Modafinil (brand name Provigil) is one of the primary drugs used in the management of narcolepsy in the UK. Narcolepsy is a rare condition that affects sleep control and results in daytime sleepiness, often sudden and uncontrollable. The public’s interest in modafinil comes from the drug’s association with a class of medicines called ‘smart drugs‘, also called nootropics and cognitive enhancers. Many individuals search for cognitive enhancement drugs, and modafinil tends to be one of the main drugs which always gets mentioned. Today I will review modafinil alternatives, drugs that promote awakeness and/or improve cognitive functions. I will not review over the counter modafinil alternatives or modafinil’s natural alternatives simply because none of the existing supplements or over the counter products have the same effect as modafinil. If they did, they would not be available over the counter (at least in the UK). Please read the related post: How to get modafinil? to learn various aspects of modafinil’s supply in the UK.
Summary of the post:
- What is modafinil?
- The legal classification of modafinil (UK)
- Is modafinil a smart drug?
- Is modafinil addictive?
- Modafinil alternatives
- Modafinil alternatives: conclusion
What is modafinil?
The legal classification of modafinil (UK)
In the UK, modafinil is classified as prescription-only medication (POM). A doctor or another qualified prescriber can only prescribe POMs.
In the UK, modafinil has narrow licensed use. It is used to manage excessive sleepiness in adults, associated with narcolepsy with or without cataplexy (the sudden muscle weakness).
The second licensed use of modafinil covers individuals who experience excessive sleepiness, defined as difficulty keeping wakefulness and an increased likelihood of falling asleep in inappropriate situations (eMC, 2020).
Well defined licensed use for modafinil means that an NHS doctor would only prescribe it to treat narcolepsy after an appropriate referral is made to a specialist.
Is modafinil a smart drug?
The mechanism of action of modafinil is not fully understood. Modafinil increases wakefulness and can potentially be a cognitive enhancing drug (‘smart drug’). When studied in patients with excessive sleepiness, modafinil produced a significant effect on wakefulness (Hirshkowitz & Black, 2007).
The available evidence shows a small capability for modafinil to be a cognitive enhancer in people who do not have a sleeping disorder (Kredlow et al., 2019). Based on current evidence, modafinil may produce ‘modest’ benefits in terms of cognitive enhancement.
Individuals who perform poorest (those with lower IQ) may achieve more significant benefits. Improvement in this group of people may be more significant. Taking ‘smart drugs’ in people with a modest level of cognitive function may lead to overconfidence (Nicholson, 2015).
A systemic review on the modafinil use by youths aged 12-25 years old suggests that modafinil improve reaction time, problem-solving and logical reasoning (Bagot & Kaminer, 2014).
Wake promoting properties of modafinil are well known. Although the mechanism underlying the wake-promoting action is fully understood, this effect is similar to other drugs, for example, amphetamines and methylphenidate, but with a distinct pharmacological profile (FDA, 2010).
When studied in animals, modafinil produced psychoactive and euphoric effects, changes in mood, thinking and awareness, all of which are associated with reactions produced by stimulants in people (ibid).
Is modafinil addictive?
Studies on modafinil in people indicate that modafinil is less likely to be abused than other ‘stimulating’ drugs, for example, methylphenidate or dexamphetamine (McClellan KJ & Spencer, 1998). Additionally, when comparing with alternative medications such as amphetamines, modafinil is considered safe with a small number (‘minimal’) of side effects (Easow et al., 2013).
How to get modafinil?
Details on the supply of modafinil in the UK was discussed in one of my previous posts. I discussed the supply of modafinil on NHS, trough private routes and current restrictions on the supply of modafinil.
Modafinil alternatives drugs
Various drugs can be used in the management o narcolepsy, most of which will be used outside their license.
1. Pitolisant – modafinil alternative drug to treat narcolepsy
Pitolisant (brand name: Wakix) is the latest drug licensed for narcolepsy in the UK. Pitolisant is a prescription-only medication. Treatment with pitolisant is usually initiated by a doctor who specialises in the treatment of sleeping disorders.
Pitolisant is extremely rarely prescribed in NHS. A quick search on OpenPrescribing.net shows that Pitolisant was prescribed less than 300 times in the last 12 months (OpenPrescribing.net, 2021). The main reason for this is the drug cost, which is £310 for a 30-day treatment with a lower dose of pitolisant and £620 for a treatment with a higher pitolisant dose (prices as of February 2017, excluding VAT).
Pitolisant vs modafinil: what’s the difference?
Pitolisant is described as a ‘first in class’ drug. Pitolisan’s mechanism of action different from modafinil. Pitolisant acts primarily on histamine receptors in the brain, with a possible effect on noradrenaline (same as modafinil) and dopamine, resulting in increased wakefulness. Histamine neurons in the brain also control various functions, including memory and attention (Romigi et al., 2018).
When studied in animals, pitolisant was found not to cause dependence or induce ‘abuse’ behaviour. Pitolisant enhanced memory performance in animals (ibid).
Armodafinil is closely related to modafinil. Modafinil comes as a 50:50 mixture of two enantiomers, which means a combination of 50% to 50% of two molecules that are mirror images of each other. To put it in a simple context, you could represent enantiomers with your left and right hand; both look the same and are mirror images of each other.
In pharmaceuticals, it is possible to market enantiomers as separate drugs. Common prescription drugs which exist as mirror images of each other are for example esomeprazole and omeprazole (see Esomeprazole vs Omeprazole post).
Armodafinil is not available in the UK, but it is used to treat narcolepsy in many countries.
Armodafinil vs modafinil: which drug is better?
When taken, armodafinil results in a higher amount of drug in the body when compared to modafinil. Thus, it is suggested armodafinil may have a better wakefulness action (Darwish et al., 2009).
Atomoxetine legal classification
Atomoxetine (brand name: Strattera) is the first drug on the list of modafinil alternatives, which is licensed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adults. Atomoxetine is a prescription-only medication, which is usually initiated by a specialist in the treatment of ADHD.
Atomoxetine availability in the UK
In the UK, atomoxetine is available as a generic drug (atomoxetine hydrochloride) and branded as Strattera.
Is atomoxetine a cognitive enhancer?
Atomoxetine is a non-stimulant drug, which primarily affects one neurotransmitter in the brain called norepinephrine (noradrenaline). Atomoxetine stops the action of the norepinephrine transporter in the brain and therefore increases the concentration (amount) of norepinephrine in the brain. Noradrenaline plays a role in the regulation of cognitive function, attention and stress reactions (Hussain et al., 2020).
Unlike some of the other drugs discussed in the following paragraphs, atomoxetine does not affect dopamine actions in the brain’s relevant parts associated with pleasure. Therefore, atomoxetine is classified as a non-addictive medication with a low tendency for abuse.
There are a large number of research papers around atomoxetine. When used in the treatment of ADHD, atomoxetine improved significantly visual memory and attention (Shang & Gau, 2012). Furthermore, atomoxetine enhanced many parts of ‘ executive function’ such as cognitive flexibility, short term/working memory, attention, susceptibility to distraction in young adults, with other evidence suggesting that atomoxetine may boost other aspects of cognition beyond attention (Callahan, 2019).
4. Modafinil alternatives: Methylphenidate
Methylphenidate is a prescription-only drug available in the UK for the treatment of ADHD. Methylphenidate is classified as a controlled drug (Schedule 2), which brings additional legal requirements for writing prescriptions and various medicine supply restrictions. Methylphenidate would only be prescribed for ADHD under the supervision of a doctor who specialises in behavioural disorders.
Methylphenidate: legal aspects
Despite its classification as a prescription-only medication in the UK, which is also a controlled drug, the purchase of methylphenidate is possible from overseas pharmacies.
Unlike with modafinil, possession of class B controlled drug (not prescribed by a doctor) is an offence that carries imprisonment and fine penalties.
Methylphenidate: availability of different brands and forms
Methylphenidate is available in many forms in the UK. Methylphenidate is broadly available in immediate-release forms, including generic methylphenidate tablets and controlled release (prolong release / modified release) tablets and capsules. Common brands of methylphenidate prescribed in the UK:
- Concerta XL prolonged-release tablets
- Equasym modified-release capsules
- Medikinet tablets (immediate-release)
- Medikinet XL prolonged-release capsules
- Ritalin immediate-release tablets
- Ritalin XL modified-release capsules
- Xaggitin prolonged-release tablets
Is methylphenidate a ‘smart drug’?
Methylphenidate became a popular choice as a cognitive enhancer by healthy individuals seeking to improve their concentration, stay awake for longer to study, and increase motivation functioning (Batistela et al., 2016). It is known, for example, that medical students in the UK take cognitive enhancement drugs, including methylphenidate (Lane et al., 2015). There is no consistent evidence to show that methylphenidate improves cognitive enhancement, although some evidence on memory has been demonstrated in laboratory tests (Nicholson & Wilson, 2017).
Similarly to modafinil, improved performance is mainly noted by individuals whose intellectual processes are ‘below optimal level’ (Batistela et al., 2016).
Methylphenidate vs modafinil
Methylphenidate has a distinct mechanism of action to modafinil. Methylphenidate is classified as a stimulant, and primarily it affects the release and increases dopamine in the brain. The end effect of increased dopamine in the brain is similar to one produced by cocaine and amphetamines (not to the same extent), yet the mechanism of action is different (Morton & Stockton, 2000).
Methylphenidate is classified as a stimulant drug, which makes it a reasonable option in treating narcolepsy. Methylphenidate is not licensed for the treatment of narcolepsy; therefore, other drugs like modafinil would be considered in the first instance.
Two amfetamines used in the UK are dexamfetamine and lisdexamfetamine. Dexamfetamine is licensed for the management of narcolepsy and ADHD, whereas lisdexamfetamine just for ADHD. Both drugs are prescription-only medicines, classified as controlled drugs Schedule 2 (class B). Both drugs need to be initiated by a specialist, i.e. a doctor is in secondary care rather than GP.
Are amfetamines cognitive enhancers?
Amfetamines have a positive impact on cognitive functioning, as demonstrated by some studies. For example, when investigated in school-aged children, amfetamines improved attention and performance and decreased the number of errors (Rapoport et al., 1978). Additionally, amfetamines may enhance the attainment of new knowledge, how is it stored in the brain and the ability to retrieve information (Bagot & Kaminer, 2014).
The positive effects of amfetamines on cognitive functioning are overshadowed by negative aspects of the treatment, including psycho-stimulation, which may be characterised by individuals being ‘high’, potential ‘high’ addictive properties of amfetamines, which all together increases the chances of the abuse.
6. Sodium oxybate as modafinil alternative
Sodium oxybate is a prescription-only medication which is licensed for narcolepsy in the UK but rarely prescribed in practice. Sodium oxybate is classified as a controlled drug Schedule 2 (class B). Sodium oxybate comes only in liquid form as a generic medication or branded as Xyrem oral solution. One of the main drivers for the low popularity of this drug in the treatment of narcolepsy in the UK is its price, which stands at £360 per 180ml of oral solution.
Sodium oxybate (known as GHB) has aa history of widespread use as an illegal drug. The exact mechanism of action of sodium oxybate is unknown, but it is believed that sodium oxybate improves sleep at night, which in turn promotes improved alertness the following day (Kothare & Kaleyias, 2010).
Does sodium oxybate affect cognitive performance?
The use of sodium oxybate by sleep-deprived, healthy voluntaries demonstrated that this drug improves daytime alertness and attention (Walsh et al., 2010).
Modafinil alternatives: conclusion
I revied the main prescription-only drugs, which can be classified as modafinil alternatives. All medicines have some evidence of cognitive enhancement and, most importantly, evidence of being effective in the treatment of narcolepsy due to significant effect on wakefulness.
Two fundamental aspects of drug use that I did not cover in this post are potential side effects and interactions with other drugs. Individuals who consider using drugs to improve cognition need to recognise the risk of treatment (side effects) and possible interaction with other medicines they may take.
The legal route of modafinil alternatives/cognitive enhancers in the UK is through a consultation with a doctor (and a specialist), which almost eliminates unlicensed use of the above medicines as cognitive enhancers in healthy individuals.
Purchasing medicines from the Internet carries the additional risk of medication not being genuine with questionable quality.
Bagot KS, Kaminer Y (2014). Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction. 2014;109(4):547-557. doi:10.1111/add.12460 Available at: https://doi.org/10.1111/add.12460 Accessed on 06/03/2021
Batistela S, Bueno OFA, Vaz LJ, Galduróz JCF (2016). Methylphenidate as a cognitive enhancer in healthy young people. Dement Neuropsychol. 2016;10(2):134-142. doi:10.1590/S1980-5764-2016DN1002009 Available at: https://dx.doi.org/10.1590%2FS1980-5764-2016DN1002009 Accessed on 06/03/2021
Callahan PM, Plagenhoef MR, Blake DT, Terry AV Jr. Atomoxetine improves memory and other components of executive function in young-adult rats and aged rhesus monkeys. Neuropharmacology. 2019;155:65-75. doi:10.1016/j.neuropharm.2019.05.016 Available at: https://dx.doi.org/10.1016%2Fj.neuropharm.2019.05.016 Accessed on 03/03/2021
Darwish M, Kirby M, Hellriegel ET, Robertson P Jr (2009). Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomised, single-dose, pharmacokinetic studies. Clin Drug Investig. 2009;29(9):613-23. doi: 10.2165/11315280-000000000-00000. PMID: 19663523. Available at: https://doi.org/10.2165/11315280-000000000-00000 Accessed on 01/03/2021
Easow Mathew M, Biswas T, Fahad S, Patnaik M (2013). Modafinil for excessive daytime sleepiness. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD010843. DOI: 10.1002/14651858.CD010843. Accessed 01 March 2021. Available at: https://doi.org/10.1002/14651858.CD010843 Accessed on 01/03/2021
eMC (2020). Summary of Product Characteristics (SmPC): Modafinil 100mg tablets. Available at: https://www.medicines.org.uk/emc/product/4319 Accessed on 01/03/2021
FDA (2010). PROVIGIL® (modafinil) Tablets [C-IV]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020717s030s034s036lbl.pdf Accessed on 04/03/2021
Hirshkowitz M, Black J (2007). Effect of adjunctive modafinil on wakefulness and quality of life in patients with excessive sleepiness-associated obstructive sleep apnoea/hypopnoea syndrome: a 12-month, open-label extension study. CNS Drugs. 2007;21(5):407-16. doi: 10.2165/00023210-200721050-00004. PMID: 17447828. Available at: https://doi.org/10.2165/00023210-200721050-00004 Accessed on 08/03/2021
Hussain LS, Reddy V, Maani CV. Physiology, Noradrenergic Synapse. [Updated 2020 May 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540977/ Accessed on 03/03/2021
Kredlow MA, Keshishian A, Oppenheimer S, Otto MW (2019). The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis. J Clin Psychopharmacol. 2019 Sep/Oct;39(5):455-461. doi: 10.1097/JCP.0000000000001085. PMID: 31433334. Available at: https://doi.org/10.1097/jcp.0000000000001085 Accessed on 02/03/2021
Kothare Sanjeev V., Joseph Kaleyias (2010). Pharmacotherapy of Narcolepsy: Focus on Sodium Oxybate. Available at: https://doi.org/10.4137%2FCMT.S1087 Accessed on 07/03/2021
Lane J, Finlay F, Marcer HG505(P) Medical students buying methylphenidate online. Archives of Disease in Childhood 2015;100:A217 Available at: http://dx.doi.org/10.1136/archdischild-2015-308599.458 Accessed on 03/03/2021
Morton WA, Stockton GG (2000). Methylphenidate Abuse and Psychiatric Side Effects. Prim Care Companion J Clin Psychiatry. 2000;2(5):159-164. doi:10.4088/pcc.v02n0502 Available at: https://dx.doi.org/10.4088%2Fpcc.v02n0502 Accessed on 05/03/2021
Nicholson (2015). Rapid response: Modafinil does enhance cognition, review finds. Available at: https://doi.org/10.1136/bmj.h4573 Accessed on 05/03/2021
Nicholson Paul J, Nigel Wilson (2017). Smart drugs: implications for general practice. Available at: https://doi.org/10.3399/bjgp17X689437 Accessed on 05/03/2021
McClellan KJ, Spencer CM (1998). Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy. CNS Drugs. 1998 Apr;9(4):311-24. doi: 10.2165/00023210-199809040-00006. PMID: 27521015. Available at: https://doi.org/10.2165/00023210-199809040-00006 Accessed on 07/03/2021
Repantis R, Schlattmann P, Laisney O, Heuser I. Modafinil and methylphenidate in healthy individuals A systematic review. Pharmacol Res. 2010;62:187–206. Available at: https://doi.org/10.1016/j.phrs.2010.04.002 Accessed on 07/03/2021
Rapoport JL, Buchsbaum MS, Zahn TP, Weingartner H, Ludlow C, Mikkelsen EJ (1978). Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys. Science. 1978;199:560–3. Available at: https://doi.org/10.1126/science.341313 Accessed on 06/03/2021
Romigi A, Vitrani G, Lo Giudice T, Centonze D, Franco V (2018). Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther. 2018;12:2665-2675. Published 2018 Aug 30. doi:10.2147/DDDT.S101145 Available at: https://dx.doi.org/10.2147%2FDDDT.S101145 Accessed on 08/03/2021
Shang CY, Gau SS. Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2012 Oct;22(5):353-63. doi: 10.1089/cap.2011.0149. PMID: 23083022. Available at: https://doi.org/10.1089/cap.2011.0149 Accessed on 03/03/2021
Walsh JK, Hall-Porter JM, Griffin KS, et al (2010). Enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss. Sleep. 2010;33(9):1217-1225. doi:10.1093/sleep/33.9.1217 Available at: https://dx.doi.org/10.1093%2Fsleep%2F33.9.1217 Accessed on 07/02/2021