Nicotine as a drug for ADHD

Nicotine has a stimulating effect and is therefore a stimulant like methylphenidate or amphetamine drugs. Nicotine reduces ADHD symptoms comparable to medicinal stimulants.¹

An ADHD-HI sufferer told us that she had quit smoking 4 years earlier and had since been able to relieve her internal tension states resulting from ADHD with nicotine lozenges. One 1 mg tablet worked for about 2 hours. Several other patients reported comparable effects. Furthermore, nicotine has a calming effect on ADHD sufferers more often.²

A small studies were described significant positive effects by nicotine patches on ADHD symptoms of smokers (at 21 mg for 4.5 hours / day) and non-smokers (at 7 mg for 4.5 hours / day).
The activity of those affected had increased significantly. Reaction times had decreased, inattention and response variability (the temporal variance of reactions) had decreased, and time perception, which is often worsened in ADHD, had improved significantly.³
Another very small study confirms the results.⁴
Very surprisingly, there does not seem to be any other professional research on this topic.
This is probably due, among other things, to the fact that research into active ingredients in the public domain is expensive and cannot be refinanced by corresponding exclusive rights (patents) to the results, so that commercial research is not profitable. This is not the fault of “the pharmaceutical industry” but a consequence of unfavorable political conditions.

Nicotine acts dopaminergically, acetylcholinergically, and increases the cortisol response to acute stress.

Nicotine:⁵

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

• 1. Nicotine increases dopamine release
• 2. Nicotine reduces dopamine transporter
• 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. Nicotine medication for ADHD
    • 8.1. Nicotine in ADHD
    • 8.2. Nicotine agonists in ADHD
    • 8.3. Nicotine antagonists

1. Nicotine increases dopamine release¶

Nicotine stimulates ATV neurons, causing their extensions in the nucleus accumbens (the main area of the brain’s reward/reinforcement system) to release dopamine.⁶ Nicotine thereby increases dopamine levels (in the case of tobacco, intensely, but only for a short time, after which they drop even lower, which accounts for the addictive potential) and acts on acetylcholine balance.

Nicotine

• increases firing rate and phasic dopamine release from dopaminergic neurons in the VTA⁷⁸ and, much more weakly, in the substantia nigra pars compacta⁹
• increases dopamine release in dopaminergic projection areas, e.g., in the nucleus accumbens⁷
• regulates dopamine transmission in the nucleus accumbens¹⁰¹¹
• modulates dopamine release in the mesolimbic reward system by:¹²
• Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) by
  • the nAChRs trigger depolarization of the nerve terminals.
  • ca2+ entry via alpha7 nAChRs causes a significant increase in the size of the readily releasable pool of synaptic vesicles. Alpha7 receptors desensitize rapidly.
• 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 ¹³
• slightly decreases phasic dopamine release in the dorsal striatum¹³
• strongly increases phasic dopamine release in the nucleus accumbens¹³
• The frequency dependence of dopamine release differs between¹³
  • dorsolateral striatum
  • NAc shell
    • therefore, the NAc shell benefits much more from nicotine-induced phasic burst firing of dopamine neurons
• Nicotine decreases tonic dopamine release in¹³
  • dorsolateral striatum
  • NAc shell
• the increased ratio of phasic bursts to tonic firing caused by nicotine led to increase in basal dopamine concentration especially in the NAc shell¹³

Dopamine release and function of dopaminergic neurons in the VTA are regulated in part by glutamatergic projections from the PFC into the VTA. Neuronal adaptations after nicotine exposure in these brain regions contribute to nicotine addiction.¹⁴

Dihydro-β-erythroidine (DHβE) is a herbal competetive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2-units (β2* NAChRs; β2-nicotinic receptors). DHβE decreases phasic dopamine release in the dorsolateral striatum¹³
It follows 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 .

2. Nicotine reduces dopamine transporter¶

Smoking significantly reduces the number of dopamine transporters in the striatum. Nicotine, like methylphenidate, causes a reduction in DAT density in the striatum.¹⁵¹⁶¹⁷

3. Nicotine / smoking reduces dopamine breakdown¶

Tobacco smoke contains significant amounts of MAO inhibitors.²⁰
MAO breaks down dopamine. MAO inhibitors thus inhibit dopamine breakdown and thereby increase dopamine.

4. Nicotine alters cortisol response¶

Nicotine (as a patch as by smoking in smokers) increased the cortisol response to acute stress in one study.²¹ Another very small study found a decreased cortisol response to acute stress in smokers.²²

Assuming an increased cortisol response, nicotine might have a better effect in ADHD-HI sufferers (who have a flattened cortisol response to stress, and therefore 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, the reverse would be true.

5. Nicotine increases basal cortisol levels¶

Smokers were found to have 5% higher basal cortisol levels.²³ Since basal cortisol levels are reduced in ADHD (somewhat more so in ADHD-HI than in ADHD-I) compared to non-affected individuals, this could possibly explain why so many ADHD sufferers smoke.
In addition, smokers have increased levels of²³

• Dehydroepiandrosterone (DHEA) (18% higher)
• Dehydroepiandrosterone sulfate (DHEAS) (13 % higher)
• Androstenedion (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 decrease in DAT, which is also increased in ADHD.²⁴ Parkinson’s suffer from a dopamine deficit just like ADHD sufferers, but this can be treated with other medications.

6. Smoking masks ADHD symptoms¶

Smoking as self-medication increases dopamine levels - albeit only ever in the short term. It further reduces stress symptoms and irritability. ADHD sufferers smoke about twice as often as non-affected people.
Smoking may therefore complicate the diagnosis of ADHD.²⁵

A study of emotional dysregulation in ADHD-affected smokers found no differences between those who smoked as usual and those who abstained from smoking for 24 hours.²⁶

Intranasal nicotine application in nicotine-naive adolescents with and without ADHD showed that ADHD sufferers responded to nicotine with greater drowsiness (dizziness) and found the effect more pleasant than healthy control subjects. ADHD sufferers subsequently chose to use nicotine more often than control subjects. This was independent of emotional state.²
In our understanding, an intranasal nicotine application corresponds to a rapid absorption of active substance via the olfactory nerves directly into the brain and thus to a drug-like application, which is to be categorically distinguished from a slow absorption as a patch or lozenge (corresponding to a drug-like effect).

7. Nicotine increases histamine¶

Nicotine increases histamine, as do all known ADHD medications:

• Amphetamine drugs
• Methylphenidate
• Modafinil
• Caffeine

Therefore, people with histamine intolerance often have problems by taking ADHD medications.
One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses.

8. Nicotine medication for ADHD¶

8.1. Nicotine in ADHD¶

fifteen nonsmoking 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 stop signal response time. SSRT was improved with no change in GO response time or accuracy. Nicotine tended to increase tolerance for delays increased and improved recall memory.²⁷
62 male nonsmokers were divided into two groups according to their attentional scores and received a 7 mg nicotine patch (6 hours) or placebo. Nicotine induced²⁸

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

In a placebo-controlled study of transdermal nicotine (7 mg, 14 mg, and 21 mg) on cognitive performance in 48 male and 48 female smokers after overnight abstinence and 6 hours of patch use, an inverted U-shaped relationship was found between nicotinic stimulation and cognitive performance:²⁹

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

8.2. Nicotine agonists in ADHD¶

Nicotine agonists are

• AZD3480
  • An initial study showed significant improvement in ADHD symptoms at 50 mg/day (but not at 5 mg/day) compared to placebo³⁰
• Pozanicline (ABT-089)
  • Pozanicline is an α4β2-receptor partial antagonist³¹
  • A small pilot study found improvements in ADHD symptomatology over placebo with good tolerability.³²
  • A randomized, double-blind, placebo-controlled, parallel-group, phase 2 pilot study of 160 subjects found no statistically significant symptom improvement in the 137 (86%) participants completing the study. Side effects were no more frequent than in the placebo group. The most common adverse events were nasopharyngitis (cold, 6.6%), upper respiratory tract infection (6.6%), and somnolence (5.7%). There were no clinically significant laboratory, electrocardiogram, or physical examination findings.³³
  • Another multicenter, randomized, double-blind, placebo-controlled crossover study in 171 subjects found symptom improvement over placebo at daily doses of 40 mg or more with good tolerability.³⁴ The most common adverse events, with rates higher than placebo, were headache, upper respiratory tract infection, irritability, insomnia, and nasopharyngitis (cold).
• AZD1446 (TC-6683)
  • For AZD1446, a double-blind study found no improvement over placebo.³⁵
• Lobelin
  • Lobelin is a bioactive piperidine alkaloid³⁶
  • A small pilot study found no symptom improvement with lobelin.³⁷ Tolerability was good. The only side effect was nausea.

8.3. Nicotine antagonists¶

• Mecamylamine

A very low dose of 0.5 mg of the nicotine antagonist mecamylamine:³⁸

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

No side effects or changes in vital signs were found.