Table 1.

Human studies on topiramate for the treatment of substance related disorders.

Alcohol Dependence
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Johnson et al, 2003	RCT, double blind	n=75 topiramate (23 female), n=75 placebo (20 female)	300mg/day×12 wks	Self-reported drinking.	Topiramate group had 2.88 fewer average drinks/d, 3.10 fewer drinks per drinking day, 27.6% fewer heavy drinking days, and 26.2% more days abstinent from alcohol.
Rubio et al, 2004	Open trial	n=24 adults (11 female) with alcohol dependence and co-morbid psychiatric disorders for which the use of topiramate was indicated. No placebo group.	Average 262mg/day (range 200–400mg)×12 weeks	Weekly drink consumption, craving, and CDT.	Improvements in craving scores (p<0.001), weekly drinks (p<0.001), CDT (p<0.05).
Huguelet et al, 2005	Case series	n=2 males with co-occurring psychiatric disorders (schizophrenia, bipolar disorder)	Case 1: 150mg/day×4 months. Case 2: 300mg/day for unknown duration.	Alcohol consumption.	Case 1: abstinence. Case 2: reduction in alcohol consumption from 3L/d to 3dL/d.
Chiu et al, 2007	Retrospective chart review	n=9 adults (2 female) with alcohol abuse or dependence and co-occurring psychiatric disorders	Variable; average dose 112.5mg/day over an unknown time period.	Partial or complete remission in alcohol consumption.	6/9 patients achieved full or partial remission from alcohol use disorders
Miranda et al, 2007	Open trial	n=64 (10 female) with co-occurring psychiatric disorders	Average 196mg/day (range 50–400mg)×12 months	Number of drinking days per month, number of drinks per day.	Decrease from 23.6 to 4.8 drinking days per month. Decrease from 16 to 2 drinks per day.
Johnson et al, 2007	RCT, double blind, multi-site	n=183 topiramate (46% female), n=188 placebo (52% female)	300mg/day×14 wks	Self-reported percentage of heavy drinking days.	Mean difference 8.44% (95%CI 3.07–13.80%)
De Sousa et al, 2008	Randomized open label trial	n=50 topiramate, n=50 disulfiram. All males with stable family supports/supervision.	Topiramate 50mg TID vs. disulfiram 250mg/day×9 months	Relapse rates, time to relapse.	Lower relapse rates in disulfiram (10%) vs. topiramate (44%). Shorter mean time to relapse in topiramate (76 days) vs. disulfiram (133 days).
Florez et al, 2008	Randomized, open label trial	n=51 topiramate (8 female), n=51 naltrexone (7 female)	Topiramate 200mg–400mg/day vs. naltrexone 50mg PO daily×6 months	Alcohol intake, craving, disability, quality of life, GGT, MCV.	No significant differences between groups in abstinence (47% in topiramate group vs. 45% in naltrexone group). Less severe cravings in topiramate group compared to naltrexone group. Trend for greater improvement in alcohol-related disability, quality of life, GGT, MCV in topiramate compared to naltrexone.
Baltieri et al, 2008	RCT, double blind	n=52 topiramate, n=49 naltrexone, n=54 placebo. All males.	Topiramate 300mg/day vs. naltrexone 50mg/day PO vs. placebo×12 weeks.	Time to first relapse, cumulative abstinence duration, weeks of heavy drinking.	Topiramate superior to placebo on all 3 outcome measures (7.8 vs. 5.0 weeks to first relapse; 8.2 vs. 5.6 weeks of cumulative abstinence; 3.4 vs. 5.9 weeks of heavy drinking). No statistically significant difference between topiramate and naltrexone, but trends toward superior outcomes in topiramate group. No statistically significant difference between naltrexone and placebo.
Miranda et al, 2008	Randomized, double-blind human laboratory study	n=20 topiramate 200mg/day (30% female), n=21 topiramate 300mg/day (38% female), n=20 placebo (40% female). All non-treatment seeking.	Topiramate 200mg/day vs. topiramate 300mg/day vs. placebo×4 weeks.	Weekly assessments of alcohol intake and craving during medication titration. Laboratory assessment of alcohol cue reactivity. Laboratory assessment of alcohol effects after alcohol challenge.	Topiramate significantly reduced drinking (fewer drinks per week and percent of heavy drinking days) compared to placebo as dose increased, but no effect on craving. No effect of topiramate on urge to drink when presented with cues. No effect of topiramate on urge to drink during alcohol administration.

Alcohol Withdrawal
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Rustembegovic et al, 2002	Open trial	n=12 patients with alcoholism who have 1–2 tonic clonic seizures a year.	50mg BID×30 days	Number of seizures during study.	No seizures observed.
Krupitsky et al, 2007	RCT, single blind	n=26 topiramate, n=25 lamotrigine, n=26 memantine, n=25 diazepam, n=25 placebo. All males.	Topiramate 25mg every 6 hrs; lamotrigine 25mg every 6 hrs; memantine 10mg every 8 hrs; diazepam 10mg every 8 hrs, all for 7 days.	Self-rated and observer-rated withdrawal scores.	Topiramate was superior to placebo, did not differ significantly from diazepam, and was slightly less effective than lamotrigine.

Nicotine Dependence
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Johnson et al, 2005	RCT, subgroup analysis	n=45 topiramate (11 female), n=49 placebo (13 female)	300mg/day×12 weeks	Smoking abstinence	OR 4.46 (95%CI 1.08–18.39)
Khazaal et al, 2006	Open trial	n=13 smokers (6 female) with ≥1 failed quit attempts	Flexible dosing strategy (Range 50–800mg/day)	Smoking abstinence at 2mths	6/13 abstinent and 2/13 decreased smoking by >50%
Sofuoglu et al, 2006	Cross-over laboratory design	n= 12 (5 female) smokers	Single doses of 25mg, 50mg, and placebo before administration of nicotine 0.5mg and 1mg IV.	Subjective ratings of nicotine effects (DEQ) and nicotine withdrawal	“Drug strength,” “good effects,” and “drug liking” greater for 25mg and 50mg topiramate vs placebo (p<0.05). “Head rush” greater for 50mg topiramate vs. placebo (p<0.05).
Reid et al, 2007	RCT, double blind	n=19 topiramate (5 female), n=21 placebo (10 female)	75mg/day×9 days	Subjective ratings of nicotine craving and withdrawal	Topiramate enhanced subjective ratings of withdrawal after the 3hr abstinence period, and increased the rewarding effects of a smoked cigarette.
Arbaizar et al, 2008	Case report	n=1 (34yo male with polysubstance dependence, diabetes, and metabolic encephalopathy)	Topiramate 200mg/day and aripiprazole 15mg/day×2 months	-----	Reduction in smoking from 80–100 cigarettes/day to 40–60 cigarettes/day.
Anthenelli et al, 2008	RCT, double blind	N=43 topiramate (27 female), n=44 placebo(22 female)	200mg/day×11 weeks	Prolonged abstinence (minimum of 4 weeks of carbon-monoxide confirmed smoking abstinence)	No difference between topiramate (7/43) and placebo (7/44). But exploratory analysis showed that topiramate-treated men (37.5%) are more likely to achieve prolonged abstinence compared to topiramate-treated women (3.7%).

Cocaine Dependence
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Kampman et al, 2004	RCT, double blind	n=20 topiramate (5% female), n=20 placebo (0% female)	200mg×13 weeks	Cocaine use, measured by urine benzoylecgonine test (UBT)	Topiramate group was more likely to be abstinent compared to placebo group after week 8 (Z=2.67, p=0.01).
Reis et al, 2008	Open trial	n=28 intranasal cocaine dependent males	Average dose 127mg/day (range 25–300mg/day)×12 weeks	Abstinence rate (number of negative UBT’s divided by total number of UBT’s). Intensity, frequency, and duration of cocaine craving.	Average rate of abstinence was 25%. Intensity and duration of cocaine craving was reduced in 25% of sample. No decrease in craving frequency.

Methamphetamine Dependence
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Johnson et al, 2007	Cross-over laboratory design	n=10 (3 females) non-treatment seeking methamphetamine-dependent adults	100mg or 200mg in divided doses (on the evening before and on the morning of study) prior to administration of IV methamphetamine 15mg and 30mg.	Multiple choice questionnaire (MCQ), End-of-Day questionnaire (EDQ), Visual analogue scale for methamphetamine effects (VAS-M), Global Rating of Stimulation (GRS).	MCQ: topiramate had trend of accentuating effect of methamphetamine to increase value of drug over money. EDQ: topiramate significantly enhanced effect of methamphetamine in increasing desire to use again. VAS-M: topiramate increased the stimulating and euphoric effects of methamphetamine. GRS: topiramate alone had trend of decreasing effect on mood, but significantly accentuated the positive effect of methamphetamine on mood.

Opioid Withdrawal
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Zullino et al, 2002	Case series	n=3 (2 female)	Variable; max dose 500mg with taper	-----	No significant withdrawal symptoms, and minimal adverse effects.
Zullino et al, 2004	Open trial	n=10 topiramate (4 female) , n=10 clonidine (4 female), n=10 carbamazepine/mianserin (3 female)	Topiramate 500mg×3 days with taper down by 100mg/day×2days then by 50mg/day×4 days; clonidine 600µg×3 days with taper×4 days; carbamazepine 600mg and mianserin 60mg×7 days with carbamazepine taper×3 days.	Dose adjustments and use of other p.r.n. medications	7/10 receiving clonidine and 9/10 receiving carbamazepine/mianserin required dose reductions due to side effects, compared to 2/10 in topiramate group. Topiramate group required less analgesics (p<0.05) and myorelaxants (p<0.001) compared to other groups.

Benzodiazepine Dependence and/or Withdrawal
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Cheseaux et al, 2003	Case report	n=1 (41yo male with intranasal midazolam use up to 90mg/day×7yrs)	500mg with taper×9 days	-----	Rapid detoxification from benzodiazepines, with minimal withdrawal symptoms.
Michopoulos et al, 2006	Case report	n=1 (44yo female with depression, subthreshold anxiety, and alprazolam addiction 5–6mg/day)	200mg×6mths	-----	Reduced alprazolam intake to 1.5mg at 6mths without withdrawal symptoms.

3,4-methylenedioxy-N-methylamphetamine (MDMA or Ecstasy) Dependence
Study	Design	Sample	Dose and Duration	Primary Outcome Measure	Results
Akhondzadeh and Hampa, 2005	Case report	n=1 (24yo male)	200mg×3 mths	-----	Decreased consumption. Attenuated sense of euphoria.