Abstract: Twenty-four trials evaluated interventions to help those who smoke to cut down the amount smoked or to replace their regular cigarettes with PREPs, compared to placebo, brief intervention, or a comparison intervention. None of these trials directly tested whether harm reduction strategies reduced the harms to health caused by smoking. Most trials (14/24) tested nicotine replacement therapy (NRT) as an intervention to assist reduction. In a pooled analysis of eight trials, NRT significantly increased the likelihood of reducing CPD by at least 50% for people using nicotine gum or inhaler or a choice of product compared to placebo (risk ratio (RR) 1.75, 95% confidence interval (CI) 1.44 to 2.13; 3081 participants). Where average changes from baseline were compared for different measures, carbon monoxide (CO) and cotinine generally showed smaller reductions than CPD. Use of NRT versus placebo also significantly increased the likelihood of ultimately quitting smoking (RR 1.87, 95% CI 1.43 to 2.44; 8 trials, 3081 participants; quality of the evidence: low). Two trials comparing NRT and behavioural support to brief advice found a significant effect on reduction, but no significant effect on cessation. We found one trial investigating each of the following harm reduction intervention aids: bupropion, varenicline, electronic cigarettes, snus, plus another of nicotine patches to facilitate temporary abstinence. The evidence for all five intervention types was therefore imprecise, and it is unclear whether or not these aids increase the likelihood of smoking reduction or cessation. Two trials investigating two different types of behavioural advice and instructions on reducing CPD also provided imprecise evidence. Therefore, the evidence base for this comparison is inadequate to support the use of these types of behavioural advice to reduce smoking. Four studies of PREPs (cigarettes with reduced levels of tar, carbon and nicotine, and in one case delivered using an electronically-heated cigarette smoking system) showed some reduction in exposure to some toxicants, but it is unclear whether this would substantially alter the risk of harm. We judged the included studies to be generally at a low or unclear risk of bias; however, there were some ratings of high risk, due to a lack of blinding and the potential for detection bias. Using the GRADE system, we rated the overall quality of the evidence for our cessation outcomes as ‘low’ or ‘very low’, due to imprecision and indirectness. A ‘low’ grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A ‘very low’ grade means we are very uncertain about the estimate. People who do not wish to quit can be helped to cut down the number of cigarettes they smoke and to quit smoking in the long term, using NRT, despite original intentions not to do so. However, we rated the evidence contributing to the cessation outcome for NRT as 'low' by GRADE standards. There is a lack of evidence to support the use of other harm reduction aids to reduce the harm caused by continued tobacco smoking. This could simply be due to the lack of high-quality studies (our confidence in cessation outcomes for these aids is rated 'low' or 'very low' due to imprecision by GRADE standards), meaning that we may have missed a worthwhile effect, or due to a lack of effect on reduction or quit rates. It is therefore important that more high-quality RCTs are conducted, and that these also measure the long-term health effects of treatments.

Plain-language summary: We found 20 randomised controlled trials that tested ways to help people to cut down the number of cigarettes they smoked. Some of these just advised smokers to smoke less, but most also provided them with a product to help them cut down: nicotine replacement therapy (NRT), varenicline, bupropion, electronic cigarettes (ecigs), or snus (a form of smokeless, oral tobacco). We also found four randomized controlled trials that tested the effects of using cigarettes designed to reduce the damage caused by smoking: reduced tar, carbon or nicotine cigarettes. Most of the studies used NRT to help people to reduce their smoking. All of the studies included people who were not planning to quit smoking soon. The research is current to October 2015. Eight studies (with 3081 smokers) found that using NRT roughly doubled the likelihood of halving the number of cigarettes smoked each day, compared to using a placebo. Using NRT in this way also nearly doubled the likelihood of quitting completely. One trial each tested bupropion, varenicline, ecigs and snus to help reduce the harms caused by smoking, and there was no evidence that any of these treatments helped smokers to reduce the number of cigarettes they were smoking each day. This may be because there has not yet been enough research into these methods. Only one of the trials testing cigarettes designed to reduce risk measured their effect on the number of people quitting smoking. It found that people were not more likely to quit smoking if they used reduced-nicotine cigarettes than if they smoked their usual cigarettes. We did not find any trials which reported the long-term health effects of the treatments, and so it remains uncertain how much health benefit there is from reducing the number of cigarettes smoked each day or smoking cigarettes designed to be less harmful. The tobacco industry funded three of the included studies of cigarettes designed to reduce risk. None of the studies looked at whether there had been a long-term change in the health of the users. We rate the quality of the evidence looking at how many people quit smoking as 'low' or 'very low', generally because the findings are based on a small number of studies. We need more studies to investigate methods of reducing the harm caused by continued smoking. These need to measure the health of the users over a long period.