Safety of long term stimulants in ADHD

While there has been concern about the safety of stimulant medication both for treatment of ADHD and for other indications, current evidence suggests that these concerns may not only be overstated, they may be totally wrong, and , in many situations, long term cause of stimulants may be so beneficial that to deny access to the may be irresponsible.

This document is meant for both patients and clinicians.

For patients the bits you need to read are in bold:

Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[12][13] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.

Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). “Toxicity of amphetamines: an update”. Arch. Toxicol. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5 (https://dx.doi.org /10.1007%2Fs00204-012-0815-5). PMID 22392347 (https://www.ncbi.nlm.nih.gov/pubmed/22392347).

Berman S, O’Neill J, Fears S, Bartzokis G, London ED (October 2008). “Abuse of amphetamines and structural abnormalities in the brain” (https://www.ncbi.nlm.nih.gov/pmc/articles /PMC2769923). Ann. N. Y. Acad. Sci. 1141: 195–220. doi:10.1196/annals.1441.031 (https://dx.doi.org/10.1196%2Fannals.1441.031). PMC 2769923 (https://www.ncbi.nlm.nih.gov /pmc/articles/PMC2769923). PMID 18991959 (https://www.ncbi.nlm.nih.gov/pubmed/18991959).

Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). “Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects”. JAMA Psychiatry 70 (2): 185–198. doi:10.1001/jamapsychiatry.2013.277 (https://dx.doi.org /10.1001%2Fjamapsychiatry.2013.277).

Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). “Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies” (https://www.ncbi.nlm.nih.gov/pmc/articles /PMC3801446). J. Clin. Psychiatry 74 (9): 902–917. doi:10.4088/JCP.12r08287 (https://dx.doi.org /10.4088%2FJCP.12r08287). PMC 3801446 (https://www.ncbi.nlm.nih.gov/pmc/articles /PMC3801446). PMID 24107764 (https://www.ncbi.nlm.nih.gov/pubmed/24107764).

Frodl T, Skokauskas N (February 2012). “Meta- analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects.”. Acta psychiatrica Scand. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x (https://dx.doi.org /10.1111%2Fj.1600-0447.2011.01786.x). PMID 22118249 (https://www.ncbi.nlm.nih.gov /pubmed/22118249).

When used at low (therapeutic) doses, amphetamine produces unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults.

Spencer RC, Devilbiss DM, Berridge CW (June 2015). “The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex”. Biol. Psychiatry 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013 (https://dx.doi.org /10.1016%2Fj.biopsych.2014.09.013).

PMID 25499957 (https://www.ncbi.nlm.nih.gov /pubmed/25499957).

Ilieva IP, Hook CJ, Farah MJ (January 2015). “Prescription Stimulants’ Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis”. J. Cogn. Neurosci.:

While Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.[80][81][41]

Westfall DP, Westfall TC (2010). “Miscellaneous Sympathomimetic Agonists” (http://www.accessmedicine.com /content.aspx?aID=16661601). In Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill. ISBN 9780071624428.

Kollins SH (May 2008). “A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders”. Curr. Med. Res. Opin. 24 (5): 1345–1357. doi:10.1185/030079908X280707 (https://dx.doi.org /10.1185%2F030079908X280707). PMID 18384709 (https://www.ncbi.nlm.nih.gov/pubmed/18384709). “When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.”

Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989.

While there had been concern about long term use of stimulants being a risk for Parkinson’s disease ( through excitotoxic nerve damage), it would now appear that the reverse is true:

http://www.ncbi.nlm.nih.gov/pubmed/23160937 CNS Drugs. 2013 Jan;27(1):1-14. doi: 10.1007/s40263-012-0017-y.Methylphenidate: a treatment for Parkinson’s Disease?Devos D1, Moreau C, Delval A, Dujardin K, Defebvre L, Bordet R.

Relationships and performance:

Children with ADHD who use stimulant medications generally have better relationships with peers and family members,[22][33] generally perform better in school, are less distractible and impulsive, and have longer attention spans.[22][33]

Millichap JG (2010). “Chapter 3: Medications for ADHD”. In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician’s Guide to ADHD (2nd ed.). New York: Springer. pp. 111–113. ISBN 9781441913968.

  1. Huang YS, Tsai MH (July 2011). “Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge”. CNS Drugs 25 (7): 539–554. doi:10.2165/11589380-000000000-00000 (https://dx.doi.org

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain’s reward system.[80] At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to induce persistent ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens;[77][80][87] consequently, when used medically and as directed, methylphenidate use has no capacity to cause an addiction.[77][80][87]

77. Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN 9780071481274. “Cocaine, [amphetamine], and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects ; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.”

Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009). “Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365). Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–20. doi:10.1073/pnas.0813179106 (https://dx.doi.org/10.1073%2Fpnas.0813179106). PMC 2650365 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365). PMID 19202072 (https://www.ncbi.nlm.nih.gov/pubmed/19202072). “Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).”

Nestler EJ (December 2013). “Cellular basis of memory for addiction” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). PMID 24459410 (https://www.ncbi.nlm.nih.gov/pubmed/24459410). “DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement … Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4″

2013 Jan;27(1):1-14. doi: 10.1007/s40263-012-0017-y.

Legal status:methylphenidate:

Legal status

Clearly given the benefits above and the lack of addictive potential at therapeutic doses this restricted use of psychostulants is not based on any sound evidence at all– is just nutty. These medications should be able to be prescribed by and any doctor competent to handle them. A permit should be required to prevent doctor shopping and to ensure that the supervising doctor is overseeing the whole tratment. ( IE ensuring that all is being done to minimise the symptoms and consequences of ADHD in all pateints being treated).

Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[131]

In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse. In the United Kingdom, methylphenidate is a controlled ‘Class B’ substance. Possession without prescription carries with a sentence up to 5 years and/or an unlimited fine, and supplying it is 14 years and/or an unlimited fine.[132] In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline, among others), and is illegal to possess without a prescription, pursuant to Part G (section G.01.002) of the Food and Drug Regulations under the Food and Drugs Act. In New Zealand, methylphenidate is a ‘class B2 controlled substance’. Unlawful possession is punishable by six-month prison sentence and distribution of it is punishable by a 14-year sentence.

In Australia, methylphenidate is a ‘Schedule 8’ controlled substance. Such drugs must be kept in a lockable safe before being handed out and possession without prescription carries hefty fines and even imprisonment. In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.[133]

In France, methylphenidate is covered by the “narcotics” schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.[134]

Finally, ADHD is a highly prevalent and highly impairing condition.

Conservative estimates in Australia are about the 4% mark in adults.

A recent paper has shown the incidence in middle aged adults is about 6%

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031500A Population-Based Study of Attention Deficit/Hyperactivity Disorder Symptoms and Associated Impairment in Middle-Aged Adults

A review of the data presented from Prof Alistair Vance of the Royal Children’s Hospital yielded the following figures:

Out of every 100 children with ADHD, about 66 will still be diagnosable as ADHD , about 5 will have full resolution of their ADHD and the remaining 29 or so will have symptoms but fall below diagnostic thresholds.

My experience in ADHD suggests that many of that group will fall back into diagnosable ADHD if hit by a crisis.

My overall observations as a GP (about 20 years in the same practice watching many of my middle aged and elderly patients slip into dementia), suggest to me that the ADHD pattern may be a precursor to neurodegenerative disorders – such as Alzheimer’s and Caparisons. In this setting symptoms like restless legs may be a prodrome of conditions such as Parkinson’s disease.

Given my current awareness of the field of evidence based neuroscience (formerly called functional neurology) and a field that specialises in neurological rehabilitation, there is every reason to believe that this would be a predicted outcome of lifelong ADHD. Given my personal experience of rehabilitation provided by practitioners of functional neurology it is clear that this downhill slide can not only be halted, it can be reversed.

The information on which this summary was based can be found on line by looking at the Wikipedia articles on Dextroamphetamine and Methylphenidate as downloaded Monday 24 May 2015. I do not regard Wikipedia as a routinely reliable source, however this material is properly referenced, so it is worth considering.

 

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6 Responses to Safety of long term stimulants in ADHD

  1. michelen7 says:

    Oh dear, I thought the comments were being moderated first. I don’t know how to delete it on my phone – or even if possible 😦

  2. Dee says:

    Hi. i’m interested in any research or links on the relationship between Adult ADD and Alzheimers.

    Also, i’m interested in anything you might have to say about whether you believe that long-term stimulant use can reverse the onset of alzheimers in adult patients or whether you think there is simply no relationship (your overall message seems to indicate the latter, but you hint at the former).

    Thanks. For context, i’m a high performing individual (PhD, work in an unstructured university environment) who has conquered ADD symptoms in personal and family life but finds that many symptoms (lack of focus and – increasingly – “mind fog”) are hindering work performance and work satisfaction. i have been taking stimulants since i was a child – for about 17 years.

    • MindBody says:

      The material I posted in that post was largely referencing studies of specific medications, and it was in answer to various concerns I have heard raised about the safety of long term medication. Those studies are broadly supportive of the safety of stimulants in individuals who are not getting any side effects.

      I have heard concerns raised that there may be a higher incidence of Alzheimer’s in ADHD, however I don’t think that there has been time to do long term prospective studies based off our current working definition of ADHD. I have not seen any convincing research.

      What is significant is that there appears to be a higher rate of Alzheimers in individuals who are depressed or socially isolated. This would make sense- both conditions are — and it is perfectly clear that those are common outcomes in ill controlled ADHD.
      So from that point of view, controlling the ADHD and focussing on achieving good life outcomes are logical ways of minimising Alzheier’s.

      RE the brain fog- the first thing is to review the situation with your own doctor.

      Its not possible for me to give any specific advice about the “brain fog”- which is a non specific symptom anyhow- but I think it is reasonable to suggest a few general comments looking at the environment in which it is occurring. You mention having a PhD and working in a University, and that may very well mean a lot of sitting in front of a computer. Our sedentary lifestyle causes all sorts of problems which can compound issues like this.

      It would be worth your looking at the book “Spark” by Dr John Ratey, a psychiatrist who has ADHD and specialises in the link between exercise and mental health. He also advocates standing desks, “treadmill desks” and exercise. In general high intensity exercise will definitely lift alertness, and complex exercise that involves a challenge to your balance system (martial arts, Tai Chi etc) also enhance alertness.
      ( interval training can be done in as little as 30 minutes 3 times a week) is helpful for alertness.

      Other items which may be relevant- as this is occurring in the workplace, would be issues like ambient noise, open work spaces, flicker from fluorescent lights, an overly warm office, compulsion to stay sitting at your desk longer than you can tolerate. Lots of workplaces are not set up at all well for people of differing needs.

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