A method to achieve extended cannabis abstinence in cannabis dependent patients with schizophrenia and non-psychiatric controls
Introduction
As more countries legalize cannabis, its use is becoming less stigmatized (Berg et al., 2015, Hall, 2015, SAMHSA, 2013). This may translate into more liberal use and increased rates of problematic cannabis use (Hasin et al., 2015, Johnston et al., 2012). While cannabis use disorders (CUD) in the general population are low (~ 3%) (UNODC, 2013), they are higher among psychiatric populations, including schizophrenia (~ 25%) (Koskinen et al., 2010).
There has been considerable work to better understand effects of cannabis in schizophrenia, with a strong emphasis on individuals with chronic use. Most studies attempting to characterize consequences of cannabis use have employed cross-sectional designs (Rabin et al., 2011), prohibiting firm conclusions regarding direct and causal effects of (non-acute) cannabis use. Thus a method using a longitudinal design may parse within-subject differences to determine changes in cannabis use over time. Accordingly, sustained abstinence among regular cannabis users may represent a robust magnitude of change in use and determine if effects of cannabis are permanent or reversible. However, a major limitation is failure to ensure that long-term effects of cannabis are not attributable to residual cannabinoids.
The primary psychoactive constituent of cannabis is delta-9-tetrahydrocannabinol (THC), which is largely responsible for psychoactive effects of the plant. Unlike other drugs of abuse, cannabis can accumulate in lipophilic compartments, resulting in the presence of metabolites long after cessation of cannabis use (Goodwin et al., 2008). THC is slowly re-released into blood, metabolized to carboxy-THC (THC-COOH), an inactive metabolite, and then excreted in urine (Hunt and Jones, 1980). Chronic users require up to 28-days for complete cannabinoid elimination using a urinary THC-COOH cut-off of 20 ng/mL (Ellis et al., 1985, Goodwin et al., 2008, Smith-Kielland et al., 1999). Urinalysis is the most common method of drug testing for determining psychoactive substances. Urine immunoassay tests detect THC-COOH at concentrations ~ 50 ng/mL (Huestis et al., 1995). The long excretion half-life of THC-COOH makes it difficult to discern the timing of last drug exposure. Therefore, results from a single urine test may not confirm sustained abstinence in the initial period post-abstinence.
Gas chromatography-mass spectrometry (GC-MS) is a method for quantifying metabolite levels allowing for normalization of THC-COOH concentrations to urinary creatinine, controlling for hydration status (Lafolie et al., 1991). Furthermore, using ratios calculated from two sequential creatinine-normalized urine specimens (Urine2/Urine1) distinguishes whether new cannabis was introduced versus residual cannabinoids (Manno et al., 1984, Schwilke et al., 2011, Smith et al., 2009). Manno et al. (1984) proposed new cannabis use was indicated if the ratio of creatinine normalized THC-COOH concentration (ng/mg) of a later specimen to an earlier specimen was ≥ 1.5. Subsequently, Huestis et al. (1995) demonstrated more precise differentiation between new cannabis and residual cannabinoid excretion occurred if this ratio was > 0.5. However, applying single ratios to data may yield either unrealistically low re-use rates, or unrealistically high re-use rates. As such, a recently published model predicts re-use of cannabis in chronic users more accurately by accounting for the time interval between urine specimens and initial cannabinoid concentrations (Schwilke et al., 2011). Extended cannabis abstinence does not imply a cannabis-free state; thus when evaluating long-term effects of cannabis on sensitive outcomes (e.g. cognitive function), investigators must ensure cannabinoids have been reduced to negligible levels (i.e. urinary THC-COOH < 20 ng/mL).
While biochemical analysis is pertinent for determining abstinence, inclusion of self-reported and clinical data may be used in conjunction to support objective data as well. For example, cannabis withdrawal syndrome is a time-dependent, pharmacologically specific phenomenon associated with a constellation of clinically relevant symptoms (e.g. anxiety, depression, sleep and appetite disturbances) (Budney et al., 1999, Copeland et al., 2001, Kouri and Pope, 2000). Withdrawal symptoms appear ~ 24 h after abstinence initiation, peak within the first week and then gradually decrease over the following three weeks (Allsop et al., 2011, Budney et al., 2004).
Therefore, in the current study, we assessed a method to achieve sustained cannabis abstinence and metabolite elimination over a 28-day period in cannabis dependent patients with schizophrenia and non-psychiatric controls using contingency management (CM). CM is a well-established behavioral intervention for changing substance-using behaviors (Higgins et al., 1991) including cannabis (Schuster et al., 2016). We addressed the following questions:
- (a)
Is the proposed abstinence paradigm effective at producing sustained cannabis abstinence across 28-days?
- (b)
Is this paradigm able to distinguish individuals who are able to abstain from those who relapse?
- (c)
Is this paradigm feasible for patients with schizophrenia?
Section snippets
Participants
Patients with schizophrenia were recruited through outpatient programs of the Centre for Addiction and Mental Health (CAMH) using flyers and through referrals made by outpatient staff. Non-psychiatric cannabis users were recruited from the community by posted advertisements. Study eligibility was assessed by telephone screening, followed by an in-person comprehensive interview. Recruitment occurred between April 2012 and December 2015.
Written informed consent was obtained from all participants
Sample demographics
Nineteen cannabis dependent patients with schizophrenia and 20 cannabis dependent controls completed the study. Demographic and clinical variables are presented in Table 1. Patients with schizophrenia and non-psychiatric controls did not differ significantly on age, race, nor on substance-using variables. Controls had a higher IQ [t(37) = − 3.64, p < 0.01] and a greater number of years of education compared to patients [t(37) = − 3.45, p < 0.01].
Self-reported abstinence
Weekly subjective data from the TLFB-cannabis, demonstrated
Discussion
The goal of this study was to determine the feasibility of a 28-day abstinence paradigm in cannabis dependent patients with schizophrenia compared to non-psychiatric controls using CM. Using this abstinence design, we were successfully able to distinguish individuals who were able to abstain from cannabis use from those who relapsed. Accordingly, we observed that biochemically-verified abstinence rates were comparable between patients and controls, 42.1% and 55% respectively. That is, by study
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