Study ID	Period	Placebo	Varenicline	Bupropion	NRT
VARENICLINE trials
Anthenelli 2013	During treatment or within 30 days of last dose	Intentional self injury; Depression with suicidal ideation; Agitation; Depression	Psychotic disorder and depression; Suicidal ideation
	Post‐treatment to week 52	Intentional self injury 2 other SAEs	2 deaths: overdose of clonazepam and morphine sulfate; Accidental fall 3 other SAEs
Aubin 2008	During treatment or within 30 days of last dose		Depression*; Constipation		Bile duct ca, sepsis; Gastrointestinal bleed; MI (2); Chest pain (2); Salivary gland tumour; Aggravation of old knee trauma
			Acute ethanol intoxication; Suicidal ideation*; No deaths reported		Abdominal cyst; No deaths reported
Baker 2016	Post‐treatment to week 52		Hospitalised due to allergic reaction to varenicline		None reported
Bolliger 2011	During treatment or within 30 days of last dose	Thyroid neoplasm; Appendicitis, peritonitis, diverticulitis; No deaths reported	Abortion (possibly *); Hypersensitivity; Overdose; Bronchitis and asthma; Nasal septum deviation; Suicidal ideation + depressed mood; Suicidal ideation*; Tachycardia, bradychardia +dyspnoea; Panic attack; Injury; Appendicitis No deaths reported
Carson 2014	During treatment	(active control: counselling): Depressive episodes x 2; Agitation; 4 N‐STEMI (died); 2 lung ca (died) 1 stroke (died)	Atrial fibrillation; Depressive episodes x 3; Aggression; 1 arrhythmia (died) 1 bradycardia (died) 2 respiratory/COPD (died) 2 N‐STEMI (died)
	Post‐treatment to 52 weeks		Depressive episode
Chengappa 2014	During treatment	Alcohol intoxication; Exacerbation of asthma; Pregnancy;	Exacerbation of anxiety; Rash; Agitation, hostility, alcohol abuse, drug abuse*; Hypoxia, asthma with COPD; Tremulousness, grogginess, left‐arm weakness;
	Post‐treatment to 52 weeks	Chest pain, left‐hand numbness	Pneuomonia
Cincripini 2013		Diabetes; Chest pain*	Chest pain; Psychiatric hospitalisation	Bilateral mammoplasty; Facial paralysis; Syncope*
EAGLES 2016	During treatment or within 30 days of last dose (Detail of SAES given in ClinicalTrials.gov posted results)	16 (non‐psych) 25 (psych) 2 deaths (suicide, non‐psych; pulmonary embolism, psych)	16 (non‐psych) 23 (psych) 2 deaths (heroin OD non‐psych; CV event, psych)	19 (non‐psych) 29 (psych)	21 (non‐psych) 24 (psych)
	> 30 days after last dose	2 deaths (RTA, non‐psych; MI, non‐psych)		1 death (lung cancer, psych)	3 deaths (prostate cancer, non‐psych; oesophageal adenoma, psych; sepsis, psych)
Ebbert 2015	During treatment or within 30 days of last dose	10 x suicidal ideation	6 x suicidal ideation
	Post‐treatment to week 52	18 other SAEs	10 other SAEs
Eisenberg 2016	Within 30 days of treatment	3 MIs 5 unstable anginas Ischaemic cardiomyopathy Sick sinus syndrome Ruptured pseudoaneurysm Bowel obstruction COPD Rheumatoid arthritis Road traffic accident Melena Non‐cardiac chest pain Allergic reaction	2 deaths (1 cardiac, 1 sudden death undefined) 3 MIs Unstable angina Depression Pulmonary embolism TIA Arrythmia and ICD implant 2 gastric bleeds 2 suspected unstable anginas (ruled out) Peroneal embolus with septic cellulitis Bowel surgery Dehydration Syncope Wound infection
Evins 2014	Randomization phase	Sepsis (died); MI; Depressed mod and discontinuation of meds; Suicidal ideation; Worsened psychosis; Worsened psychosis and MJ intoxication; Manic symptoms	Pancreatitis; Hyperglycaemia; Depressed mood; Worsened psychotic symptoms
Gonzales 2006	During treatment or within 7 days of last dose	Lung cancer; Acute MI; Acute exacerbation of schizophrenia; Chest pain (2); UTI Atrial fibrillation	Abdominal pain; Atrial fibrillation*; Pneumonia; Possible stroke	Cholecystitis, septic shock; Headache; Grand mal seizure*
	Post‐treatment to week 52	Mediastinal mass; Fall, fractured elbow, collapsed lung, death   unexplained; I death (as above)	Non‐cardiac chest pain; Acute appendicitis; No deaths reported	Appendicitis; UTI; No deaths reported
Gonzales 2014	During treatment or within 30 days of last dose	Acute coronary syndrome; Ligament rupture; Hyperventilation; Drug sensitivity	Knee arthroplasty; pyelonephritis; Intervertebral disc protrusion; Ankle fracture; Chest pain*; Drug sensitivity to amoxicillin; Drug sensitivity to hair dye
	Post‐treatment to week 52		Acute on chronic alcoholism (died)
Jorenby 2006	During treatment or within 7 days of last dose	Ruptured ovarian cyst; Ischaemic heart disease; Ruptured appendix; Pneumonia; Allergic reaction	Lung or brain cancer; Acute coronary syndrome; Chest pain; Dehydration, periorbital cellulitis; Acute psychosis, emotional lability; Vertigo, raised BP, chest pain*	Ectopic pregnancy; Angiodoema*; Gunshot wound; Post‐op bleeding; Lower Leg pain; Breast cancer (female)
	Post‐treatment to week 52	Appendicitis; No deaths reported	Staphylococcal cellulitis; Acute psychosis; No deaths reported	Occlusion coronary artery; Miscarriage; 1 death (RTA)
Nahvi 2014a	During treatment	Chest pain; Alcohol detoxification	Hypoglycaemia; Alcohol and cocaine rehab; Knee replacement
	Post‐treatment to 24 weeks	Total hip relacement	Alcohol rehab, acute cholecystitis; Asthma exacerbation
Nakamura 2007	During treatment	Subarachnoid haemorrhage; Contusion; Foot fracture	0.25 mg bid: Gastroenteritis; Cholecystitis*; Gastric cancer; Cholecystitis, peritonitis; Herpes Zoster 0.5mg bid: Haemorrhoids, intestinal    prolapse; Pituitary haemorrhage; 1 mg bid: Neurosensory deafness; Angina pectoris*, intervertebral disc protrusion, MS; 1 death (RTA)
NCT00828113	During treatment	Road traffic accident
	More than 30 days after treatment		Bladder surgery
Niaura 2008	Post‐treatment or within 30 days of last dose	None reported No deaths reported	MI; Ventricular fibrillation; Spontaneous abortion; No deaths reported
Nides 2006	During treatment	None reported No deaths reported	Transient ischaemic attack*, transient loss of vision*; No deaths reported	Syncope, possible seizure*; Grand mal convulsion*; Bloody diarrhoea*; No deaths reported
Oncken 2006	During treatment	Syncope	Syncope; Duodenal ulcer; Cholesteatoma; Generalised tonic‐clonic       seizure; Unstable angina; Paroxysmal supraventricular       tachycardia; Cholelithiasis; Aseptic meningitis; Relapsing MS	None reported
	Post‐treatment	Suicide attempt; No deaths reported	Carcinoid colon cancer; Diabetes (> 30d post‐treat); No deaths reported	None reported No deaths reported
Rennard 2011	During treatment and within 30 days of last dose	Suicidal ideation	Intervertebral disc protrusion x 2; Carotid artery stenosis; Syncope; PAOD; Ureteric calculus
Rigotti 2010	During treatment	Atrial fibrillation*; Congestive cardiac failure*; Chest pain*; Acute coronary     syndrome*; + 17 others 1 death (unrelated)	Chest pain*; MI*; Gingival bleeding*; CVA*; + 19 others
	Post‐treatment to week 52	4 deaths (unrelated)	2 deaths (unrelated)
Stein 2013	During and post‐treatment		Rashes x 2		Heart attack
Steinberg 2011	During and post‐treatment to week 24	5 events (no detail) No deaths	6 events (no detail) No deaths
Tashkin 2010	During treatment or within 28 days of last dose	Bronchitis; CVA; Cholelithiasis; Lung cancer; Pneumonia; Musculoskeletal pain; Acute MI; Appendicitis; COPD; Chest pain; Anxiety	Acute MI; Vocal cord polyp; Hyperkeratosis; Back pain; Angina pectoris; CVA; Cellulitis;
	Post‐treatment	COPD; Pneumonia; Palpitations; Chest pain; 1 death (amyotrophic lateral sclerosis)	L Ventricular dysfunction; Aortic valve stenosis; COPD; Chest pain; Laryngeal cancer; 2 deaths (1 cardiac, I RTA)
Tønnesen 2013	Post‐treatment	Rectal cancer with ileostomy, peritonitis; Gall stone; Malignant melanoma; Exacerbation of COPD	Stroke; Severe constipation; Bradycardia; Cardiac arrest; Probable dengue fever
Tonstad 2006	Open‐label phase (during treatment)		R Breast indeterminate path; Suicidal ideation; Menorrhagia; Glandular adenocarcinoma; Diminshed vision; Accidental injury; Headache; Abdominal pain*; Acute psychosis*; Acute pancreatitis; Neopharyngeal carcinoma; Raised AST, ALT, LDH, CPK; Grand mal convulsion; Atrial fibrillation; Ureteral stones; Persistent epistaxis; Worsening kidney stones; Loss of teeth, dislocated shoulder
	Open‐label phase (post‐treatment)		MI; Miscarriage
	Double‐blind phase (during treatment)	Increased    dysmenorrhoea; Appendicitis; Spinal cord    compression; Abdominal pain	Injury to tibial artery; Uterine & bladder prolapse, suspected MI; Alcohol poisoning, costal fracture; Transient vision loss*; MI
	Double‐blind phase (post‐ treatment)	Acute cholecystitis; No deaths reported	Colon cancer; Tumour; Ovarian tumour; Cerebral infarct, deep cerebral vein thrombosis; Supraventricular tachycardia; 3 deaths (unrelated)
Tsai 2007	During treatment or within 28 days of last dose	3 RTAs; No deaths reported	Unstable angina*; Acute pyelonephritis; Peritonitis, acute appendicitis; No deaths reported
Tsukahara 2010		None reported	None reported
Wang 2009	During treatment or within 7 days of last dose	Intestinal ulcer; 1 not described; No deaths reported	None reported No deaths reported
Williams 2007	Up to week 52	Vertebral compression    fracture; DVT, pulmonary    embolism; Worsening coronary    artery disease; No deaths reported	Coronary artery disease; Herniated disc; Bilateral subcapsular cataracts* Chest pain, hypoglycaemia; Sinus bradycardia,    hypotension, ventricular bigeminy, coronary angioplasty; Stroke; Cardiac catheterization; Tachycardia; Suspected GI bleed; Saphenous vein occlusion,    ischaemia; MI, DVT; Ileus; Chest wall pain; Non‐cardiac chest pain, chronic bronchitis,    pneumonia, chest pain; Spinal stenosis; No deaths reported
Williams 2012	During treatment and within 30 days of last dose	Hyperglycaemia; Breast cancer; Aggression; Suicidal ideation; No deaths	Chest pain; Convulsion; "Psychiatric symptom"; Suicidal ideation; Suicidal attempt; Asthma; 1 death
CYTISINE trials
Scharfenberg 1971	CYTISINE	Not reported	Not reported
Vinnikov 2008	CYTISINE	None reported	None reported
Walker 2014			56 events in 45 people (see Table S5 in NEJM supplementary data)		45 events in 39 people (see Table S5 in NEJM supplementary data)
West 2011	CYTISINE	COPD (died); Stroke (died); Lung cancer (died)	Stroke; Tracheal cancer; Cardiac arrest (died); Lung cancer (died);
DIANICLINE trial
Tonstad 2011	DIANICLINE	Subileus; Thrombophlebitis; SVT; No deaths reported	Appendicitis; Severe asthma; MI; No deaths reported
* Possibly, probably or definitely attributable to study medication Abbreviations:  ALT: Alanine transaminase; AST: Aspartate transaminase; BP: blood pressure; COPD: Chronic Obstructive Pulmonary Disease;  CPK: Creatine phosphokinase; CVA: cerebrovascular accident;  DVT: deep vein thrombosis; LDH: Lactate dehydrogenase; MI: myocardial infarction;  MS: Multiple Sclerosis;  N/STEMI: non‐ST‐elevation myocardial infarction; PAOD: peripheral arterial occlusive disease; RTA: road traffic accident;  SVT: supraventricular tachycardia; UTI: urinary tract infection