ADHD is a common neurodevelopmental condition affecting both children and adults worldwide. Medication is a frontline treatment for ADHD, and includes stimulant and non-stimulant options. Non-stimulant options are sometimes preferred because they are non-addictive and have a lower potential for adverse side effects.
- Stimulant medications are the first-line treatment for ADHD, but they have a high potential for abuse and addiction.
- Non-stimulant medications can be an effective alternative treatment for ADHD and carry a lower risk for tolerance, abuse, and dependence.
- Alongside medications, people with ADHD can utilize psychological and behavioral therapies to manage their symptoms. Treatment plans should be tailored to the needs of the individual.Â
What are non-stimulant ADHD medications?
Non-stimulant ADHD medications are treatment options for attention-deficit/hyperactivity disorder (ADHD) that do not contain a psychostimulant substance.
Commonly used ADHD medications, such as Ritalin and Adderall, are stimulant substances that are Schedule 2 controlled substances that carry a high risk for abuse and dependence. Although they can be very effective at managing ADHD symptoms, they can cause many side effects and are commonly abused for recreational purposes. Non-stimulant medications can be used concurrently or as an alternative, and have lower abuse and addiction potential. [1]
Non-stimulant ADHD medication options
Four non-stimulant ADHD medications are approved by the Food and Drug Administration (FDA), while various options are used off-label. Typically, a stimulant medication will be prescribed as a first-line treatment, and if this is ineffective, monotherapy or adjunctive non-stimulant medication is prescribed. [1][2]
FDA-approved non-stimulant options
Atomoxetine
Atomoxetine is approved in the United States by the FDA for the treatment of ADHD in children and adults, and it is also approved in other countries, including in Europe. Atomoxetine works as a norepinephrine reuptake inhibitor, thus increasing norepinephrine levels in the brain, while also increasing dopamine. This helps to optimize prefrontal cortex activity, executive function, and attention. [1][3]
Viloxazine
Once used as an antidepressant, viloxazine is now approved in the US only for the treatment of ADHD. It works as a selective norepinephrine reuptake inhibitor (SNRI), helping to regulate levels of serotonin and norepinephrine in the brain. [2][4]
Clonidine and Guanfacine
Clonidine and guanfacine are approved in extended-release formulations in the US for the treatment of ADHD as a monotherapy or for use alongside stimulant medications. As adjunctive therapies, clonidine and guanfacine can enhance stimulant medication effects and decrease their side effects. [1]
Guanfacine and clonidine have similar actions, working as alpha-2 adrenergic receptor agonists. This mechanism helps to reduce blood pressure, which is the traditional use of these medications, and also contributes to increased norepinephrine activity. This helps to regulate prefrontal cortex activity and improve attention and memory. [1][3]
Guanfacine is around ten times less potent than clonidine and causes less sedation. Aside from this, their side effect profiles are very similar. [1]
Off-label non-stimulant medications
Some research has found that other medications can be beneficial in ADHD treatment, including: [1][2][5]
- Centanafadine: A serotonin, norepinephrine, and dopamine reuptake inhibitor, centanafadine has shown some promise in the management of ADHD symptoms in recent trials.
- Tipepidine hibenzate: Limited studies and trials have found some promise in the use of tipepidine hibenzate, a non-opioid antitussive, in the treatment of ADHD.Â
- Antidepressants: Antidepressants that impact norepinephrine, including bupropion, desipramine, and venlafaxine, might be prescribed off-label to help manage ADHD, although some of these (particularly tricyclic antidepressants) may cause significant side effects.
- Modafinil: Although technically a stimulant, modafinil displays less abuse potential than traditional stimulants and does not cause euphoric effects. It is sometimes used off-label to treat ADHD and can enhance cognitive function.
How effective are non-stimulants?
Atomoxetine, viloxazine, guanfacine, and clonidine have demonstrated positive effects in the treatment of ADHD. In particular, atomoxetine and guanfacine have been found to contribute to improvements in quality of life and daily functioning, and can provide continued benefits long-term. [1][3]
Other benefits of non-stimulant ADHD medications include: [1][2][3]
- Their effects can last ‘round-the-clock’, meaning that they do not need to be administered more than once per day. In some cases, atomoxetine is preferred in two doses per day to reduce adverse effects.Â
- They are not controlled substances.
- These medications are often more easily tolerated than stimulants, including carrying a lower risk for irritability, insomnia, and reduced appetite.
Limitations of non-stimulants include: [1][3][4]
- The therapeutic effects of atomoxetine and viloxazine can take six to 12 weeks to emerge, while the effects of clonidine and guanfacine can take two to four weeks.Â
- Compared to placebo groups, the effect sizes of these medications are found to be in the medium range.
- They may contribute to suicidal ideation at the start of a new or increased treatment, particularly in young people, thus requiring careful monitoring of mood and behavior.Â
- Non-stimulant medications for ADHD don’t work for everyone, since their effects tend to be more subtle in nature.
Comparing effectiveness and side effects with stimulants
Comparatively, the widely proven effectiveness of stimulant ADHD medications is more significant than that of non-stimulant medications. As such, stimulants are considered first-line treatment. [1][6]
Other positive effects of stimulant medications include reductions in: [1]
- Suicidal ideation
- Unintentional injuries
- Criminality
- Substance misuse
- Functional impairments
Of particular note is the impact of these medications on suicidal ideation. While stimulant medications reduce suicidal ideation, atomoxetine and viloxazine are found to cause an increased risk, particularly in the first few months of treatment and among children and adolescents. [1][4]
Other notable comparison points include: [1][2][3][6]
- Long-term efficacy: Studies have shown that, despite large effect sizes, stimulant medications may not continue to be effective in long-term treatments of over ten years, whereas non-stimulant medications maintain their effectiveness long-term. Stimulants should be regularly reviewed and discontinued or paused at intervals to redetermine their effectiveness.
- Impact on appetite: Stimulants can significantly impact appetite, which may cause growth impairments in children and adolescents. This risk is much lower with non-stimulant medications.
- Side effects: The side effect profile of stimulants tends to be more significant than that of non-stimulants, although certain adverse effects are more pronounced in non-stimulant medications. Suicidal ideation is of concern with atomoxetine and viloxazine use. Clonidine and guanfacine typically cause fatigue and sedation, which can impact functioning. However, stimulants are more likely to produce long-term adverse effects.
- Onset of effects: Stimulants cause a rapid onset of effects, while non-stimulants can take several weeks or months.Â
- Addiction potential: Non-stimulants have a low potential for abuse and addiction, while stimulants have a high risk.
When are non-stimulant medications recommended?
Non-stimulant medications are a second-line treatment choice. However, they can be the preferred option if: [1][2][5]
- The individual has a history of substance use issues or is currently abusing drugs or alcohol in ways that could increase the risk for dependence or negative drug interactions.
- If the individual has co-occurring conditions, such as tic disorder or Tourette’s syndrome, or has experienced cardiovascular impairments. Atomoxetine or viloxazine may be preferred in individuals with co-occurring ADHD and anxiety.
- Stimulant medications have shown little or no effect, or have caused intolerable side effects, including insomnia, mood swings, irritability, or significant weight loss.
Addressing addiction and recovery concerns
Non-stimulant medications are not controlled substances, as they are not deemed to have potential for abuse and addiction. Stimulant medications, methylphenidate and amphetamines, are Schedule II controlled substances. This is due to their high risk of abuse and addiction.Â
Comorbid conditions are common among people with ADHD, including substance use disorders (SUDs). People in recovery requiring pharmacological treatment for ADHD might benefit from non-stimulant medications to reduce their risk of relapse. [1][5]
If stimulant medications are deemed necessary, it can be helpful to utilize delayed-release formulations. This form of medication does not produce the same rewarding or euphoric effect as immediate-release formulations and may, therefore, have less abuse potential. [5]
Managing the co-occurring symptoms of ADHD and SUD can be complex and challenging, and should be evaluated on an individual basis, considering each person's needs and the severity of their symptoms. Additionally, ongoing substance use can reduce the effectiveness of ADHD medications, affect medication adherence, and influence medication tolerance. [5]
Patient considerations and safety tips
People utilizing stimulant and/or non-stimulant ADHD medications should:
- Take their medication exactly as prescribed, never taking more or less than advised.
- Report concerning side effects to their prescribing doctor, as adjustments may be required.
- Inform the prescribing doctor of any recent or current physical or mental health concerns, as these may impact the effectiveness or appropriateness of certain medications.
- Ensure that they attend regular medication reviews with their prescribing physician to determine the ongoing safety and effectiveness of their treatment.
- Consider utilizing psychological and behavioral therapies alongside pharmacological therapies to manage ADHD symptoms.
- Report past or present substance use issues to the prescribing doctor, so that both ADHD and SUD symptoms can be managed.
- Ensure they are aware of the potential adverse effects of their medication and how they should be managed.
- Never adjust medications or doses without guidance from a physician.
- Talk to their prescriber about the possibility of taking ‘drug holidays’, breaks, or days off from stimulant medications to lower the risk of tolerance and dependence.
