Background:Many studies report a positive association between smoking and mental illness. However, the literature remains mixed regarding the direction of this association. We therefore conducted a systematic review evaluating the association of smoking and depression and/or anxiety in longitudinal studies.Methods:Studies were identified by searching PubMed, Scopus, and Web of Science and were included if they: (1) used human participants, (2) were longitudinal, (3) reported primary data, (4) had smoking as an exposure and depression and/or anxiety as an outcome, or (5) had depression and/or anxiety as the exposure and smoking as an outcome.Results:Outcomes from 148 studies were categorized into: smoking onset, smoking status, smoking heaviness, tobacco dependence, and smoking trajectory. The results for each category varied substantially, with evidence for positive associations in both directions (smoking to later mental health and mental health to later smoking) as well as null findings. Overall, nearly half the studies reported that baseline depression/anxiety was associated with some type of later smoking behavior, while over a third found evidence that a smoking exposure was associated with later depression/anxiety. However, there were few studies directly supporting a bidirectional model of smoking and anxiety, and very few studies reporting null results.Conclusions:The literature on the prospective association between smoking and depression and anxiety is inconsistent in terms of the direction of association most strongly supported. This suggests the need for future studies that employ different methodologies, such as Mendelian randomization (MR), which will allow us to draw stronger causal inferences.Implications:We systematically reviewed longitudinal studies on the association of different aspects of smoking behavior with depression and anxiety. The results varied considerably, with evidence for smoking both associated with subsequent depression and anxiety, and vice versa. Few studies supported a bidirectional relationship, or reported null results, and no clear patterns by gender, ethnicity, clinical status, length to follow-up, or diagnostic test. Suggesting that despite advantages of longitudinal studies, they cannot alone provide strong evidence of causality. Therefore, future studies investigating this association should employ different methods allowing for stronger causal inferences to be made, such as MR.

Background and AimsCannabidiol (CBD), a non‐intoxicating cannabinoid found in cannabis, may be a promising novel smoking cessation treatment due to its anxiolytic properties, minimal side effects and research showing that it may modify drug cue salience. We used an experimental medicine approach with dependent cigarette smokers to investigate if (1) overnight nicotine abstinence, compared with satiety, will produce greater attentional bias (AB), higher pleasantness ratings of cigarette‐related stimuli and increased craving and withdrawal; and (2) CBD in comparison to placebo, would attenuate AB, pleasantness of cigarette‐related stimuli, craving and withdrawal and not produce any side effects.DesignRandomized, double‐blind cross‐over study with a fixed satiated session followed by two overnight abstinent sessions.SettingUK laboratory.ParticipantsThirty non‐treatment‐seeking, dependent cigarette smokers recruited from the community.Intervention and comparator800 mg oral CBD, or matched placebo (PBO) in a counterbalanced orderMeasurementsAB to pictorial tobacco cues was recorded using a visual probe task and an explicit rating task. Withdrawal, craving, side effects, heart rate and blood pressure were assessed repeatedly.FindingsWhen participants received PBO, tobacco abstinence increased AB (P = 0.001, d = 0.789) compared with satiety. However, CBD reversed this effect, such that automatic AB was directed away from cigarette cues (P = 0.007, d = 0.704) and no longer differed from satiety (P = 0.82). Compared with PBO, CBD also reduced explicit pleasantness of cigarette images (P = 0.011; d = 0.514). Craving (Bayes factor = 7.08) and withdrawal (Bayes factor = 6.95) were unaffected by CBD, but greater in abstinence compared with satiety. Systolic blood pressure decreased under CBD during abstinence.ConclusionsA single 800‐mg oral dose of cannabidiol reduced the salience and pleasantness of cigarette cues, compared with placebo, after overnight cigarette abstinence in dependent smokers. Cannabidiol did not influence tobacco craving or withdrawal or any subjectively rated side effects.

ALH and HVC (Grant number: L-023032) is registered at ClinicalTrials.gov (ID: NCT02649231).We would furthermore like to thank Dr. Evgeny Krupitsky for his pioneering research into ketamine as a treatment and his input into the design of the study. This paper is dedicated to the memory of our colleague Dr. David Gilhooly.