Associations of the MRI outcome measures with measures of neurocognitive test performance used Pearson’s correlations.In this cross-sectional volumetric MRI study, one-monthabstinent alcohol dependent individuals without current psychostimulant dependence , ALC individuals with current dependence on at least one psychostimulant ,and drug-free LD differed significantly on regional GM and WM volumes normalized to ICV: PSU had significantly larger lobar WM volumes than LD and ALC, whereas ALC showed no regional WM volume differences compared to LD. GM volumes in PSU were lower only in the temporal lobe, thalami and lenticular nuclei compared to LD. In ALC however, most lobar cortical GM volumes, thalamic GM, and total cerebellar volume were significantly smaller than in LD. Consistent with these tissue volume differences, sulcal CSF volumes of the frontal and temporal lobes in PSU were smaller than in both ALC and LD. All effect sizes for the significant WM differences between PSU and LD or ALC were greater than 0.50, indicating moderate to-large magnitude group differences. Parietal WM volume in PSU correlated positively with prior year cocaine use, suggesting a substance-relatedparietal WM volume expansion. Frontal,parietal,mobile vertical rack and total cortical GM volumes were associated with some critical neurocognitive domain measures in both PSU and ALC, but not in LD. These neuroimaging abnormalities may serve as poly substance abuse biomarkers and as potential targets for pharmacological and behavioral PSU-specific treatment aimed at decreasing the high relapse rates in PSU.

MR-based structural neuroimaging of individuals with different substance use disorders have yielded mixed findings regarding brain tissue volume alterations. Smaller WM volumes , particularly of the frontal, temporal and cerebellar regions relative to drug-free controls were reported in middle-aged active and abstinent users of cocaine and cannabis . A few reports showed similar WM volumes in active or abstinent users of these substances compared to controls . However, enlarged volumes or density of frontal, temporal, and sub-cortical WM were reported in active amphetamine users and in amphetamine users in both early and long-term abstinence . Here, we found larger WM volumes in one-month abstinent PSU compared to both LD and one-month abstinent ALC. Our PSU cohort was dependent on alcohol , cocaine , and methamphetamine . When the four PSU individuals with methamphetamine dependence were removed from the entire PSU sample, all WM volumes remained significantly larger compared to LD or ALC. This observation, together with the positive correlation of parietal WM volume with cocaine use quantities in the PSU suggests that, the larger WM volumes in our PSU cohort were not driven simply by methamphetamine dependence in the PSU group. Larger WM volumes in recently abstinent methamphetamine users were postulated to be a result of tissue inflammation and/or reactive astrogliosis as a response to tissue injury sustained from the chronic substance abuse . A dose-related enhancement of neurological and histological signs of acute encephalomyelitis following in vivo administration of amphetamine or cocaine in rats was described . Also, in rats administered with cocaine daily for 7 days, increases in glial fibrillary acidic protein and vimentin expressions, the hallmarks of reactive astrocytes and reactive gliosis , were observed in the prefrontal cortex and nucleus accumbens at 3 weeks after substance administration . These findings support the theory of brain tissue enlargement due to reactive astrogliosis. Therefore, it is not out of context to interpret the observed larger lobar WM volumes in our PSU cohort as inflammation and/or glial scarring associated with reactive astrogliosis observed at one month after withdrawal from chronic consumption of both alcohol and illicit substances.

Results of quantitative MRI-based regional GM volume/density in individuals, who purportedly depended on or abused primarily a single drug, have been inconsistent. Some cross-sectional studies reported smaller regional GM volumes/densities in both active and abstinent users of cocaine , cannabis , methamphetamine and heroin compared to controls. Others reported larger GM volumes/densities in cocaine dependent individuals , cannabis abusers and methamphetamine abusers compared to controls; and yet others found no effects of chronic cannabis misuse on brain morphology . On the other hand, while previous reports on the effects of PSUD on brain GM volumes are sparse, they are at least consistent: GM volumes were reduced compared to age-matched drug-free controls in prefrontal and temporo-parietal cortices of active cocaine dependent individuals, many of whom were dependent also on other drugs , in the orbitofrontal cortex of poly-substance abusers abstinent for at least 15 days , and in prefrontal cortex of poly-substance dependent individuals abstinent for more than 2 years . This suggests GM atrophy in active, short-term and long-term abstinent poly-substance users. We found appreciable GM volume loss in our one-month-abstinent PSU only in the temporal cortex, lenticular and thalamic GM. The apparent “normal” frontal and parietal cortical GM volume in our PSU sample could be the result of reactive astrogliosis described above , or where GM loss is offset by a neuroadaptive response to the need for greater cognitive control over substance use . The discrepancies between regional GM volume findings from our PSU participants and those of the previous studies could relate to the differences in age , the duration and type of drugs used, and/or the duration of abstinence: i.e., the younger cohorts in the previous studies could have been less prone to brain inflammation from chronic substance use, brain inflammation may not be present in active users or in poly-substance abusers abstinent for a few weeks , or brain inflammation could have subsided after 2 years of abstinence .

However, this is speculative and can only be tested in longitudinal studies of abstinent poly-substance users: if our speculation/interpretation were correct, the observed GM differences – and particularly the larger WM volumes – should diminish with duration of abstinence as the substance withdrawal-related inflammation subsides over time. Such a dynamic change has been suggested in abstinent methamphetamine users . Methodological issues in studying brain effects of poly-substance dependence with relevance to the above discussion were recently reviewed . Larger ventricular and lobar CSF volumes have been reported consistently in short-term abstinent and active AUD individuals compared to controls . However, our findings showed smaller CSF spaces in PSU compared to ALC with similar drinking severities or controls, possibly compensating for the larger lobar WM volumes within the physical confines of the skull. Whereas both Ersche papers showed larger sub-cortical GM volumes in currently using PSUD individuals, our abstinent PSU patients had smaller lenticular and thalamic GM as well as normal caudate, cerebellar and brainstem volumes. As the authors speculate that some of these increases may reflect a compensatory response to reduced dopamine neurotransmission, this may have normalized in our abstinent PSU sample. Our study has limitations: the substance dependent cohort was treatment-seeking and abstinent at time of study, and it included only a few female participants. Our findings may therefore not generalize to female or treatment-naïve substance dependent individuals. The variance of the sub-cortical volume measures obtained with our automated segmentation method is larger than that shown in manually outlined structures of cocaine dependent individuals , which might have made it impossible to detect small group differences.Thus, our lobar outcome measures lack functional specificity, which likely contributed to the few correlations with neurocognitive measures. Finally, we did not screen participants for DSM-IV Axis II disorders, such as antisocial personality disorders , nor did we measure potential group differences in nutrition,vertical grow rack exercise and genetic predispositions. All these conditions may also influence brain morphometry and should ideally be considered in future studies of both treatment-naïve and treatment-seeking individuals with well defined dependence on alcohol and illicit substances. To address the issue of regional specificity of volume changes within the relatively large lobes and to increase the functional relevance of such measures, reliable segmentation and examination of small brain regions or of the cortical ribbon may be needed, such as provided by whole-brain voxel-based morphometry and cortical thickness measures . These limitations notwithstanding, our neuroimaging study reveals gross brain structural differences between PSU and ALC that may have implications for different treatment approaches of poly-substance dependence and alcohol dependence. The findings complement previous neuronal and glial differences we detected in the frontal lobe of these substance dependent groups . Here, we confirmed commonly reported smaller lobar GM and cerebellar volumes and more sulcal CSF in one-month-abstinent middle-aged ALC compared to age-matched LD. However, these volume measures were largely unaffected in one-month-abstinent alcohol dependent PSU. Furthermore, PSU had larger lobar WM volumes than both ALC and LD. The larger WM and the lack of apparent GM volume loss in PSU, despite a very long drinking history similar to that of ALC who showed marked cortical GM volume loss, suggest hypertrophic processes in short-term abstinent PSU, perhaps astrogliosis associated with neuro-inflammation. These processes may mask underlying cortical GM tissue loss associated with chronic poly-substance misuse.Many meta-analyses and reviews have been published in recent years.

Studies of cannabinoid efficacy vary greatly: some have tested whole-leaf marijuana ; others assess isolated compounds such as THC, or known/controlled combinations of plant-derived products , and some study only synthesized products like nabilone. These differences make comparisons difficult. A recent Cochrane-style review looked at the quality of evidence supporting the use of cannabinoids in CINV, as appetite stimulant in HIV/AIDS, in chronic pain, spasticity from MS or paraplegia, depression, anxiety, sleep problems, psychosis, glaucoma, or Tourette’s syndrome. Seventy-nine randomized trials involving 6462 patients were identified. Moderate quality evidence supports the use of cannabinoids for chronic pain and spasticity. Low quality evidence supports the use of cannabinoids for CINV, wasting, sleep problems, and Tourette’s syndrome. Many other uses of cannabinoids are rationalized based on cultural traditions, small case series, open label trials, anecdote, or opinion. The American Academy of Neurology completed its own recent review and concluded that cannabinoids, particularly nabiximols, provide small benefits for patients with MSrelated spasticity, central pain, and urinary symptoms but shows little evidence of efficacy for other neurologic conditions.Orrin Devinsky, a leading U.S. investigator in the useof CBD for treatment-refractory pediatric epilepsy, has published an open-label trial showing some efficacy that warrants randomized controlled trials. The already-mentioned National Academies monograph draws nearly identical conclusions to those above. Readers are referred to it for a comprehensive review of the evidence. There is also interesting preclinical data suggesting that cannabinoids may have a role in reversing opioid-associated hyperalgesia,may reduce craving and relapse risk in opioid dependence,and could help prevent or treat chemotherapy induced peripheral neuropathic pain.There is emerging, equivocal data regarding whether cannabinoids improve quality-of-life and reduce symptom burden or disease activity in inflammatory bowel disease.In a recent review of the common indications for use listed in state cannabis regulations, Alzheimer’s disease, amyotrophic lateral sclerosis , cachexia, cancer, Crohn’s/ inflammatory bowel disease , epilepsy, severe/chronic pain, glaucoma, hepatitis C, HIV/AIDS, MS, and post-traumatic stress disorder appear regularly. This listing suggests the degree to which state guidelines depart from, and generally exceed, evidence-based uses, and in turn the degree to which lawmaking may be influenced by popular beliefs or political processes. For the palliative care practitioner, these efficacy data are complicated not just by the generally low volume of only moderate quality evidence, and by state regulations that regularly depart from that evidence, but also increasingly by the growing reach of our field beyond cancer and HIV into the realms of adult degenerative diseases of the central nervous system, heart, lung, liver, digestive tract, and to serious non-cancer childhood disorders.As the National Academies monograph and other recent excellent reviews suggest, recreational use of cannabinoids is particularly concerning in young people with still-developing brains, persons with preexisting mental illness, and those with existing substance abuse problems. In these populations regular cannabis use can unmask or hasten the onset of psychotic illness, is associated with reduced IQ, addiction/dependence, and a withdrawal syndrome. Other widely recognized sequela of regular/chronic use include dropping out of school, decreased motivation, socialization, and life-satisfaction, and chronic bronchitis. Other than bronchitis, the data regarding respiratory consequences of cannabis consumption are equivocal. Inhaled cannabis does NOT appear to confer increased risk for lung cancer or head and neck cancer. The data on marijuana use and cardiac disease have not shown compelling evidence for concern.