The effects of cannabis use on depression have not been well-understood, and variance in opinions have surfaced ranging from detrimental effects of cannabis to the potential of cannabis to treat depression. Cannabis Use Disorder (CUD) is a term to characterize the problematic use of cannabis, which assesses the level of physical dependence, withdrawal effects, continued use despite negative psychosocial consequences, and functional impairments in various aspects of life. People often question the addictive potential of cannabis, but the emerging evidence shows clear harms of CUD including increased life years of disability, psychiatric and medical comorbidities, poor performance in school, and legal consequences.1–3 In the United States, approximately 3 out of every 10 cannabis users met criteria for the diagnosis of CUD.3 Major depressive disorder (MDD) is a devastating illness that affects 300 million people and is one of the leading causes of disability globally.4,5 In a study analyzing the National Epidemiologic Survey on Alcohol and Related Conditions (NSEARC) data from 2001 to 2002, individuals diagnosed with MDD demonstrated CUD at a rate of 3.1% compared to those without mental illness at 0.6%.6 It is likely that recent change in legislation of cannabis in Canada and several states have produced changes in these reported comorbidity rates. Given the high prevalence of both MDD and cannabis use, it is important to determine whether a relationship exists between the 2 phenomena.
Since the recent transition of cannabis from the black market to the legal market, there has been widespread information disseminated by the cannabis industries regarding the medicinal potential of the cannabis plant, including its potential for treating mental illness. However, the majority of the existing scientific research surrounding cannabis use and depression raises the potential harms that chronic cannabis use contributes to MDD.7 Recent epidemiological evidence from the NESARC study demonstrated that individuals with mental illness were more likely to exhibit problematic cannabis use and meet criteria for cannabis use disorder (CUD).6 Additionally, 2 separate cross-sectional studies have identified a 4-fold risk of developing depression in individuals using cannabis.8,9 However, studies utilizing cross-sectional designs carry limitations of potential confounders that limit the ability to determine causation. To address this aspect, a 2014 meta-analysis examined data from 14 longitudinal studies and found that cannabis use contributed an increased risk for developing depression (OR = 1.17, 95% CI), 1.05–2.30).10 A more recent meta-analysis emerged using data from 11 longitudinal studies and found adolescent cannabis consumption to be associated with an increased risk of developing depression (OR = 1.37, 95% CI, 1.16–1.62), suicidal behavior (OR = 3.46, 95% CI, 1.53–7.84), and suicidal ideation (OR = 1.50, 95% CI, 1.11–2.03).11 A recent prospective study examined varying levels of cannabis use on psychiatric symptoms in individuals diagnosed with MDD at 2 time points. The researchers found that cannabis use at the first time point (day 0) was associated with an increased number of depressive symptoms (ie, anhedonia, changes in body weight, insomnia, hypersomnia, psychomotor difficulties) at the second time point (day 28), but significance was limited by sociodemographic confounding factors.12 This study was unique in its examination of cannabis’ effects on symptom progression of MDD, and further studies in individuals with MDD are warranted using well-controlled designs to remove potential confounding factors and more accurately capture the effect.
Interestingly, similarities in neuroanatomical findings have been described in individuals using cannabis and in individuals diagnosed with MDD. Neuroimaging studies have demonstrated that regular consumption of cannabinoids, particularly Δ(9)-tetrahydrocannabinol (THC), results in a decrease in brain matter volume in regions that are dense in CB1 receptors, such as the hippocampus, prefrontal cortex, amygdala, and cerebellum.13 These structural changes are associated with earlier age of use and higher quantity of use, suggesting that cannabis use in adolescence may interfere with development and maturation of the brain.13 Similar decreases in brain matter volume have been found in the limbic and cortical regions of individuals with MDD.14
Taken together, the evidence is suggestive that chronic cannabis use may be harmful to individuals with MDD or increase the risk of developing MDD, but due to the reliance on epidemiological methods, it is difficult to establish causality and eliminate potential confounding variables. Thus, we aimed to design a research study to examine the state-specific effects of cannabis abstinence in individuals with MDD and CUD using a 28-day cannabis abstinence paradigm from a previous study.15 Our hypothesis was that participants who successfully abstained or reduced their cannabis use would experience clinically significant improvements in characteristic symptoms of depression such as mood, anxiety, and anhedonia.
MATERIALS AND METHODS
Participants were recruited through the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada via study flyers, clinician referrals, and online advertising. Eligibility was assessed through an initial telephone screen, followed by an in-person interview after written informed consent was obtained. The study was approved by the CAMH Research Ethics Board (REB, #2017–069). Recruitment began in January 2017 and ended in July 2019. The clinicaltrials.gov registration number was NCT03624933.
Both male and female participants between the ages of 18 and 55 were recruited for the study. The maximum age of 55 was set to minimize the potential effects of cognitive decline with aging.16 All patients met criteria for current CUD and a current major depressive episode (MDE) using the Structured Clinical Interview for DSM-5 (SCID-5-CV).17 Participants were sought out that had been on a stable dose of antidepressant medication for at least 1 month prior to enrollment in the study. The presence of a CUD was assessed via the Cannabis Use Disorder Identification Test (CUDIT) with a required score of >12 indicating moderate to severe CUD. A positive urine screen for 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol (THC-COOH) levels, a metabolite of THC detected in the urine, of at least 150 ng/mL was to confirm current and heavy cannabis use. Heavy use is defined by high frequency and quantity of use, however due to variation in cannabinoid products, specific quantities have not yet been established.18 Participants were required to achieve a Full-Scale Intelligence Quotient (FSIQ) score of ≥80 as assessed by the Wechsler Test of Adult Reading (WTAR). Current level of depressive symptoms were assessed via the Hamilton Depression Rating Scale (HDRS-17) ≥14 indicating a moderate severity depressive episode. Current suicidal ideation was exclusionary to protect patient safety and was assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) screener version.
Participants were excluded if they met criteria for diagnosis of any substance use disorder (SUD) in the past 6 months based on the SCID-5 (except cannabis, nicotine, or caffeine) or if indication of any illicit drug use other than cannabis based on the semi-quantitative urine test was found. Participants who have met criteria for a lifetime psychotic disorder or bipolar disorder as assessed by the SCID-5 were excluded from the study. The presence of an anxiety disorder was not exclusionary due to common overlap found with MDD. Participants prescribed medicinal cannabis that were using it to treat a medical condition were excluded. Finally, any neurological or medical condition that was deemed to affect cognitive function, such as a recent concussion, was exclusionary.
Participants were required to attempt 28 days of abstinence from cannabis, which was biochemically confirmed using weekly THC urinalysis. Upon successful 28-day abstinence, participants were eligible to receive a $300 contingent bonus. Participants attended weekly study visits and a 1-month follow-up visit that included urinalysis, clinical measures, and behavioral coaching sessions. Behavioural coaching sessions (20 minutes) were conducted by a research analyst in the lab and were designed to support successful abstinence. Figure 1 provides an overview of the study design.
Clinical measures were administered on a weekly basis throughout the intervention. Our primary outcome of interest was the interview-rated Hamilton Depression Rating Scale (HDRS-17), which was used to assess the severity of depressive symptoms overall. Anxiety was indexed using the self-report Beck Anxiety Inventory (BAI). Finally, anhedonia was measured using the self-report Snaith-Hamilton Pleasure Scale (SHAPS), which provides the degree of consummatory pleasure experienced.19 For all assessments, a higher score is indicative of more severe symptomology.
Substance Use Measures
The Enzyme Multiplied Immunoassay Technique (EMIT) semi-quantitative test was utilized at the screening session to identify any recent substance use other than cannabis. The EMIT test is able to identify the presence of cannabis, opioids, amphetamines, PCP, cocaine, and benzodiazepines. The NarcoCheck® THC PreDosage was administered at the screening session and weekly visits to monitor ongoing abstinence. This semi-quantitative urinalysis of THC-COOH, a metabolite of THC, has 5 detection levels: negative, low (25 ng/mL), medium (60 ng/mL) and high (150 ng/mL) and highest (600 ng/mL).
Self-reported cannabis use and substance use was assessed weekly using the Timeline Follow-Back (TFB), which determined the of frequency of cannabis, alcohol, tobacco, and caffeine use over the past 7 days. Cannabis withdrawal was assessed weekly using the Marijuana Withdrawal Checklist (MWC).
Biochemical Verification of Abstinence
Using the semi-quantitative NarcoCheck® THC PreDosage test, an endpoint THC-COOH indication of <50 ng/mL was used to confirm eligibility for the contingent reinforcement. However, final classification of abstinence for purposes of analysis was determined using a formula for examining the creatinine-normalized THC-COOH to identify any new incidences of consumption of cannabis.17,20
To obtain the creatinine-normalized THC-COOH, weekly urine samples of intervention completers were stored and sent collectively for gas chromatography-mass spectroscopy (GCMS) analysis, which provides a more sensitive THC-COOH concentration in the unit ng/mg that accounts for the level osmolality by assessing urinary Creatinine using the following formula:
After receiving the normalized THC-COOH value, ratios were calculated by dividing the most recently collected sample (U2) by the sample collected a week previous (U1).21 New cannabis use was identified given U2/U1 ≥ 1.5.
Data collected was analyzed using IBM's Statistical Program for Social Sciences (SPSS) Version 25. All tests were conducted with a significance level of <0.05 and the tests were two-tailed. Using F tests for MANOVA repeated measures, we conducted a power analysis for a medium effect size in change of depressive symptoms (d = 0.66) and determined a sample size of n = 11 would be required to achieve 80% power at a significance level of P = 0.05. This effect size was borrowed from a previous study conducted in our lab which assessed depression in a sample of comorbid schizophrenia and MDD using a comparable study design.22
Linear Mixed Models (LMM) were used to determine the effect that creatinine-normalized THC-COOH, as a time-varying covariate, had on clinical symptoms (depression, anxiety, and anhedonia) throughout the abstinence period.23 Repeated Measures Analysis of Variance (RM-ANOVA) was also conducted with time as a within factor to determine the trajectory of symptoms throughout the abstinence period. Additionally, the Fisher's Least Significant Difference (LSD) post hoc test was used to identify if any particular time points were statistically significant within the abstinence period. Assumptions of normality were tested for each variable and any adjustments that were required are reported, and for variables that failed the test of sphericity, Greenhouse-Geisser statistics are reported.
A total of N = 14 participants met eligibility criteria and were enrolled in the study. The attrition rate of the study was 21.4%, with a total of 11 participants completing the study, and 3 participants who were classified as dropouts after study baseline. Reasons for dropout included 2 participant self-withdrawals due to relapse and, 1 participant who suffered from chronic pain experienced suicidal ideation in addition to worsening of pain symptoms and was withdrawn from the study by the investigators for safety reasons. Dropouts from the intervention occurred at the week 2 time point.
Table 1 provides an overview of the demographic and clinical characteristics at baseline of the sample of enrolled participants including the dropouts using means and standard deviations. Participants demonstrated THC-COOH levels indicative of chronic and heavy cannabis use. The average HDRS and BAI scores were indicative of moderate depression and anxiety, respectively.
Abstinence Rates and Substance Use
Urine samples were collected from each study visit (11 participants x 5 session; N = 55) and analyzed using tandem GC-MS analysis by the CAMH Clinical Laboratory. Urine samples from the participant dropouts were collected and stored but were not analyzed. These values were used as a final classification of abstinence status. Based on the parent study which utilized the same abstinence paradigm in a sample of individuals with schizophrenia and non-psychiatric controls, we anticipated a relapse rate of 50%.17,24 Using the ratio calculations of the THC-COOH levels, it was determined that a total of 8/11 [72.7%] of intervention completers remained abstinent, while 3/11 (27.2%) relapsed. The ratio calculations also revealed that relapses occurred at week 2 of the intervention, however all participants including relapsers considerably reduced their cannabis use, and urinary data of relapsers indicates that they did not continue using cannabis after a single incidence of use at week 2. Additionally, it should be noted that the 3 intervention non-completers were not abstinent.
Figure 2 depicts the change in normalized THC-COOH/creatinine concentration throughout the duration of the study based on our quantitative analysis. The change in THC between baseline and week 4 overall was statistically significant at [F(1.073,9.660) = 18.348, P = 0.002]. However, there was no significant difference between the 2 groups based on abstinence status [F(1.073,9.660) = 0.241, P = 0.651].
Finally, 50% of participants at follow-up continued to maintain their abstinence. This was unexpected based on previous studies where participants typically revert back to their regular pattern of use.17
Cigarette smoking (F(1,52.926) = 2.663, P = 0.109), alcohol use (F(1,57.490) = 0.000, P = 0.984), and caffeine use (F(1,51.104) = 0.466, P = 0.498) as measured using the Timeline Follow Back did not exhibit a significant change over the 28 day abstinence period.
Cannabis Use Reduction on Clinical Symptoms
Change in THC was found to be significantly associated with change in the HDRS score over time (F(1,53.054) = 7.520, P = 0.008). The HDRS-17 demonstrated a 43.6% reduction in overall depressive symptoms from baseline to week 4. Significant main effects of time emerged for total symptom score of the interview-rated HDRS-17 depression scale (F(4,40) = 8.257, P < 0.001). These findings are depicted graphically in Figure 2.
In addition to the overall score, specific symptoms were examined for change throughout the abstinence period. Individual symptom items that emerged as significant and showed robust improvements on the HDRS-17 include low mood (F(4,40) = 3.649, P = 0.013), feelings of guilt (F(4,40) = 6.473, P < 0.001), motivation/work and interests (F(4,40) = 10.158, P < 0.001), and energy (F(4,40) = 2.954, P = 0.031).
There was a nonsignificant trend observed for THC reduction and reduction in the BAI score over time [F(1,51.804) = 3.567, P = 0.065]. The BAI demonstrated a 57.3% reduction in anxiety symptoms from baseline. However, significant main effects of time emerged for total symptom score of the self-reported BAI anxiety index, however a violation of Mauchly's test of sphericity emerged, and thus Greenhouse-Geisser statistics are reported [F(1.647, 19.471) = 5.121, P = 0.023]. Post-hoc analyses indicates a significant effect between the week 1 and week 2 time point [M = 6.091, P = 0.004].
The SHAPS assessment was added to the study after the first participant had completed, and therefore this analysis has been performed with data from 10 participants. Using the LMM, associations between THC reduction and reduction in the SHAPS score over time were significant [F(1,47.851) = 15.273, P < 0.001]. SHAPS demonstrated an 88.7% reduction from baseline. Significant main effects of time emerged for total symptom score on the SHAPS anhedonia index [F(4, 36) = 11.910, P < 0.001]. This finding is depicted graphically in Figure 3.
Using the RM-ANOVA, we found a statistically significant change in withdrawal severity over time based on the MWC, however a violation of Mauchly's test of sphericity emerged, and thus Greenhouse-Geisser statistics are reported [F(3.004,20.038) = 4.551, P = 0.023]. Post-hoc comparisons using LSD revealed that a significant increase in withdrawal severity occurred between weeks 1 and 2; [M = 6.364, P = 0.010].
Overall, the withdrawal symptoms rated as the most severe were depressed mood, strange dreams, sleep difficulty, and irritability. The symptoms rated as the most severe at week 4 were strange dreams, sleep difficulty, irritability and depressed mood.
The available literature that examines the effect of cannabis use on depression relies on epidemiological research, and largely focuses on the link between cannabis use and onset of depressive symptoms. There is limited literature related to the question whether changes in cannabis use alters symptoms of depression in individuals who are diagnosed with MDD. This study attempted to address this gap.
Consistent with our hypothesis a 28-day period of cannabis abstinence led to a significant reduction in overall depressive symptoms and particularly anhedonic symptoms. The most robust changes in specific depressive symptoms measured by the HDRS-17 were observed for low mood, feelings of guilt, motivation, and energy. To our knowledge, 1 other study has been conducted examining the effects of cannabis use in individuals with MDD. The results of that study were consistent with our findings, in that increased cannabis use at an initial time point was associated with more severe depressive symptoms.12
Anxiety was not found to be statistically associated with THC-COOH levels, despite the observation of a 57.3% reduction in anxiety severity throughout the intervention. We suggest that the observed reduction in anxiety was associated with another element of the study other than THC-COOH level reductions, such as reduced depressive symptoms or improved psychosocial functioning.
Participants’ final SHAPS scores were indicative of improvement of anhedonia at week 4 and an 88.7% reduction from baseline was observed. The most significant change in HDRS-17 symptoms occurred within the “work and interests” subscale, which is indicative of consummatory pleasure, motivation and interest. This finding complements our observed change in anhedonia, in that both measures highlight different levels of function involved in reward processing. There is clear evidence that elevated anhedonic symptoms are associated with lower motivation directed towards reinforcing stimuli, especially in the situation of higher effort tasks that lead to larger rewards.25,26 Therefore, cannabis may be contributing to depressive symptoms by producing impairments within the reward circuit and interfering with the individual's ability to form and attain long-term goals. Another potential mechanism by which the observed changes in anhedonia may occur lies within the endogenous opioid system, which has been found to play a mediating role in reward processing and has been found to have functional interactions with the endogenous cannabinoid system (ECS).27–29 Furthermore, experimental activation of κ opioid receptors has led to increased symptoms of depression and anhedonia.30,31 Taken together, it is possible that disruption of the ECS following chronic cannabis use leads to dysfunction in the opioid receptors involved in reward processing, which is reversed with sustained abstinence, contributing to the effect of reduced anhedonic symptoms.
This robust improvement in anhedonia is particularly significant in light of research which has established that high levels of anhedonia as a predictor of poorer depression outcomes, duration, and longevity of symptoms in MDD.32 Furthermore, symptoms of anhedonia have been found to persist after treatment with first-line pharmacotherapies.33 Thus, targeting problematic cannabis use in individuals that demonstrate severe symptoms of anhedonia may have important treatment implications in improving the overall depressive outcomes and response to validated treatments.
This study is the first of its kind to examine the course of cannabis withdrawal syndrome in a patient population with MDD. The course of withdrawal symptoms was consistent with previous reports, where a peak of withdrawal symptoms was observed at week 1 followed by a gradual reduction in severity.17,34 Sleep difficulty and strange dreams were the only symptoms that were rated as more severe at week 4 compared to baseline on the MWC. This finding is consistent with the literature in that sleep represents one of the most prominent and longest lasting features of cannabis withdrawal, with reports of sleep difficulties of up to 45 days post-cessation.34 Research involving cannabis use and sleep have had mixed findings, but indicates that short-term cannabis use may have a beneficial impact on sleep, where chronic cannabis use may lead to risk for dependence.35 Moreover, many cannabis users have reported using cannabis to help with their depression, however there has been a lack of clinical research data to support this indication.36
It should also be noted that this study is the first of its kind to utilize a prospective abstinence design to examine state-dependent effects of cannabis use on symptoms of depression, rather than the trait-effects of the population of cannabis users with depression as a whole as observed in epidemiological research. The outpatient laboratory setting of this longitudinal study allows for improved external validity, as participants are exposed to their home environment and are exposed to their normal drug cues. Despite this, participants still achieved high success rates of abstinence.
Several limitations of this study should be acknowledged. First, the lack of a randomized non-contingent or non-abstinent group for comparison limited the ability to account for any confounding factors within the study intervention that could have led to our clinical findings. Furthermore, this study had a small sample size. Future research including a control group and larger sample size is warranted to confirm result and confirm a causal relationship between cannabis abstinence and reductions in depression. A potential confounding factor could be the presence of antidepressant pharmacotherapy in the majority of our participants. However, the participants were assessed as moderately symptomatic despite being on stable antidepressant treatment for at least 1 month, and it is therefore unlikely that the remission of symptoms is due entirely to the presence of these medications. However, future studies should examine a sample of participants that are not being treated with antidepressant medication to enhance generalizability of the sample. Another concern is whether the behavioural coaching contributes to the clinical outcomes but based on previous research a low-intensity (20 minutes) behavioural intervention as used in our study has minimal effects.37 Additionally, urinalysis for dropouts was not conducted, and thus LMM analysis could not be performed for these individuals. These dropout participants exhibited baseline features of more severe and chronic use pattern of cannabis, and thus the intervention we provided may have been insufficient to provide them with the ability to successfully abstain.
In summary, the abstinence intervention was highly successful in a population of individuals with comorbid MDD and CUD. Cannabis abstinence and reduction allowed for significant improvements in depression and anhedonia scores. Additional improvements were observed in anxiety but were not statistically significant. Sleep difficulty was resistant to change, and some elements of sleep (ie, strange dreams, trouble falling asleep) worsened at day 28 compared to baseline. Our findings may have important clinical implications, including potential benefits of targeting problematic cannabis use in individuals with MDD, the importance of clinical monitoring throughout cannabis cessation, and the need to assess and treat sleep disturbance in this population.
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