Adverse Event	RCTs P = patch, G = gum, S = spray, I = inhalator, L = lozenge, T = tablet. EX = excluded study	Active n events	Active total	Control n events	Control total	Notes
Headache	Anthenelli 2016 (P)	233	2022	199	2014	Totals are numbers assessed for adverse events
	Areechon 1988 (G)	1	98	0	101	‐
	Berlin 2014 (P)	12	203	9	199	‐
	Blondal 1989 (G)	14	92	14	92	From %
	Coleman 2012 (P)	25	521	16	529	Pregnant women
	Daughton 1991 (P) 24 h 16 h	8 3	51 55	5	52	‐
	Gourlay 1995 (P)	8	315	13	314	‐
	Harackiewicz 1988 (G)	6	99	8	85	First 6 weeks
	Hays 1999 (P)	24	321	24	322	Excludes pay group
	Hjalmarson 1994 (S)	27	116	18	107	First 2 weeks
	Hurt 1994 (P)	14	120	21	120	‐
	Jarvis 1982 (G)	14	47	17	44	‐
	Jorenby 1999 (P)	69 63	243 244	52	159	P vs placebo P + B vs placebo
	Lerman 2015 (P)	139	418	169	408	Number of events summed over time, not number of people
	Lewis 1998 (P)	1	62	1	62	‐
	Llivina 1988 (G)	11	113	8	101	From %
	Paoletti 1996 (P)	19	147 (LC15 + HC25)	15	150 (LCP + HC15)	Active vs placebo (Pl + Pl or lowA+Pl)
	Puska 1979 (G)	20	80	14	74	From %; missing data removed from denominator
	Sachs 1993 (P)	7	113	5	107	‐
	Schneider 1995 (S)	41	128	32	127	From %
	Shiffman 2002 (2 mg) (L) Shiffman 2002 (4 mg) (L)	23 36	459 450	27 15	458 451	From %
	Stapleton 1995 (P)	84	761	30	364	‐
	Stein 2013 (P)	10	104	6	33	‐
	Sutherland 1992 (S)	49	111	41	103	‐
	Tønnesen 1991 (P)	6	145	6	144	From %
	Ward 2013 (P)	< 5%	134	< 5%	135	‐
	EX Batra 2005 (G)	43	184	52	180	‐
	EX CEASE 1999 (P) 25 mg 15 mg	80 76	1430 1431	28	714	‐
	EX Ebbert 2009 (L)	10	136	7	134	Smokeless (from %)
	EX Hanson 2003 (P)	27	50	34	50	adolescents
	EX Mulligan 1990 (P)	1	39	0	36	‐
	EX Rigotti 2009 (P)	31	367	22	362	All were on rimonabant
	EX Schnoll 2010 (P)	0	182	2	134	At 12 weeks
	EX Stapleton 2011 (S)	320	506	154	255	‐
Dizziness/light‐headedness	Ahluwalia 1998 (P)	0	174	1	168	‐
	Anthenelli 2016 (P)	85	2022	66	2014	Totals are numbers assessed for adverse events
	Areechon 1988 (G)	2	98	0	101	‐
	Berlin 2014 (P)	< 5%	203	< 5%	199	‐
	Daughton 1991 (P) 24 h 16 h	7 4	51 55	6	52	‐
	Gourlay 1995 (P)	5	315	4	314	‐
	Harackiewicz 1988 (G)	9	99	12	85	First 6 weeks
	Hjalmarson 1994 (S)	24	116	16	107	First 2 weeks
	Hughes 1989a (G)	71	210	18	105	From %
	Jarvis 1982 (G)	15	47	11	44
	Jorenby 1999 (P)	8 20	243 244	10	159	P vs placebo P + B vs placebo
	Lerman 2015 (P)	42	418	56	408	Number of events summed over time, not number of people
	Lewis 1998 (P)	0	62	1	62	‐
	Puska 1979 (G)	16	80	16	74	From %;
	Sachs 1993 (P)	1	113	0	107	‐
	Schneider 1995 (S)	61	128	69	127	From %
	Stapleton 1995 (P)	46	761	24	364	‐
	Stein 2013 (P)	5	104	1	33	‐
	Sutherland 1992 (S)	61	111	50	103	‐
	Tønnesen 1991 (P)	6	145	0	144	From %
	Ward 2013 (P)	<5%	134	<5%	135	‐
	EX Hanson 2003 (P)	20	50	22	50	adolescents
	EX Mulligan 1990 (P)	1	39	0	36	‐
	EX Oncken 2009 (P, S)	P3 S0	7 7	3	7	Pregnant women
	EX Rigotti 2009 (P)	25	367	16	362	All were on rimonabant
	EX Schnoll 2010 (P)	2	182	1	134	At 12 weeks
	EX Stapleton 2011 (S)	308	506	139	255	‐
Nausea/vomiting	Ahluwalia 1998 (P)	1	174	3	168	‐
	Anthenelli 2016 (P) Nausea	199	2022	137	2014	Totals are numbers assessed for adverse events
	Areechon 1988 (G)	2	98	2	101	‐
	EX Batra 2005 (G)	19	184	11	180	‐
	Berlin 2014 (P) Nausea Vomiting Total	4 5 9	203	3 8 11	199	‐
	Campbell 1996 (P)	14	115	4	119	‐
	Coleman 2012 (P)	16	521	19	529	Pregnant women
	Dautzenberg 2001 (L)	7	214	11	222	‐
	Garvey 2000 (G)	11	209	1	69	(2 mg + 4 mg) %
	Glover 2002 (T)	14	120	3	121	‐
	Gourlay 1995 (P)	10	315	7	314	‐
	Harackiewicz 1988 (G)	17	99	6	85	First 6 weeks
	Hays 1999 (P)	19	321	16	322	Excludes pay group
	Heydari 2012 (P) Nausea	0	92	0	91	‐
	Hjalmarson 1994 (S)	16	116	7	107	First 2 weeks
	Hughes 1989a (G)	69	210	18	105	From %
	Hurt 1994 (P)	6	120	3	120	‐
	Jarvis 1982 (G)	20	47	9	44	‐
	Jorenby 1999 (P) P P + B	19 28	243 244	8	159	‐
	Lerman 2015 (P) nausea vomiting	88 10	418	111 16	408	Number of events summed over time, not number of people
	Lewis 1998 (P)	4	62	3	62	P + counselling vs Pl + counselling
	Richmond 1994 (P)	9	156	2	157	From %
	Sachs 1993 (P)	4	113	10	107	‐
	Schneider 1995 (S)	24	128	11	127	From %
	Schneider 1996 (I)	14	112	13	111	‐
	Shiffman 2002 (2 mg) (L) Shiffman 2002 (4 mg) (L)	56 68	459 450	22 24	458 451	From %
	Stapleton 1995 (P) (= Russell 1993)	34	761	12	364	‐
	Stein 2013 (P) Nausea	9	104	2	33	‐
	Sutherland 1992 (S)	26	111	20	103	‐
	Tønnesen 1988 (G) 2 mg 4 mg	1 0	87 27	0	47	‐
	Tønnesen 1991 (P)	6	145	1	144	From %
	Tønnesen 1993 (I)	1	145	1	141	severe
	Wallstrom 2000 (T)	30	123	9	124	From %
	Ward 2013 (P)	< 5%	134	< 5%	135	‐
	EX Bolliger 2000a (I)	9	200	8	200	‐
	EX CEASE 1999 (P) 25 mg 15 mg	104 77	1430 1431	26	714	‐
	EX McRobbie 2010 (L,G,S)	L17 G15 S16	45 45 45	2	47	‐
	EX Rennard 2006 (I)	11	215	5	214	‐
	EX Rigotti 2009 (P)	54	367	36	362	All were on rimonabant
	EX Roddy 2006 (P)	2	49	3	49	“Dizziness, nausea or headache”
	EX Schnoll 2010 (P)	1	182	1	134	At 12 weeks (i.e. 4 weeks on placebo or patch)
	EX Stapleton 2011 (S)	336	506	168	255	‐
	EX Tsukahara 2010 (P)	4	16	0	16	V vs Gum, no placebo
Gastro‐intestinal symptoms	Berlin 2014 (P) Reflux Pyrosis Total	8 4 12	203	5 4 9	199	‐
	Campbell 1991 (G)	3	107	7	103	From %
	Daughton 1991 (P) 24 h 16 h	1 4	51 55	0	52	‐
	Dautzenberg 2001 (L)	2	214	8	222	‐
	Glover 2002 (T)	11	120	6	121	‐
	Harackiewicz 1988 (G)	23	99	8	85	First 6 weeks
	Hjalmarson 1984 (G)	25	92	11	91	‐
	Hurt 1994 (P)	4	120	6	120	‐
	Hughes 1989a (G)	65	210	18	105	‐
	Jarvis 1982 (G)	24	47	12	44	‐
	Joseph 1996 (P)	5	294	6	290	‐
	Lerman 2015 (P) Gas Abdominal pain Constipation Diarrhoea Flatulence Indigestion	199 53 100 54 154 81	418	211 41 111 77 159 92	408	Number of events summed over time, not number of people
	Lewis 1998 (P)	1	62	2	62	‐
	Llivina 1988 (G)	11	113	6	101	From %
	Paoletti 1996 (P)	16	147 (LC15+HC25)	11	150 (LCP+HC15)	(Pl+Pl or lowA+Pl)
	Puska 1979 (G)	12	80	13	74	From %
	Sachs 1993 (P)	2	113	4	107	‐
	Shiffman 2002 (2 mg) (L) Shiffman 2002 (4 mg) (L)	16 24	459 450	10 17	458 451	From %
	Shiffman 2009 (2 mg) (G) Shiffman 2009 (4 mg) (G)	213 216	819 830	118 120	817 831	From %
	Schneider 1996 (I)	16	112	11	111	‐
	Sønderskov 1997 (P)	7	255	9	267	First 4 wks
	Stein 2013 (P) Diarrhoea	0	104	1	33	‐
	Tønnesen 1988 (G) 2 mg   4 mg	11 4	87 27	5	47	‐
	Wallstrom 2000 (T)	22	123	11	124	From %
	Ward 2013 (P)	< 5%	134	< 5%	135	‐
	EX Batra 2005 (G)	12	184	5	180	‐
	Bullen 2010 (P,G) serious non‐serious	24 19	249 249	12 26	246 249	‐
	EX Ebbert 2010 (L)	3	30	0	30	Smokeless (from %)
	EX Ebbert 2009 (L)	15	136	1	134	Smokeless (from %)
	EX Molander 2000 (T)	1	20	1	20	‐
	EX Mulligan 1990 (P)	3	39	0	36	‐
	EX Oncken 2009 (P, S)	P3 S0	7 7	1	7	Pregnant women
	EX Tsukahara 2010 (P)	14	16	1	16	V vs Gum, no placebo
Sleep/dream problems	Ahluwalia 1998 (P)	0	174	0	168	In first week
	Anthenelli 2016 (P) Insomnia Initial insomnia Sleep disorder Nightmare	195 20 45 56	2022	139 6 42 17	2014	Totals are numbers assessed for adverse events
	Berlin 2014 (P)	7	203	5	199	‐
	Dautzenberg 2001 (L)	2	214	3	222	‐
	Gourlay 1995 (P)	43	315	19	314	‐
	Hays 1999 (P)	30	321	20	322	Excludes pay group
	Heydari 2012 (P) Abnormal dreams	0	92	0	91	‐
	Hurt 1994 (P)	9	120	5	120	‐
	ICRF 1994 (P)  Mild                    Moderate                    Severe	45 95 32	842	10 40 13	844	‐
	Jorenby 1999 (P) P P+B	73 116	243 244	31	159	‐
	Joseph 1996 (P)	10	294	6	290	‐
	Lerman 2015 (P) Sleep Abnormal dreams	203 182	418	190 132	408	Number of events summed over time, not number of people
	Llivina 1988 (G)	7	113	10	101	From %
	Oncken 2007 (P)	5	57	2	95	‐
	Paoletti 1996 (P)	19	147 (LC15+HC25)	36	150 (LCP+HC15)	(Pl+Pl or lowA+Pl)
	Perng 1998 (P)	2	30	0	32	‐
	Puska 1979 (G)	26	80	20	74	From %;
	Richmond 1994 (P)	41	156	25	157	From %
	Sachs 1993 (P)	4	113	5	107	‐
	Stein 2013 (P) Insomnia/sleep problems/ awakening Dreaming or nightmares	38 19	104	12 8	33	‐
	Ward 2013 (P)	11	134	14	135	‐
	EX CEASE 1999 (P) 25 mg 15 mg	70 77	1430 1431	42	714	‐
	EX Ebbert 2009 (L)	15	136	1	134	Smokeless (from %)
	EX Ebbert 2010 (L)	0	30	3	30	Smokeless (from %)
	EX Hanson 2003 (P)	30	50	23	50	Adolescents
	EX Mulligan 1990 (P)	2	39	0	36	‐
	EX Rigotti 2009 (P)	35	367	11	362	All were on rimonabant
	EX Schnoll 2010 (P)	2	182	6	134	At12 weeks
	EX Tsukahara 2010 (P)	6	16	2	16	V vs Gum
CV (palpitations, chest pain)	Berlin 2014 (P) palpitations CV other	< 5% < 5%	203	< 5% < 5%	199	‐
	Gourlay 1995 (P)	5	179	3	143	‐
	Hays 1999 (P)	5	321	2	322	Excludes pay group
	Hjalmarson 1994 (S)	9	116	2	107	First 2 weeks
	Lerman 2015 (P) Chest pain Palpitations Irregular heartbeat	18 35 11	418	26 50 19	408	Number of events summed over time, not number of people, therefore excluded from meta‐analysis 6.1.
	Oncken 2007 (P)	1	57	1	95	‐
	Schneider 1995 (S)	23	128	10	127	From %
	Shiffman 2009 (2 mg) (G) Shiffman 2009 (4 mg) (G)	3 3	819 830	3 3	817 831	From %
	Sønderskov 1997 (P) “cardiac”	1	255	4	267	First 4 weeks
	Sutherland 1992 (S)	26	111	15	103	‐
	Tønnesen 1988 (G) 2 mg 4 mg	0 1	87 27	0	47	‐
	Ward 2013 (P) Palpitations CV other	< 5% < 5%	134	< 5% < 5%	135	‐
	EX Bolliger 2000a (I)	1	200	2	200	‐
	EX Brantmark 1973a (G)	3	46	4	42	‐
	EX Bullen 2010 (P,G)	9	249	1	246	‐
	EX CEASE 1999 (P) 25 mg 15 mg	32 37	1430 1431	6	714	‐
	EX Schnoll 2010 (P)	0	182	2	134	At12 weeks (i.e. 4 weeks on placebo or patch)
	EX Wennike 2003a (G)	6	205	4	206	‐
Wisborg 2000 states 5 women had palpitations, but no distribution info
Skin reactions	Abelin 1989 (P)	12	156	1	155	Combined studies
	Ahluwalia 1998 (P)	8	174	5	168	‐
	Anthenelli 2016 (P)	109	2022	16	2014	Totals are numbers assessed for adverse events
	Berlin 2014 (P)	23	203	8	199	‐
	Buchkremer 1988 (P)	6	42	6	43	From %
	Campbell 1996 (P)	54	115	40	119	‐
	Coleman 2012 (P)	97	521	28	529	Pregnant women
	Daughton 1991 (P)	1 3	51 (24 h) 55 (16 h)	1	52	‐
	Dautzenberg 2001	0	214	2	222	‐
	Davidson 1998 (P)	100	401	52	401	From %
	Gourlay 1995 (P)	44	315	27	314	‐
	Hays 1999 (P)	124	321	48	322	Excludes pay group
	Hurt 1990 (P)	19	31	10	31	Over 6 weeks
	Hurt 1994            Mild                      Moderate                           Severe	68 5 1	120	24 3 0	120	‐
	ICRF 1994 (P)     Mild                       Moderate                           Severe	18 75 40	842	8 26 9	844	‐
	Jorenby 1999 (P) P P+B	45 37	243 244	11	159	‐
	Joseph 1996 (P)	6	294	3	290	‐
	Kornitzer 1995 (P,G)	9 7	149 150	1	75	P+G vs Pl P+PlG vs Pl
	Lerman 2015 (P) Redness Swelling/rash	68 48	418	32 44	408	Number of events summed over time, not number of people
	Lewis 1998 (P)	16	62	11	62	‐
	Oncken 2007 (P)	8	57	2	95	‐
	Paoletti 1996 (P)	59	147 (LC15+HC25)	30	150 (LCP+HC15)	Active vs placebo (Pl+Pl or lowA+Pl)
	Perng 1998 (P)	7	30	5	32	‐
	Richmond 1994 (P)	36	156	19	157	From %
	Sønderskov 1997 (P)	75	255	49	267	First 4 weeks
	Stapleton 1995 (P)	108	761	18	364	‐
	Stein 2013 (P) Flushing or sweating	30	104	11	33	‐
	Ward 2013 (P)	12	134	16	135	‐
	EX Bullen 2010 (P,G)	6 5	249 249	8 3	246 246	Skin SAEs
	EX CEASE 1999 (P) 25 mg 15 mg	206 185	1430 1431	36	714	‐
	EX Hanson 2003 (P)	31	50	24	50	adolescents
	EX Levin 1994 (P)	24	31	21	31	‐
	EX Mulligan 1990 (P)	10	39	10	36	‐
	EX Oncken 2009 (P, S)	P3 S0	7 7	0	7	Pregnant women
	EX Roddy 2006 (P)	16	49	7	49	‐
	EX Rose 1990 (P) mod.                            severe	12 4	33	0 0	32	From %
	Ex Schnoll 2010 (P)	1	182	1	134	@12wks
	EX Tsukahara 2010 (P)	0	16	9	16	V vs Gum, no placebo
Oral/nasal reactions	Areechon 1988 (G)	1	98	2	101	‐
	Berlin 2014 (P)	< 5%	203	< 5%	199	‐
	Campbell 1991 (G)	9	107	6	105	From %
	Dautzenberg 2001 (L)	5	214	0	222	‐
	Garvey 2000 (G)	2	209	0	69	(2 mg + 4 mg)
	Glover 2002 (T)	24	120	23	121	Weeks 1 to 2
	Harackiewicz 1988 (G)	34	99	1	85	First 6 wks
	Hjalmarson 1984 (P)	24	92	14	91	‐
	Hjalmarson 1994 (S)	85	116	40	107	First 2 wks
	Hughes 1989a (G)	160	210	56	105	From %
	Jarvis 1982 (G)	28	47	23	44	‐
	Jorenby 1999 (P) P P+B	16 25	243 244	10	159	‐
	Lerman 2015 (P)	173	418	160	408	Number of events summed over time, not number of people
	Llivina 1988 (G)	13	113	4	101	From %
	Perng 1998 (P)	4	30	0	32	‐
	Schneider 1995 (S)	125	128	65	127	From %
	Schneider 1996 (I)	47	112	26	111	‐
	Shiffman 2002 (2 mg) (L) Shiffman 2002 (4 mg) (L)	12 23	459 450	12 18	458 451	From %
	Stein 2013 (P) Dry mouth Change in taste	17 14	104	4 1	33	‐
	Sutherland 1992 (S)	105	111	67	103	‐
	Tønnesen 1988 (G) 2 mg   4 mg	20 8	87 27	11	47	‐
	Tønnesen 1993 (I)	72	145	24	141	From %
	Wallstrom 2000 (T)	66	123	62	124	From %
	Ward 2013 (P)	< 5%	134	< 5%	135	‐
	EX Adelman 2009 (S)	7	20	0	20	Open‐label, no spray for controls
	EX Batra 2005 (G)	8	184	33	180	‐
	EX Bolliger 2000a (I)	14	200	4	200	‐
	EX Brantmark 1973a (G)	6	46	3	42	‐
	EX McRobbie 2010 (L,G,S)	L8 G6 S16	45 45 45	2	47	‐
	EX Molander 2000 (T)	5	20	0	20	‐
	EX Oncken 2009 (P, S)	P1 S2	7 7	0	7	Pregnant women
	EX Rigotti 2009 (P)	23	367	24	362	All were on rimonabant
	EX Stapleton 2011 (S)	194	506	135	255	‐
Hiccups	Berlin 2014 (P)	< 5%	203	< 5%	199	‐
	Blondal 1989 (G)	13	90	0	92	‐
	Glover 2002 (T)	18	120	1	121	‐
	Harackiewicz 1988 (G)	8	99	1	85	First 6 weeks
	Hjalmarson 1984 (P)	7	92	0	91	‐
	Hughes 1989a (G)	103	210	22	105	From %
	Jarvis 1982 (G)	14	47	2	44	‐
	Schneider 1996 (I)	3	112	0	111	‐
	Shiffman 2002 (2 mg) (L) Shiffman 2002 (4 mg) (L)	16 38	459 450	0 0	458 451	From %
	Tønnesen 1988 (G) 2 mg 4 mg	2 4	87 27	0	47	‐
	Wallstrom 2000 (T)	14	123	0	124	From %
	Ward 2013 (P)	< 5%	134	< 5%	135	‐
	EX Batra 2005 (G)	28	184	3	180	‐
	EX Brantmark 1973a (G)	11	46	2	42	‐
	EX McRobbie 2010 (L,G,S)	L17 G15 S16	45 45 45	2	47	‐
	EX Molander 2000 (T)	1	20	0	20	‐