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 stopped smoking 4 years earlier and had since been able to relieve her internal tension 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 the perception of time, 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 through 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 has dopaminergic, acetylcholinergic effects and increases the cortisol response to acute stress.
- 1. Nicotine increases dopamine release
- 2. Nicotine reduces dopamine transporter
- 3. Nicotine alters cortisol response
- 4. Nicotine increases basal cortisol levels
- 5. Smoking masks ADHD symptoms
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.5 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.
- increases firing rate and phasic dopamine release from dopaminergic neurons in the VTA67 and, much more weakly, in the substantia nigra pars compacta8
- increases dopamine release in dopaminergic projection areas, e.g., in the nucleus accumbens6
- regulates dopamine transmission in the nucleus accumbens910
- modulates dopamine release in the mesolimbic reward system by:11
- 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.12
- slightly decreases phasic dopamine release in the dorsal striatum12
- strongly increases phasic dopamine release in the nucleus accumbens12
- The frequency dependence of dopamine release differs between12
- 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 in12
- 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 shell12
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.13
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 striatum.12
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
ADHD is associated with altered numbers of dopamine transporters. In a SPECT study of 31 adults with ADHD, a greater increase in DAT was found in ADHD-HI sufferers than in ADHD-I sufferers. However, DAT were still elevated in ADHD-I sufferers compared with nonaffected individuals. Smoking significantly decreased DAT in both subtypes.17
Another study reported a large reduction in DAT in ADHD sufferers when they were also users of dopaminergic drugs.18
In contrast, other studies found no DAT increase in ADHD.
3. Nicotine alters cortisol response
Nicotine (as a patch as by smoking in smokers) increased the cortisol response to acute stress in one study.19 Another very small study found a decreased cortisol response to acute stress in smokers.20
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.
4. Nicotine increases basal cortisol levels
Smokers were found to have 5% higher basal cortisol levels.21 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 of21
- 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.22 Parkinson’s patients suffer from a dopamine deficit just like ADHD patients, but this can be treated with other medications.
5. 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 can therefore complicate the diagnosis of ADHD.23
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.24
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 nicotine intake more frequently 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).
6. Nicotine increases histamine
Nicotine increases histamine, as do all known ADHD medications
- Amphetamine drugs
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.
Gehricke, Whalen, Jamner, Wigal, Steinhoff (2006): The Reinforcing Effects of Nicotine and Stimulant Medication in the Everyday Lives of Adult Smokers with ADHD: A Preliminary Examination; Nicotine & Tobacco Research, Volume 8, Issue 1, February 2006, Pages 37–47, https://doi.org/10.1080/14622200500431619; n = 10 ↥
Kollins, Sweitzer, McClernon, Perkins (2020): Increased subjective and reinforcing effects of initial nicotine exposure in young adults with attention deficit hyperactivity disorder (ADHD) compared to matched peers: results from an experimental model of first-time tobacco use. Neuropsychopharmacology. 2020 Apr;45(5):851-856. doi: 10.1038/s41386-019-0581-7. PMID: 31785588; PMCID: PMC7075924. ↥ ↥
Levin, Conners, Sparrow, Hinton, Erhardt, Meck, Rose, March (1996): Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 1996 Jan;123(1):55-63. n = 17 ↥
Gehricke, Whalen, Jamner, Wigal, Steinhoff (2006): The reinforcing effects of nicotine and stimulant medication in the everyday lives of adult smokers with ADHD: A preliminary examination. Nicotine Tob Res. 2006 Feb;8(1):37-47. doi: 10.1080/14622200500431619. PMID: 16497598. ↥
Kleijn, Folgering, van der Hart, Rollema, Cremers, Westerink (2011): Direct effect of nicotine on mesolimbic dopamine release in rat nucleus accumbens shell. Neurosci Lett. 2011 Apr 8;493(1-2):55-8. doi: 10.1016/j.neulet.2011.02.035. PMID: 21352892. ↥ ↥
Leri F, Vaccarino FJ. Tribute to: Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area [William Corrigall, Kathleen Coen and Laurel Adamson, Brain Res. 653 (1994) 278-284]. Brain Res. 2016 Aug 15;1645:61-4. doi: 10.1016/j.brainres.2015.12.064. PMID: 26867702. REVIEW ↥
Keath, Iacoviello, Barrett, Mansvelder, McGehee (2007): Differential modulation by nicotine of substantia nigra versus ventral tegmental area dopamine neurons. J Neurophysiol. 2007 Dec;98(6):3388-96. doi: 10.1152/jn.00760.2007. PMID: 17942622. ↥
Stoker, Markou (2013): Unraveling the neurobiology of nicotine dependence using genetically engineered mice. Curr Opin Neurobiol. 2013 Aug;23(4):493-9. doi: 10.1016/j.conb.2013.02.013. Epub 2013 Mar 29. PMID: 23545467; PMCID: PMC3735838. ↥
Zhang, Doyon, Clark, Phillips, Dani (2009): Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum. Mol Pharmacol. 2009 Aug;76(2):396-404. doi: 10.1124/mol.109.056317. PMID: 19460877; PMCID: PMC2713129. ↥
Turner (2004): Nicotine enhancement of dopamine release by a calcium-dependent increase in the size of the readily releasable pool of synaptic vesicles. J Neurosci. 2004 Dec 15;24(50):11328-36. doi: 10.1523/JNEUROSCI.1559-04.2004. PMID: 15601939; PMCID: PMC6730353. ↥
Zhang, Zhang, Liang, Siapas, Zhou, Dani (2009): Dopamine signaling differences in the nucleus accumbens and dorsal striatum exploited by nicotine. J Neurosci. 2009 Apr 1;29(13):4035-43. doi: 10.1523/JNEUROSCI.0261-09.2009. PMID: 19339599; PMCID: PMC2743099. ↥ ↥ ↥ ↥ ↥ ↥ ↥
Liu, Seaman, Siemian, Bhimani, Johnson, Zhang, Zhu, Hoener, Park, Dietz, Li (2018): Role of trace amine-associated receptor 1 in nicotine’s behavioral and neurochemical effects. Neuropsychopharmacology. 2018 Nov;43(12):2435-2444. doi: 10.1038/s41386-018-0017-9. Epub 2018 Feb 5. PMID: 29472642; PMCID: PMC6180004. ↥
Krause, Dresel, Krause, Kung, Tatsch, Ackenheil (2002): Stimulant-like action of nicotine on striatal dopamine transporter in the brain of adults with attention deficit hyperactivity disorder. International Journal of Neuropsychopharmacology, 5, 111–113, zitiert nach Diamond: Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit (with hyperactivity), Development and Psychopathology 17 (2005), 807–825, Seite 812 ↥
Krause, Krause, Dresel, la Fougere, Ackenheil (2006): ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine. Dialogues Clin Neurosci. 2006;8(1):29-36. doi: 10.31887/DCNS.2006.8.1/jkrause. PMID: 16640111; PMCID: PMC3181750. REVIEW ↥
Silva, Szobot, Shih, Hoexter, Anselmi, Pechansky, Bressan, Rohde (2014): Searching for a neurobiological basis for self-medication theory in ADHD comorbid with substance use disorders: an in vivo study of dopamine transporters using (99m)Tc-TRODAT-1 SPECT. Clin Nucl Med. 2014 Feb;39(2):e129-34. doi: 10.1097/RLU.0b013e31829f9119. ↥
Kirschbaum, Strasburger, Langkrär (1993): Attenuated cortisol response to psychological stress but not to CRH or ergometry in young habitual smokers; Pharmacology Biochemistry and Behavior; Volume 44, Issue 3, March 1993, Pages 527-531; https://doi.org/10.1016/0091-3057(93)90162-M; Vorsicht, geringes n = 20 ↥
Field, Colditz, Willett, Longcope, McKinlay (1994): The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men; J Clin Endocrinol Metab. 1994 Nov;79(5):1310-6. ↥ ↥
Itti, Villafane, Malek, Brugières, Capacchione, Itti, Maison, Cesaro, Meignan (2009): Dopamine transporter imaging under high-dose transdermal nicotine therapy in Parkinson’s disease: an observational study. Nucl Med Commun. 2009 Jul;30(7):513-8. doi: 10.1097/MNM.0b013e32832cc204. ↥
Mitchell, McClernon, Beckham, Brown, Lejuez, Kollins (2019): Smoking abstinence effects on emotion dysregulation in adult cigarette smokers with and without attention-deficit/hyperactivity disorder. Drug Alcohol Depend. 2019 Sep 27;205:107594. doi: 10.1016/j.drugalcdep.2019.107594. ↥