An example of cytisine overdose with no consequent side-effects: a case report

Abstract

Background

Cytisine is an alkaloid that is molecularly similar to nicotine and it is commonly used to treat smoking cessation. While it is considered a reasonably safe treatment option, cytisine intoxication in humans exhibits several adverse effects. These involve the gastrointestinal system (nausea, vomiting, diarrhea), the central nervous system (drowsiness, fatigue, delirium), and the motor system (muscle twitching and fasciculation, difficulties in walking).

Case presentation

We present a unique case report in which a Caucasian patient (an Italian 64-year-old woman) who was undergoing smoking cessation treatment with cytisine, and due to her misunderstanding of the therapeutic indications provided, took twice the recommended dose every day for 8 days, leading to an intake of 54 mg/dl of cytisine for 3 consecutive days. Notwithstanding the high dosage, the patient did not report any adverse reactions.

Conclusion

This confirms the safety of the drug, even at high doses, in patients aiming to quit smoking.

Introduction

Cytisine is the main alkaloid in plants belonging to the Faboideae subfamily of the Fabaceae family. These plants are common in northern Europe and in the mountains of southern Europe. Since ancient times, all of their parts and particularly their seeds have been recognized as being poisonous and causing symptoms such as vomiting, dilation of the pupils, tachycardia, prostration, torpor, excytisineement, delirium, hallucinations, muscle twitches, diarrhea, sweating, and even death due to respiratory paralysis [1–3].

Cytisine is considered to be the oldest medication for smoking cessation and has been used for this purpose in some Eastern/Central European and Central Asian countries for over 50 years [4, 5].

Starting from the first pharmacological studies on cytisine, it appeared evident that its activity is very similar to that of nicotine, suggesting that the most relevant targets of the drug are cholinergic nicotinic acetylcholine receptors (AChRs).

Like varenicline, it is a partial agonist of the nicotinic acetylcholine receptors (nAChRs), with high affinity for the alpha-4 beta-2 nAChR subtype, and its main action is to reduce withdrawal symptoms following smoking cessation [6, 7].

Several sources point toward cytisine’s efficacy and effectiveness; it is well tolerated when taken at the recommended dose, and the only adverse events reported in trials are typically non-serious and self-limiting gastrointestinal and sleep disturbances [8, 9].

In humans (particularly in children), cytisine intoxication may manifest with adverse effects on the gastrointestinal system (nausea, emesis, and bowel movements), the central nervous system (drowsiness, fatigue, dizziness, delirium), and the motor system (muscle twitching and fasciculation, difficulty in walking) [10]. The ingestion of seeds of cytisine-containing plants, particularly Spartium junceum, or Spanish broom, by children or animals can induce nicotine-like symptoms that usually fully resolve, although some fatal cases have been reported [11, 12].

We report a case of cytisine overdose below.

Case presentation

We report the case of a 64-year-old woman (Caucasian) who mistakenly took high doses of cytisine during her smoking cessation treatment, with no resulting evidence of a serious adverse reaction. In September 2021 the patient came to the Unit of Addiction Medicine in Verona, Italy, looking to quit smoking and to treat her alcohol use disorder (she has signed informed consent to present this case report).

She reported smoking from the age of 18 with a score of 8 out 10 at the Fagerström [13] Test for Nicotine Dependence. The patient also reported three previous attempts to quit smoking: two during her two pregnancies, during which she obtained abstinence without any pharmacological support, and the third in 2019, during which she quit smoking for 8 months with the help of nicotine patches, but then relapsed due to stress. Furthermore, she reported a family history of alcoholism.

She also suffered from an alcohol use disorder (drinking about 1.5 L/day of wine) from 2019 to 2021, which was treated by her general practitioner with 400 mg/day of Disulfiram. No other comorbid addiction was present.

At the time of the patient’s first medical examination, she was following a pharmacological regimen consisting in 1.25 mg/day of bisoprolol, 100 mg/day of sertraline, 2.5 mg/day of clonazepam and 400 mg/day of disulfiram.

Cytisine’s therapeutic protocol is what is termed “inductive,” similarly to the one usually used with varenicline; this means it consists in gradually increasing the daily capsules the patients take, with a simultaneous parallel reduction in the number of cigarettes they smoke, until complete cessation is obtained between the 5th and 9th day of therapy (quit day); the number of cytisine capsules taken is then gradually reduced until complete cessation, which is reached around the thirtieth day of treatment.

The patient, due to a misunderstanding of the indications that were provided to her verbally by her therapist and that were written on the protocol that was given her, took twice the recommended daily dose every day in the first 8 days of treatment, leading up to a maximum of 54 mg of cytisine that she took for 3 consecutive days.

At the second check-up visit, during the 8th day of therapy, the patient had stopped smoking and reported taking 36 capsules of cytisine (54 mg/day). Once the error in the dosage was detected, the patient was again instructed on how to properly take cytisine.

Discussion

In scientific literature there are several reports of people poisoned from seeds of Cytisus laburnum, which contain cytisine [14], with only one fatal case [15]. Actually, the lethal dose in humans is unknown. One report described two suicide attempts by the same patient, who swallowed 40–50 Tabex tablets (60–75 mg cytisine) on her first suicide attempt and 90 tablets (135 mg cytisine) on her second attempt. These suicide attempts were not fatal [16]. Acute adverse symptomatology was observed in this case report, including headache, clonic spasms, profuse sweating and trembling, vertigo, and residual symptoms included renal pain, but no objective organ lesions [16]. No fatal cytisine overdoses are reported in scientific literature. Our case report is the first overdose registered during a smoking cessation therapy in scientific literature.

Cytisine has been used since the 1960s as a smoking cessation drug in East and Central European countries [17]; unfortunately, it has not been available for clinical use outside Eastern and Central Europe. In Italy, cytisine could be used only in galenic formulation. Over the past 40 years of research conducted in Central and Eastern Europe, it is suggested that cytisine is effective and safe for smoking cessation [18].

Moreover, cytisine can be manufactured at a very low cost; this is an important aspect because despite other tobacco addiction treatments, it could be more affordable by more people from several social classes.

Cytisine is extracted from Cytisus laburnum, which is one of the best-known toxic plants in antipoison centers. Its most poisonous parts, which have effects that are similar to cytisine, are especially (but not only) the seeds. C. laburnum’s toxicity varies depending on the species, the part of the plant ingested, and the age of the plant. Data demonstrating toxicity are derived from studies on rodents, dogs, cats, and horses. The therapeutic index of cytisine is broad. The acute toxicity of cytisine has been studied in several species of animals and its estimated oral median lethal dose (LD₅₀) in rats is considered to be 5–50 mg/kg of body weight. When chronically administered to mice (3.3 mg/kg) for 45 days, and in rats (0.45 and 0.9 mg/kg) and dogs (0.45 mg/kg) for 6 months, cytisine did not cause any changes in clinical laboratory parameters and neither in histomorphology; although, in some cases, liver dystrophia was observed. Cytisine does not seem to be embryotoxic, teratogenic, or cytotoxic [19]. Oral administration of ground seeds in larger animals (sheep) did not produce any effect up to a dose of 2.4 g/kg, but twice that dose provoked tremor, difficulty walking, and a state of semi-consciousness [19].

One of the first cases of human C. laburnum poisoning was published in 1878. In the following years there were numerous reports of cases of human poisoning due to the ingestion of laburnum seeds. The first symptoms occur quickly (within 1 hour from ingestion) and resemble intoxication from nicotine: nausea, vomiting, paleness, drowsiness, dizziness, incoordination, and muscle contractions, while delirium and coma occur in severe cases [20].

In clinical settings, the majority of adverse drug reactions after cytisine administration comprise changes in the perception of taste, dryness of the mouth and throat, decreased appetite, nausea, headache, and irritability [21].

Cytisine is proving to be one of the most effective drugs in promoting smoking cessation. Interest in the molecule has grown strongly from 2006 to today, after about 40 years of experience in Bulgaria, Poland, and other Eastern European countries. Randomized controlled trials suggest high efficacy and good tolerability.

Since February 2016, the Verona University Hospital (1200 total beds) provides a cytisine galenic formulation to smokers that are admitted to the hospital.

Three principal points to note for cytisine treatment are: offering efficient and safe pharmacological support to hospitalized smokers, promoting the continuity of their care and after their discharge to reduce the risk of relapses, and cost-cutting related to nicotine replacement therapy.

Cytisine could be the ideal drug for hospitalized smoker patients because its fast onset allows to apply protocols without titration, unlike varenicline; moreover, cytisine presents rare pharmacological interactions, which is reassuring for clinicians. Finally, its very low cost is a good option for patients and stakeholders. The Verona Hospital Pharmacy prepares cytisine galenic tablets (1.5 mg). Hospital units require cytisine for smoker patients with prescription from a specialist consultant in smoking cessation.

This clinical case put the focus on the importance to explain therapeutic plan clearly to avoid these mistakes. Induction modality is not always easy to understand, it is necessary to give a tablet to the patients and explain clearly this modality.

Study limitation: no long-term follow-ups and laboratory exams are absent.

Conclusion

Despite taking conspicuously high doses of cytisine, the patient did not report any adverse reaction, confirming the safety of using the drug even at high doses in patients aiming to quit smoking.

We recommend the use of cytisine to treat tobacco addiction, because this drug is not expensive, it is efficacious, and it is safe.

Abbreviations

AChRs

Cholinergic nicotinic acetylcholine receptors

nAChRs

Nicotinic acetylcholine receptors

Author contributions

FL and SC were responsible for the study concept and design. SC, IB, and LZ contributed to the data acquisition. LZ, SC, IB, FF, and FL drafted the manuscript. All authors critically reviewed the content and approved the final version of the manuscript for publication.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethical Review Board of the University Hospital (approval code 683CESC).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

None.