hydrolysis in the blood, meaning that is is a pro-drug of dexamphetamine.

Efficacy

Within a study by Wigal and colleagues (2010), it was found that Vyvanse significantly improved ADHD symptoms and maintained improvement throughout the day from the first 2 hours and lasted 14 hours.

Similarly, in a study completed by Dupaul and colleagues (2012), an evaluation of Vyvanse on symptoms and functioning of college adult students with ADHD was done. Within this study, Vyvanse was examined for ADHD participants over 5 weekly phases, with increments of no drug baseline, placebo, 30mg, 50mg and 70mg of Vyvanse per day. Self report scales of functioning and assessment of ADHD symptoms, memory, and the adverse side effects were recorded. The results from this investigation showed an 86.4% reduction of ADHD symptoms for participants, with Vyvanse also leading to improvements in executive functioning and a small effect for psychosocial functioning.

Side-Effects

Wigal and colleagues (2010) looked at the effects of lisdexamfetamine dimesylate in adults with ADHD. Patients who took lisdexamfetamine experienced decreased appetite (experienced by 37%), dry mouth (30%), headaches (20%), insomnia (18%) and irritability (9%). These effects were reported to be mild to moderate in severity (Wigal et al., 2010).

4. Concerta

Concerta is an extended release, long acting form of methylphenidate, also known as OROS-methylphenidate. The pill contains an outside coating of methylphenidate that allows for the immediate release and affect of the drug (FDA, 2013). The core contains two components: the active ingredient and an osmotically active component that allows for the extended release and affect of methylphenidate on the body (FDA, 2013).

Efficacy

A 2007, Biederman and colleagues recruited adults diagnosed with ADHD to take part in a randomised 6-week study. The study examined the safety and efficacy of once-daily OROS methylphenidate (MPH). Participants were given either a placebo or OROS MPH. It was found that OROS MPH, was significantly more effective than the placebo at controlling and ADHD symptoms and inattentiveness. However, for those who took OROS MPH it was noted that they had side effects in relation to blood pressure and heart rate. The authors suggest that these side effects are not much of a concern, however, users of such medication should monitor their heart rate and blood pressure over the course of their medication.

Reimher and colleagues (2007) investigated OROS MPH and found that such medication helped reduce the symptoms of inattentiveness, and hyperactivity. Those on OROS MPH had a decrease of 42% of ADHD symptoms, compared to 13% who took the placebo. Furthermore, scores for the ADHD-Rating Scale, decreased by 41% versus 14% for those on OROS MPH compared to the placebo.

Side-Effects

Studies which have reviewed the research around MPH and OROS MPH suggest that when the dosage is controlled correctly, the side effects of this medication should be minimal (Godfrey, 2009). In a more comparative meta-analysis MPH and OROS MPH where both compared to a placebo (Sopko and colleagues, 2010). The meta-analysis looked at the most common side effects across the different studies, and then calculated approximately how many participants felt those affects. In the studies that they reviewed it was found that 12% – 41% of participants noted a loss of appetite when on MPH. In relation to headaches, the evidence from the various studies were highly variable with 16% to 53% participants noting headaches. About 24% of participants on MPH/OROS MPH mentioned insomnia as a side-effect compared to 16% on the placebo. Dry mouth was a common side effect mentioned by participants across most trials. Again, some studies noted that mean heart-rate increased in the rage of 3.6 – 9.8 bpm.

ADHD Non-Stimulant Medication in Australia

1. Strattera

Atomoxetine (Strattera) is a non-stimulant drug that has been found to be effective in treating ADHD symptoms. Atomoxetine is a norepinephrine reuptake inhibitor, which increases the amount of norepinephrine available in the brain to help with attention and focus (Spencer, 2002).

Efficacy

In one randomised control study, young adults with ADHD either took atomoxetine or a placebo (Durell and colleagues, 2013). It was found that atomoxetine was more effective than the placebo in treating ADHD symptoms. Participants on atomoxetine, rated their quality of life to be higher than those on the placebo.

A meta-study conducted by Walker and colleagues (2015) investigated atomoxetine against placebos. The study concluded that sides effects were noted in under 10% of participants who took atomoxetine. These side effects include nausea, dry mouth, decreased appetite, insomnia, and fatigue. As such, the authors concluded that atomoxetine is a possible treatment option for certain patients.

Side-Effects

As mentioned earlier side effects for atomoxetine are like that of stimulant drugs for ADHD. These side effects include nausea, dry mouth, decreased appetite, insomnia, and fatigue. A meta-analysis which looked at the impact these drugs have on heart rate and blood pressure found that heart rate increased between 3.8 – 4.4 beats per minute (Fredriksen and colleagues, 2013).

A study which compared the effects of atomoxetine against methylphenidate in children with ADHD, found that most children had better sleep when taking atomoxetine compared to methylphenidate (Sangal and colleagues, 2006). This study found that when children were taking atomoxetine, they were able to get to sleep within 12 minutes, compared to 39 minutes when on methylphenidate. Furthermore, they had better sleep and they also found it easier to wake up in the mornings. All this was supported by the children’s sleep diaries and parental reports.

2. Guanfacine

Guanfacine, or Intuniv, is an extended-release non-stimulant medication. This activates postsynaptic α2A adrenoceptors in the midbrain and pyramidal cells of the prefrontal cortex. The importance of this to adults with ADHD is that these areas of the brain are related to attention, organisation, planning and impulse control.

Efficacy

Within a study completed by Iwanami and colleagues (2020), an analysis of the efficiency of this medication for adults with ADHD was assessed. Within this study, participants received a single dosage of Guanfacine daily, starting at a minimum dosage of 2mg and increasing to 4-6mg for a 50-week period. The results from this investigation showed significant improvements in ADHD symptoms in all patient populations, former placebo patients, former Guanfacine patients and new patients during the long-term treatment with Guanfacine. This study assessed assessed; carelessness, difficulty maintaining attention, listening skills, planning, organisation, sustained attention, distractibility, forgetfulness, hyperactivity and interruptive tendencies. Rapid improvements in ADHD were observed within the first 1–6 weeks of long-term treatment, which were sustained up to week 50 for all populations.

Within another study completed by Taylor and colleagues (2001), a comparison of Guanfacine and Dextroamphetamine was completed. For both of the drugs, subjects had significantly less severe ADHD symptoms than for the placebo group. The symptom means of the drugs did not differ significantly between the two conditions. These results were also noted in the subjects significant improvement in the Stroop colour percentile scores for both drugs over the placebo condition, but there were only significantly improved colour-word sub scores for the Guanfacine group. The significance of this is that the Stroop Task is a specific measure of focused attention and response inhibition, suggesting that these drugs may be useful to specifically to improve focused attention for ADHD. The study shows that the α-2a agonist guanfacine improved performances on the Colour-Word Subtest (associated with prefrontal pathology when low), whereas DAMP did not.

Side-Effects

The side effects of Guanfacine is mostly sedation and fatigue. The rate of sedation for the studies ranged from 16% to 35% and fatigue from 12% to 60%. Dry mouth, headaches, stomach aches, sleep disturbance, and irritability were prominent as well (Cornish 1988, Chappell and colleagues 1995, Hunt and colleagues 1995, Scahill and colleagues 1999). Hypomania, possibly with hallucinations is a rare but possible side effect (Boreman and Arnold 2003). If a patient has bipolar or mood disorder, they should be monitored carefully if on Guanfacine. Overdosing with guanfacine may cause sleepiness, dizziness, low blood pressure and slow heart rate.

3. Clonidine

Clonidine is an alpha-adrenergic agonist medication, a group of drugs that relax blood vessels to help increase blood flow. This medication works best when used in conjunction with stimulants or as an alternative to stimulants which are not appropriate for people with ADHD who also have sleep disorders or other conditions that stimulants may negatively affect.

Efficacy

A study by Fankhauser and colleagues (1992), the efficacy of Clonidine for ADHD adults was completed. The results from this investigation showed that clonidine treatment showed a significant difference from placebo treatment in relation to social relationship to people, affectual responses, and sensory responses. It was also found that significant improvement on severity of illness, global improvement, and efficacy index for therapeutic effect. Adverse effects included sedation and fatigue during the first 2 weeks of clonidine treatment.

Side-Effects

Clonidine, is sometimes prescribed by doctors. It is usually prescribed to reduce persisting aggression and hyperactivity in children with ADHD, or for children with ADHD who are experiencing sleep disturbances. Due to its cardiovascular side effects, a careful medical history of the patient should be taken and rapid changes to dosage should be avoided.