Nicotine as a medication for ADHD

Nicotine has a stimulating effect and is therefore a stimulant like methylphenidate or amphetamine medication. Nicotine reduces ADHD symptoms in a similar way to medicinal stimulants.¹ However, unlike MPH and AMP, it is not legally considered a narcotic.

A person with ADHD-HI told us that she had stopped smoking 4 years previously and had since been able to relieve her inner tension resulting from ADHD with nicotine lozenges. A 1 mg tablet worked for around 2 hours. Several other people with ADHD reported comparable effects. Furthermore, nicotine often has a calming effect on people with ADHD.²

A small study described significant positive effects of nicotine patches on ADHD symptoms in smokers (at 21 mg for 4.5 hours/day) and non-smokers (at 7 mg for 4.5 hours/day).
The activity of the people with ADHD had increased significantly. Reaction times had decreased, inattention and reaction variability (the temporal variance of reactions) had decreased and the perception of time, which is often impaired in ADHD, had improved significantly.³ Another very small study confirms the results.⁴ Nicotine patches also improved attention, reaction time variance and reduced omission errors without increasing confirmation errors in non-smokers without attention problems.⁵
In smokers, a 21 mg nicotine patch significantly worsened word memory; in non-smokers, a 7 mg nicotine patch tended to improve word memory compared to placebo.⁶ In smokers, only low-dose nicotine patches improved cognitive performance.⁷
Very surprisingly, there do not appear to be any further specialist studies on this topic.
One of the reasons for this is probably that research into active ingredients in the public domain is expensive and cannot be refinanced through corresponding exclusive rights (patents) to the results, meaning that commercial research is not profitable. This is not the fault of “the pharmaceutical industry”, but a consequence of unfavorable political conditions. In addition, nicotine has a very poor image, which impairs its marketability among patients.

Nicotine has a dopaminergic and acetylcholinergic effect and increases the cortisol response to acute stress.

Nicotine:⁸

• improves attention
• does not improve decision-making
• reduces the willingness to make a cognitive effort
• increases impulsivity

• 1. Nicotine increases dopamine release
• 2. Nicotine reduces dopamine transporters
• 3. Nicotine / smoking reduces dopamine breakdown
• 4. Nicotine alters cortisol response
• 5. Nicotine increases basal cortisol levels
• 6. Smoking masks ADHD symptoms
• 7. Nicotine increases histamine
• 8. Smoking addresses MAO
• 9. Nicotine has an age-dependent effect
• 10. Nicotine medication for ADHD
  • 10.1. Nicotine for ADHD
  • 10.2. Nicotine agonists for ADHD
  • 10.3. Nicotine antagonists
  • 10.4. Nicotine overdose can cause ADHD symptoms

1. Nicotine increases dopamine release¶

Nicotine stimulates ATV neurons, causing their projections in the nucleus accumbens (the main area of the brain’s reward/reinforcement system) to release dopamine.⁹ Nicotine thus increases the dopamine level (in the case of tobacco, intensely, but only for a short time, after which it drops even lower, which accounts for the addictive potential) and has an effect on the acetylcholine balance.

Nicotine

• increased the firing of neurons of the substantia nigra pars compacta¹⁰
• increased DA turnover and homovanillic acid concentration in the striatum¹⁰
• increases the firing rate and phasic dopamine release of dopaminergic neurons in the VTA¹¹¹² and, to a much lesser extent, in the substantia nigra pars compacta¹³
• increased the firing rate of DA cells in a dose-dependent manner¹⁴
  • of the substantia nigra pars compacta (A9) by up to 25 %
  • of the VTA (A10) three times as strong
  • whereby the effect is presumably not direct via DA receptors, but indirect via cholinergic receptors
• increases the release of dopamine in the dopaminergic projection areas, e.g. in the nucleus accumbens¹¹
• regulates dopamine transmission in the nucleus accumbens¹⁵¹⁶
• modulates the release of dopamine in the mesolimbic reward system:¹⁷
  • Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) by
    • the nAChRs trigger a depolarization of the nerve endings.
    • ca2+ entry via alpha7 nAChRs causes a significant increase in the size of the readily releasable pool of synaptic vesicles. Alpha7 receptors desensitize rapidly.
    • Nicotine appears to bind to nicotinic acetylcholine receptor subtypes consisting of alpha4beta2 (but not alpha7) subunits¹⁸
• increases the frequency of tonic dopaminergic signals from 4 to 7 Hz and the number of pulses within phasic burst signals from 5 to 10 pulses at 20 Hz ¹⁹
• slightly reduces the phasic release of dopamine in the dorsal striatum¹⁹
• strongly increases the phasic release of dopamine in the nucleus accumbens¹⁹
• The frequency dependence of dopamine release differs between¹⁹
  • dorsolateral striatum
  • NAc shell
    • therefore, the NAc shell benefits much more from nicotine-induced phasic burst firing of dopamine neurons
• Nicotine reduces tonic dopamine release in¹⁹
  • dorsolateral striatum
  • NAc shell
• the increased ratio between phasic bursts and tonic firing caused by nicotine led to an increase in basal dopamine concentrations, especially in the NAc shell¹⁹

Nicotine and the endocannabinoid system:

• Nicotine does not appear to bind to cannabinoid CB1R or CB2R receptors¹⁸
• Nicotine (like cocaine) triggers 2-AG synthesis in the VTA.²⁰ This suppresses the GABAergic input, which disinhibits the dopamine neurons.²¹

Dopamine release and function of dopaminergic neurons in the VTA is regulated by glutamatergic projections from the PFC to the VTA, among other factors. Neuronal adaptations after nicotine exposure in these brain regions contribute to nicotine addiction.²²

Dihydro-β-erythroidine (DHβE) is a plant-derived competitive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2 units (β2* NAChRs; β2 nicotinic receptors). DHβE reduces the phasic release of dopamine in the dorsolateral striatum¹⁹
Consequences are that reward anticipation, which is controlled by phasic dopamine in the striatum and even more so in the nucleus accumbens, is also increased by β2-nicotinic receptor agonists - such as nicotine - .

Nicotine stimulates dopaminergic neurotransmission.²³²⁴ Nicotine dose-dependently increased the release of dopamine in the striatum of rats in vitro.²⁴ Furthermore, the specificity of dopamine release appears to depend on the specific subtypes of cholinergic active ingredients.²⁴²⁵

2. Nicotine reduces dopamine transporters¶

Smoking significantly reduces the number of dopamine transporters in the striatum. Like methylphenidate, nicotine causes a reduction in DAT density in the striatum.²⁶²⁷²⁸

3. Nicotine / smoking reduces dopamine breakdown¶

Tobacco smoke contains significant amounts of MAO inhibitors.³¹
MAO breaks down dopamine. MAO inhibitors therefore inhibit the breakdown of dopamine and thus increase dopamine.

4. Nicotine alters cortisol response¶

Nicotine (as a patch, as in smokers) increased the cortisol response to acute stress in one study.³² Another very small study found a reduced cortisol response to acute stress in smokers.³³

Assuming an increased cortisol response, nicotine could have a better effect in people with ADHD-HI (who have a flattened cortisol response to stress, which is why the HPA axis is not sufficiently downregulated after stress) than in ADHD-I (who have an exaggerated cortisol response to acute stress); assuming a decreased cortisol response, it would be the other way around.

5. Nicotine increases basal cortisol levels¶

Smokers were found to have a 5% higher basal cortisol level.³⁴ Since the basal cortisol level is lower in ADHD (slightly more in ADHD-HI than in ADHD-I) compared to people with ADHD, this could possibly explain why so many people with ADHD smoke.
In addition, smokers have increased levels of³⁴

• Dehydroepiandrosterone (DHEA) (18% higher)
• Dehydroepiandrosterone sulphate (DHEAS) (13 % higher)
• Androstenedione (33 % higher)
• Testosterone (9 % higher)
• Dihydrotestosterone (DHT) (14% higher)
• Sex hormone binding globulin (SHBG) (8 % higher)

Parkinson’s patients responded to high-dose nicotine patch treatment, with a significant reduction in the number of DAT, which is also increased in ADHD.³⁵ People with Parkinson’s disease suffer from a dopamine deficit, just like persons with ADHD, but this can be treated with other medications.

6. Smoking masks ADHD symptoms¶

Smoking as self-medication increases dopamine levels - albeit only in the short term. It also reduces stress symptoms and irritability. People with ADHD smoke about twice as often as people without ADHD.
Smoking can therefore make the diagnosis of ADHD more difficult.³⁶

A study of emotional dysregulation in smokers with ADHD found no differences between those who smoked as usual and those who abstained from smoking for 24 hours.³⁷

Intranasal nicotine application in nicotine-naïve adolescents with and without ADHD showed that people with ADHD responded to nicotine with greater dizziness and found the effect more pleasant than healthy control subjects. As a result, the persons with ADHD chose nicotine intake more frequently than the control subjects. This was independent of their emotional state.²
In our understanding, intranasal nicotine application corresponds to rapid absorption of the active substance via the olfactory nerves directly into the brain and thus a drug-like application, which must be categorically distinguished from slow absorption as a patch or lozenge (corresponding to a medicinal effect).

7. Nicotine increases histamine¶

Nicotine increases histamine, as do all known ADHD medications:

• Amphetamine drugs
• Methylphenidate
• Modafinil
• Caffeine

This is why people with histamine intolerance often have problems due to taking ADHD medication.
A person with ADHD with histamine intolerance reported that she could not tolerate AMP and sustained release MPH at all, but could tolerate immediate release MPH in small doses.

8. Smoking addresses MAO¶

Smoking is considered an inhibitor of monoamine oxidase. Monoamine oxidase breaks down dopamine, noradrenaline and serotonin. Smoking therefore indirectly increases dopamine. The effect is not directly linked to nicotine, but probably to other ingredients of tobacco smoke. Roll-your-own tobacco seems to contain more MAO inhibitors than ready-made cigarettes.³⁸ Flavorings and menthol in cigarettes seem to release dopamine.³⁹ In Germany, menthol is no longer permitted in tobacco products.

9. Nicotine has an age-dependent effect¶

Nicotine exposure in adolescence downregulates the AMPA-GluR2/3 subunits of the acetylcholine receptor in the striatum in a dose-dependent manner. This indicates reduced neuroplasticity in adulthood⁴⁰
Nicotine exposure in adulthood upregulates AMPA-GluR2/3 subunits in the striatum in a dose-dependent manner.

10. Nicotine medication for ADHD¶

10.1. Nicotine for ADHD¶

15 non-smoking young adults with ADHD-C received nicotine (7 mg patch for 45 minutes) or placebo.
3 subjects showed side effects. In the remaining 12 subjects, nicotine significantly improved the stop signal response time. SSRT was improved without any change in GO response time or accuracy. Nicotine tended to increase tolerance for delays and improved recognition memory.⁴¹
62 male non-smokers were divided into two groups according to their attention levels and received a 7 mg nicotine patch (6 hours) or placebo. Nicotine had the following effect⁴²

• in the group with less attention:
  • classic Stroop task
    • no significant differences between drugs or groups
  • Conners Continuous Performance Test
    • in the nicotine-treated group with low attention compared to placebo in this group
    • significantly fewer access errors
    • better stimulus detection
    • fewer perseverations
• in a group with high attention
  • Wisconsin Card Sorting Test (WCST)
    • Nicotine impaired the ability to learn effective strategies to complete the test with fewer attempts.

In a placebo-controlled study of transdermal nicotine (7 mg, 14 mg and 21 mg) on the cognitive performance of 48 male and 48 female smokers after nightly abstinence and 6 hours of patch application, an inverted U-shaped relationship was found between nicotinic stimulation and cognitive performance:⁴³

• the probability of attention problems (according to Conners CPT) was greater in men than in women
• in women, 7-mg and 14-mg nicotine resulted in better performance on the Conners CPT and faster reaction time on the emotional Stroop test than women on placebo or 21-mg nicotine.
• Men showed
  • a moderate overall advantage in the mental arithmetic task
  • the greatest improvement in recall of affective material among 14-mg group compared to 21-mg

One study found that nicotine skin patches reduced ADHD symptoms in children with ADHD, particularly learning problems and hyperactivity.⁴⁴ One study found nicotine to have a comparable Effect size to methylphenidate in adolescents with ADHD.⁴⁵ Two studies showed a relevant improvement in symptoms in adults with ADHD as a result of chronic nicotine administration.⁴⁶⁴⁷⁴⁸

10.2. Nicotine agonists for ADHD¶

Nicotine agonists are

• AZD3480
  • An initial study showed a significant improvement in ADHD symptoms at 50 mg/day (but not at 5 mg/day) compared to placebo⁴⁹
• Pozanicline (ABT-089)
  • Pozanicline is an α4β2 receptor partial antagonist⁵⁰
  • A small pilot study found improvements in ADHD symptoms compared to placebo with good tolerability.⁵¹
  • A randomized, double-blind, placebo-controlled, parallel-group phase 2 pilot study in 160 subjects found no statistically significant symptom improvement in the 137 (86%) participants who completed the study. Side effects were not more frequent than in the placebo group. The most common side effects were common cold (nasopharyngitis, 6.6 %), upper respiratory tract infections (6.6 %) and somnolence (5.7 %). There were no clinically significant laboratory, electrocardiogram or physical examination results.⁵²
  • Another multicenter, randomized, double-blind, placebo-controlled crossover study in 171 subjects found an improvement in symptoms compared to placebo at daily doses of 40 mg or more with good tolerability.⁵³ The most common side effects, with higher rates than placebo, were headache, upper respiratory tract infections, irritability, insomnia and common cold (nasopharyngitis).
• AZD1446 (TC-6683)
  • A double-blind study found no improvement for AZD1446 compared to placebo.⁵⁴
• Lobelin
  • Lobelin is a bioactive piperidine alkaloid⁵⁵
  • A small pilot study found no improvement in symptoms with lobelin.⁵⁶ Tolerance was good. The only side effect was nausea.
• ABT-418²³
  • ABT-418 is a potent and selective agonist for α-4 β-2 nicotinic receptors in the CNS. ABT-418 shares some structural similarities with nicotine and is as potent as nicotine in enhancing cognitive performance in animal models
  • ABT-418 showed improvement in ADHD symptoms in adults in a pilot study
  • 47% of subjects showed symptom improvement of 30% or more, which is on par with atomoxetine but worse than methylphenidate
  • The side effects were minor (dizziness, nausea, headache and dysphoria)

10.3. Nicotine antagonists¶

A very low dose of 0.5 mg of the nicotine antagonist mecamylamine:⁵⁷

• significantly improved recognition memory
• reduced tolerance to delays
• increased the subjectively perceived irritability
• increased the restlessness assessed by the auditor

There were no side effects or changes in vital signs.

10.4. Nicotine overdose can cause ADHD symptoms¶

In animal studies, nicotine can trigger ADHD symptoms such as hyperactivity in non-ADHD model animals.⁵⁸
This is explained by the inverted-U model of the effect of dopamine, for example. Dopaminergic regions of the brain require a certain level of dopamine to function properly. A dopamine deficiency (as associated with ADHD) can trigger very similar symptoms to a dopamine excess. Increasing dopamine with stimulants causes dopamine levels in ADHD to normalize, thereby reducing or eliminating ADHD symptoms. After a certain level of overdose, these symptoms reappear.