Meta-Analysis Of Functionality In Current And Abstinent Cannabis Users

Cannabis is the most commonly used illicit drug worldwide, and legislative changes have been made in some parts to remove its controlled substance status. This is despite evidence to suggest cannabis’ association with adverse effects, such as decreased memory functioning, failure to hold attention and, most worryingly, the development of psychotic disorders. What alterations underlie the observation of these adverse effects is still poorly understood. The prolonged use of cannabis has been found to alter the activation levels and patterns in brain functioning activation, although robust evidence of this has been hard to obtain.

Previous investigations into functionality in cannabis users have been limited. Defining the levels of use, such as strength and regularity, is difficult, partly due to the legality of the substance. Studies using functional magnetic resonance imaging have generally had small sample sizes, limiting their power to draw more definitive conclusions due to cost. Meta-analysis has been used to overcome this by combining all studies of whole brain functional activation and has found cannabis users to have altered functionality compared to non-cannabis users (Blest-Hopley et al., 2018). Furthermore, the resilience of the changes that have been observed in cannabis users remaining past the point of which the drug has washed out of the system and a period of abstinence from its use has been maintained, is currently poorly understood.

Abstinence from cannabis use, at least to ensure that the main psychoactive component of cannabis (delta-9-teretrahydrocanabinol (THC)) is no longer detectable, can take up to four weeks in heavy users (Lowe et al., 2009). Interestingly, four weeks of abstinence does hold some consistency with the length of time it takes for task performance deficits in cannabis users, such as lower recall in a memory task, to become no longer detectable (Schreiner and Dunn, 2012). Could these cognitive improvements also represent a return to normal functioning following ceasing cannabis use long enough for the substance to be no longer detectable in the body? We aimed to address this in our study, using a meta-analysis of functional magnetic resonance studies to investigate the differences in current and abstinent cannabis users’ brain functioning.

Although in our study we added a number of cognitive tasks used by different studies together, this allowed us to investigate more broadly over all brain regions, as cannabis is likely to have an effect on regions specific to particular tasks and also more globally. Also, we know the main cannabis receptors are present throughout the brain (Iversen, 2003).

We combined whole-brain functional test results that compared cannabis users to non-users, splitting the study into two groups. One, current cannabis users, contained studies that lasted a maximum of 48 hours since the last use of cannabis by the participants; the second, abstinent cannabis users, had 25 days of abstinence and a negative screening for the presence of THC. We then compared all current users to non-using control groups, all abstinent users to non-using control groups, and, finally, current users to abstinent users. The latter was carried out again separately using only adolescent studies in both groups, as to-date, no current studies matching our criteria using adult abstinent cannabis users exists.

We found that abstinent cannabis users still had altered functioning compared to non-using controls in regions of the brain that are involved in Central Executive Functioning; these regions are responsible for higher ordered thinking, such as memory and attention. They also had altered functioning in the Default Mode Network, an area active when the brain is not focused on performing a task. Interestingly, all activation observed occurred during engagement with a cognitive task. When we compared current and abstinent cannabis users of the same age group (adolescents) we found no significant differences in activation between them.

Our results could demonstrate that some changes in brain functioning are comparatively more permanent, however, these may alter after much longer periods of abstinence, and the permanency in adult users may not be the same. These changes were observed in adolescents. The adolescent period is when the brain is evolving and rewiring, therefore, could cannabis use during this period cause more permanent harm? Although we were limited in our study by the number of papers available and our results are largely only interpretable for adolescent users, these results underscore adolescent vulnerability to drug-induced neurological changes that remain after the drug has been excreted from the body.

We have discussed the observation of functional differences as caused by cannabis use, but could they be a consequence of it? Do neuro-functioning differences seen in cannabis users pre-exist cannabis use, making those people more likely to become users? Much more research is required of bigger and better-defined cannabis-using populations, as well as studies linking genetics or assessing the neuro-functional changes seen over time compared to cannabis use to address causality.

One thing our study certainly highlighted is the lack of current studies addressing neuro-functional changes in cannabis users; the permanency of those changes, particularly after drug use has ceased; and, most importantly, what the consequences of those are on cognition and mental health. Recent evidence has further implicated cannabis use and the role of THC in the development of psychotic disorders (Di Forti, 2019) (who also present with disordered functioning of central executive and default mode networks (Buckner, 2013)). We are still in the infancy of fully understanding the long-term consequences to neuro-functioning following the use of cannabis.

References:

1. Blest-Hopley, G., Giampietro, V., Bhattacharyya, S., 2018. Residual effects of cannabis use in adolescent and adult brains – A meta-analysis of fMRI studies. Neurosci Biobehav Rev 88, 26-41.
2. Buckner R. L., 2013. The brain’s default network: origins and implications for the study of psychosis. Dialogues in clinical neuroscience, 15(3), 351–358.
3. Di Forti et al, 2019. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. The Lancet Psychiatry.
4. Iversen, L., 2003. Cannabis and the brain. Brain 126, 1252-1270.
5. Lowe, R.H., Abraham, T.T., Darwin, W.D., Herning, R., Cadet, J.L., Huestis, M.A., 2009. Extended urinary Delta9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug Alcohol Depend 105, 24-32.
6. Schreiner, A.M., Dunn, M.E., 2012. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol 20, 420-429.