on August 16, 2026
Tobacco dependence is not simply a habit that is difficult to break. It is the result of progressive neurobiological changes induced by repeated exposure to nicotine, a psychoactive substance capable of altering the functioning of brain circuits involved in reward, learning, and stress response.
When nicotine reaches the brain, it binds to nicotinic acetylcholine receptors, particularly those containing the α4β2 subunits and other subtypes expressed in different brain areas. Their activation influences the release of several neurotransmitters, including dopamine, noradrenaline, acetylcholine, glutamate, GABA, and serotonin. In the mesolimbic system, increased dopaminergic transmission contributes to the perception of reward and the consolidation of use behavior. With chronic exposure, the nervous system adapts to the presence of nicotine, and when it is suddenly withdrawn, withdrawal symptoms emerge.
It is precisely this neuroadaptation that explains why the urge to smoke can persist even when the person is fully aware of the damage caused by tobacco. Craving is not merely a matter of willpower: it represents the interaction between pharmacological dependence, associative memory, environmental stimuli, stress, and brain reward circuits.
Nicotine is metabolized mainly in the liver through cytochrome CYP2A6, which converts it primarily into cotinine. The speed at which this metabolism occurs varies among individuals and can influence both smoking behavior and response to cessation treatments. A systematic review of 12 studies highlighted, in some populations of European origin, a greater likelihood of cessation in individuals with slower nicotine metabolism, while the results are less uniform in other populations. This represents one of the most interesting examples of how pharmacogenetics and precision medicine can contribute to the understanding of nicotine dependence.
The serotonergic system and nicotine withdrawal
Serotonin, or 5-hydroxytryptamine (5-HT), is not the only neurotransmitter involved in nicotine dependence, but it participates in the regulation of mood, anxiety, appetite, sleep, and stress response. Furthermore, serotonergic neurons indirectly modulate the dopaminergic circuits involved in reward.
Experimental studies have shown that different subtypes of serotonergic receptors can alter the behavioral effects of nicotine. In particular, the 5-HT2C receptor has been studied for its role in modulating mesolimbic dopaminergic transmission and nicotine-seeking behaviors. However, the fact that a biological pathway is involved in dependence does not automatically mean that indiscriminately increasing serotonin through a supplement promotes cessation. Serotonergic physiology is, in fact, much more complex than a simple "more serotonin = less craving" relationship.
This point is also important when discussing herbal medicine.
St. John's Wort: an interesting mechanism, but negative clinical results in smoking cessation
Hypericum perforatum, commonly known as St. John's Wort, contains numerous bioactive components, including hypericin and hyperforin. Hyperforin has been studied for its ability to interfere with the transport and reuptake of several neurotransmitters, contributing to the neuropharmacological effects of the extract.
St. John's Wort has significant clinical documentation in the treatment of some forms of mild-to-moderate depression, but these results should not be automatically transferred to nicotine dependence. The specific question is, in fact, whether taking St. John's Wort increases the likelihood of quitting smoking.
On this point, clinical studies are much less favorable.
A randomized, placebo-controlled trial conducted on 118 smokers compared different doses of St. John's Wort with placebo, in combination with a behavioral intervention. No significant differences were observed in abstinence rates at 12 and 24 weeks, and St. John's Wort did not reduce withdrawal symptoms. The authors therefore concluded that the extract had no significant role in the treatment of tobacco dependence.
A previous pilot study had produced apparently more encouraging results, but it was uncontrolled and included only 28 smokers; at 12 months, no participant was still abstinent.
A subsequent randomized proof-of-concept trial also showed substantially negative results: prolonged abstinence at four weeks was 8.5% with St. John's Wort compared to 12.5% with placebo, with no evidence of an intervention advantage.
Therefore, the biological hypothesis that the neurotransmitter action of St. John's Wort can influence some aspects of the neurobiology of dependence is interesting, but cannot be translated into demonstrated clinical efficacy for quitting smoking.
There is also a major safety issue. St. John's Wort is one of the herbal products with the greatest potential for drug interaction because it induces cytochrome P450 enzymes and P-glycoprotein. It can reduce the efficacy of numerous medications and, if combined with certain drugs that affect serotonin, increase the risk of even severe serotonergic effects.
For this reason, it should not be considered a simple "natural supplement" to be freely combined with other treatments.
Griffonia and 5-HTP: biological plausibility that does not equate to anti-smoking therapy
Griffonia simplicifolia is an African plant whose seeds are a natural source of 5-hydroxytryptophan (5-HTP), a metabolic precursor of serotonin.
From a biochemical point of view, 5-HTP is located in the sequence:
L-tryptophan → 5-HTP → serotonin → melatonin
This is where the interest in Griffonia arises in relation to mood, appetite, stress, and sleep.
However, in this case too, it is necessary to distinguish the biological mechanism from clinical efficacy. There is no robust clinical evidence demonstrating that Griffonia or 5-HTP consistently increase smoking cessation rates. The theoretical possibility of modulating some withdrawal symptoms cannot therefore be presented as demonstrated efficacy in the treatment of dependence.
Contemporary research on serotonin and nicotine dependence itself shows that the serotonergic system is composed of numerous receptors with different and sometimes opposing functions. Effective pharmacological intervention should therefore be extremely selective, while a systemic increase in the serotonergic precursor does not necessarily reproduce this level of precision.
GABA, anxiety, and craving: the possible role of Valerian and Passionflower
During nicotine withdrawal, irritability, restlessness, anxiety, difficulty concentrating, and sleep disturbances are common. The GABAergic system, the main inhibitory system of the central nervous system, therefore represents another interesting neurobiological target.
Valeriana officinalis contains valerenic acid and other compounds that can modulate GABAergic transmission. Pharmacological studies have highlighted interactions with the GABA-A system, providing a plausible explanation for its sedative and anxiolytic effects.
This does not mean, however, that Valerian is a proven treatment for nicotine dependence. Its potential usefulness should be considered primarily in the context of associated symptoms such as nervous tension and sleep disorders, not as a replacement therapy for cessation treatments.
A similar reasoning applies to Passiflora incarnata. Several flavonoids in the plant have been studied for their neuropharmacological properties and their interaction with GABAergic systems.
A small randomized, double-blind trial compared a Passionflower extract with oxazepam in 36 patients with generalized anxiety disorder. Both treatments produced an improvement in anxiety, with no significant differences at the end of the four weeks; however, oxazepam had a faster action and the group treated with the medication presented more problems related to impaired work performance.
It is important, however, not to turn this result into evidence of efficacy against smoking. Passionflower has been studied mainly for anxiety, not to directly increase tobacco abstinence. A Cochrane review also highlighted that the available clinical studies on Passionflower in anxiety disorders are few and insufficient to establish efficacy and safety with certainty.
The possible role of Valerian and Passionflower in a cessation journey can therefore be conceived, at most, as support for neurovegetative symptoms associated with withdrawal, and not as a treatment of dependence in the strict sense.
The myth of nicotine "detoxification"
One of the aspects to correct in communication about smoking cessation concerns the concept of "detoxification".
Nicotine does not necessarily need to be "flushed out" of the body through cleansing products. The body already has specific metabolic systems to eliminate it. Most nicotine is converted in the liver, mainly through CYP2A6, into cotinine and subsequently into other metabolites, which are eliminated from the body.
The real smoking detoxification strategy consists above all in stopping exposure to the thousands of substances present in tobacco smoke.
This is a fundamental conceptual step: no supplement can neutralize the biological effects of continuing to smoke.
Oxidative stress and nutrients: why nutritional support can make sense
Cigarette smoking generates a significant oxidative load and contributes to a systemic inflammatory state. Among the micronutrients most studied in smokers is vitamin C.
A controlled study on smokers and non-smokers observed a significant reduction in plasma ascorbic acid associated with smoking. Moderate supplementation allowed the restoration of vitamin C levels in smokers. This data demonstrates that smoking can influence the antioxidant status, but it does not mean that vitamin C constitutes a therapy to quit smoking.
The distinction is essential: correcting a possible nutritional deficiency is different from treating dependence.
For this reason, the nutritional approach should be individualized and based, when necessary, on the assessment of diet and nutritional status, avoiding indiscriminate megadoses of antioxidant vitamins.
Resveratrol: interesting for oxidative stress, not for "eliminating" nicotine
Resveratrol is a polyphenol studied for its antioxidant properties and its ability to modulate several cellular pathways involved in inflammation and oxidative stress.
In the context of tobacco use, scientific interest is particularly linked to the possibility of countering some cellular alterations induced by smoke.
A randomized, double-blind crossover trial conducted on healthy smokers studied the effects of resveratrol on markers of inflammation and oxidative stress, precisely because smoking is associated with an oxidative-antioxidant imbalance and low-grade systemic inflammation.
Another line of research concerns bone tissue. In experimental models, exposure to cigarette smoke compromises the osteogenic differentiation of human mesenchymal stem cells. In vitro, resveratrol reduced the production of free radicals and protected the structure of primary cilia, improving the osteogenic differentiation of cells exposed to smoke extract.
Animal models have also suggested a possible protective effect of resveratrol on bone healing processes compromised by smoking.
These results are scientifically interesting, but must be interpreted correctly: they do not demonstrate that resveratrol accelerates "detoxification" from nicotine in humans nor that it directly promotes smoking cessation.
The most effective treatment remains multimodal
Contemporary research therefore leads to a very different conclusion from the idea of a single plant capable of "turning off" the urge to smoke.
Nicotine addiction simultaneously involves the dopaminergic system, nicotinic receptors, the serotonergic system, GABA, glutamate, stress circuits, and learning and memory mechanisms. It is therefore reasonable that the most effective treatment acts on multiple levels.
The World Health Organization guidelines published in 2024 recommend behavioral interventions and evidence-based pharmacological treatments. Among the recommended pharmacological options are nicotine replacement therapy, varenicline, bupropion, and cytisine. The combination of pharmacotherapy with behavioral support increases the chances of success compared to the isolated use of a single strategy.
The WHO itself does not issue a recommendation in favor of traditional, complementary, or alternative therapies for smoking cessation, precisely due to the insufficiency of the available evidence.
This does not mean that natural substances are necessarily useless. It means that their role must be defined with greater precision: some may have a biological rationale or clinical evidence for specific symptoms, but this does not equate to demonstrating an effect on smoking cessation.
A scientifically sound approach can therefore involve a distinction between three levels: treatment of nicotine addiction, management of withdrawal symptoms, and support of nutritional and metabolic status.
It is above all the first level that determines the success of cessation. The others may eventually contribute to the person's well-being during the process, but they must not replace therapeutic strategies with greater evidence.
When phytotherapy requires particular attention
"Natural" does not automatically mean "free of interactions".
The case of St. John's wort is emblematic. The ability to alter the activity of enzymes and transporters involved in drug metabolism can significantly reduce the plasma concentration of important medications. Documented interactions include those with certain antidepressants, anticoagulants, oral contraceptives, immunosuppressants, digoxin, and other drugs.
The combination with substances or drugs that increase serotonergic transmission also requires caution.
Consequently, a smoking cessation journey that includes phytotherapeutics should be evaluated by a doctor or pharmacist, especially when the person takes chronic medications.
The real goal is not to replace one addiction with another empirical strategy, but to support the brain in the process of adapting to the new condition of non-exposure to nicotine.
Quitting smoking is, in fact, a process of neurobiological reorganization: the circuits that for years have associated nicotine with reward must gradually learn that that reward is no longer available. In this journey, psychological support, possible pharmacological therapy, stress management, sleep, physical activity, and proper nutrition can contribute to building a new balance.
Phytotherapy can be the subject of research and, in selected circumstances, complementary use, but the distinction between biological plausibility, benefit for symptoms, and real efficacy in cessation must always remain at the center of proper medical-scientific communication.
Bibliographic references
- World Health Organization. WHO clinical treatment guideline for tobacco cessation in adults. Geneva: WHO; 2024.
- Benowitz NL. Nicotine addiction. N Engl J Med. 2010;362:2295-2303.
- Balfour DJK, Fagerström KO. Pharmacology of nicotine and its therapeutic use in smoking cessation and neurodegenerative disorders. Pharmacol Ther. 1996;72(1):51-81.
- Dani JA, Harris RA. Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci. 2005;8:1465-1470.
- Kenny PJ, Markou A. Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav. 2001;70:531-549.
- Fletcher PJ, et al. Serotonin receptors as potential targets for modulation of nicotine use and dependence. Int Rev Neurobiol. 2008.
- Parsons A, et al. A proof of concept randomised placebo controlled factorial trial to examine the efficacy of St John's wort for smoking cessation and chromium to prevent weight gain on smoking cessation. Drug Alcohol Depend. 2009;102(1-3):116-122.
- Barnes J, et al. A pilot randomised, open, uncontrolled, clinical study of two dosages of St John's wort herb extract as an aid to motivational/behavioural support in smoking cessation. Planta Med. 2006;72(4):378-382.
- Sood A, et al. A randomized clinical trial of St. John's Wort for smoking cessation. Drug Alcohol Depend. 2010.
- Akhondzadeh S, et al. Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther. 2001;26:363-367.
- Miyasaka LS, et al. Passiflora for the treatment of anxiety disorders in adults. Cochrane Database Syst Rev.
- Jones SK, et al. Nicotine Metabolism Predicted by CYP2A6 Genotypes in Relation to Smoking Cessation: A Systematic Review. Nicotine Tob Res. 2022;24(5):633-642.
- Lykkesfeldt J, et al. Ascorbate is depleted by smoking and repleted by moderate supplementation. Am J Clin Nutr. 2000;71(2):530-536.
- Bo S, et al. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers: a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem. 2013.
- Resveratrol protects primary cilia integrity of human mesenchymal stem cells from cigarette smoke to improve osteogenic differentiation. PubMed.
- Effects of resveratrol and cigarette smoking on bone healing: histomorphometric evaluation. PubMed.
- National Center for Complementary and Integrative Health. St. John's Wort: Usefulness and Safety.
