Albert Stuart Reece - Medical School, University of Queensland

 

Ph: 61738444000

 

FAX: 61738444015

 

Email: sreece@bigpond.net.au ; asreece@bigpond.net.au  .

 

Conflicts of Interest – Nil.

 

Word count (excluding abstract and references): 2862

 

Word count (Abstract): 244

 

Keywords – 

 

Cannabis, psychopathology, respiratory pathology, psychosis, depression, chronic bronchitis, chronic asthma, genotoxicity, oncogenesis

 

Abstract

 

Introduction. Cannabis is the most widely used illicit drug worldwide.  As societies reconsider the legal status of cannabis, policy makers and clinicians require sound knowledge of the acute and chronic effects of cannabis. This review focuses on the latter.  Methods.  A systematic review of Medline, PubMed, PsychInfo, Google Scholar using the search terms “cannabis”, “marijuana”, “marihuana”, “toxicity”, “complications,” and “mechanisms” identified 5,198 papers.  This list was screened by hand and papers describing mechanisms and those published in more recent years were chosen preferentially for inclusion in this review. Findings. There is evidence of psychiatric, respiratory, cardiovascular and bone toxicity associated with chronic cannabis use.  Cannabis has now been implicated in the aetiology of many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state. Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis.  Cannabis has been linked in a dose dependent manner with elevated rates of myocardial infarction and cardiac arrythmias.  It is known to affect bone metabolism and also has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including in children after in utero maternal exposure, and multiple molecular pathways to oncogenesis exist.  Conclusion.  Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular and bone effects. It also has oncogenic, teterogenic and mutagenic effects all of which depend upon dose and duration of use. 

 

Introduction

 

According to the United Nations Office of Drugs and Crime there are some 165 million users of cannabis worldwide, making it the most widely used illicit drug. 1 This review examines the psychiatric, respiratory, cardiovascular and bone effects associated with chronic cannabis use and the neurodevelopmental, genotoxic, mutagenic and oncogenic effects of cannabis.

 

Methodology

 

A systematic review of Medline, PubMed, PsychInfo, Google Scholar, Scopus, Proquest, Web of Knowledge and EbscoHost using the search terms “cannabis”, “marijuana” or “marihuana” identified 14,065 papers, excluding duplicates.  When the search terms “toxicity”, “complications,” and “mechanisms” were added, the list narrowed to 5,198 papers.  This list was screened by hand and original papers describing mechanisms and those published in more recent years were chosen preferentially.  Review papers are cited where appropriate to introduce a large or detailed field for the interested reader.  Few case reports are included and they are specifically flagged where they occur; those that are cited have been included largely because they suggest important pathophysiological mechanisms.

 

Psychiatric and social disorders

 

An authoritative meta-analysis of cannabis related psychopathology has been published, 2 with an accompanying editorial. 3  Another review found an elevated risk of psychosis in many studies, with a odds ratio of about 2.3. 4  A similar meta-analysis from the Netherlands found a pooled O.R. for psychosis of 2.1. 5 Several studies from diverse cultures have confirmed the elevated risk of psychosis and schizophreniform spectrum disorders 5-17 following high levels of cannabis use, particularly when cannabis consumption has commenced at a young age. 14, 18  Cannabis use has been found to exacerbate pre-existing psychotic disorders. 5, 15

 

There is a similar and increasing literature around both bipolar disorder 19-21 and depression. 22, 23,24, 25  Although the psychoneurological effects of cannabis are usually stereotypically characterized as a depressant, both its use and the withdrawal state is accompanied frequently by psychomotor agitation, which has been implicated causally with inter-personal violence. 26  Interestingly, in a series of forensic examinations of suicide, cannabis use was associated with the most violent means of death, particularly severe motor vehicle accidents. 27

 

In 1972 Nahas28 drew attention to the devastating effects of cannabis in Egypt as quantified by carefully prepared and formally psychologically documented surveys from that country.  Higher levels of anxiety, impaired memory, poor concentration, impaired learning ability, psychomotor impairment including reduced quality and quantity of work, were seen in these users. In addition, a common dependency syndrome was observed which made exit from the dependent state both difficult and rare.28  Geographical micro-clustering of cannabis use has been demonstrated which has the effect of establishing local socially normative use patterns. 29  Both in Northern Africa and in New Zealand communities exist where cannabis use is common and intellectual impairment, psychomotor slowing, poor work capacity, and severe social deprivation are entrenched. 30-32

 

Lee and colleagues33, 34 have published several descriptions of heavy, problematic and refractory cannabis use in remote indigenous communities of the Northern Territory and across northern Australia more generally.  A substantial proportion (31-62%) of users’ median weekly income, and up to 10% of the total community income was spent on cannabis.  Ninety per cent smoked cannabis heavily (more than six cones daily) and were not able to cease use.  Severe mental illness was commonplace, as were depression, suicidal ideation, auditory hallucinations and imprisonment.  There was less participation in employment, education or training.  Community violence escalated when cannabis supplies from distant centres were interrupted.  Most users had not “matured out” of dependent cannabis use even five years later.  It is particularly noteworthy that these same communities had largely successfully defeated alcohol abuse, primarily by tightly restrictive policies aimed at severely curtailing alcohol supply.  The authors concluded that cannabis was both an important cause and a consequence of ongoing severe social disadvantage and deprivation. 

 

Respiratory effects

 

Both the Thoracic Society of Australia and New Zealand 35 and the British Lung Foundation 4 have issued major statements in recent years acknowledging the known deleterious effects of cannabis on the lungs.  Cannabis is smoked differently from tobacco. Users commonly inhale deeply to a maximal breath and then retain the smoke in the lungs, which generates higher pressures during breath holding and on expiration. 35-37

 

Cannabis smoke stimulates inflammation in the airways so that its long-term use is associated with the development of chronic bronchitis. A New Zealand study 38  demonstrated large airways inflammation and obstruction and hyperinflation, but was seldom associated with macroscopic emphysema, with a dose equivalence of one cannabis joint to 2.5-5 cigarettes. These findings were supported by an accompanying editorial.39, 40 Decreased lung density has also been noted with increased lung volumes, signs of destruction of lung tissue, cyst formation and emphysematous change with secondary pneumothorax due to bullous rupture. 41-43 

 

Cannabis smoke is known to contain several potent carcinogens including anthrocyclines, nitrosamines, polycyclic aromatic hydrocarbons, terpenes and vinyl chloride. 4, 35, 44-47  As a consequence, cannabis use is associated with cancer of the lung.30-32

 

Cardiovascular effects

 

Cannabis exposure is known to cause phasic systemic vasodilation, mild hypertension and tachycardia often associated with postural hypotension, and a reduced duration and increased heart rate response to exercise.48-51   Some but not all of these effects are mediated by the autonomic nervous system.  Tolerance appears to many of these acute effects with time.  In most young healthy patients such changes are clearly generally well tolerated,48, 50 but this is not universally true and several exceptions cited below are of considerable pathophysiological interest.  Such generic reassurances cannot be provided to patients with pre-existing coronary or atherosclerotic disease. 50, 52

 

Several case reports associate cannabis use with infarctions of kidney,53 brain,54-60 heart61-65 and digits,66, 67 and of priapism in a man with sickle cell disease. 68  An association between cannabis use and pedal gangrene has also been described in a 27-year-old. 67   Some 50 cases of cannabis arteritis have been reported in the literature.67  Cannabis use can acutely trigger myocardial infarction69 which has also been documented in a 25-year-old man with no other cardiac risk factors and normal coronary arteries at angiography.62  Coronary no-flow phenomenon has been observed after acute cannabis use.57  Cardiomyopathy has also been reported in a young man.70  One large study of 1913 adults conducted in the US found both a significant association between myocardial infarction and cannabis use, and a dose response effect, with adjusted hazard ratios of 2.5 and 4.2 for less than weekly and weekly use respectively.52 

 

Reversible cerebral vasospasm 71 as well as slowing and flow reversal in the middle cerebral artery 72  has also been documented and attributed to cannabis use, Contrariwise, the same authors also reported an increase of blood flow in the cerebral frontal lobes.73  Several case reports have described a cannabis associated inflammatory angiitis,61, 74, 75 which can be so severe as to mimic Buerger’s disease (thromboangiitis obliterans or “disappearing artery syndrome”).

 

In a study in 19 patients, alterations of the cardiac pressure cycle were found with a highly significant prolongation both of electromechanical systole (by 17 msec) and left ventricular ejection time, in the context of a reduced pre-ejection period (systolic pressure upstroke), a tachycardia of 132 bpm and unchanged brachial systemic pressures.76  These more abrupt cardiac pressure changes imply increased cardiac work in the context of a prolonged QTc interval and reduced opportunity for myocardial perfusion (the “Buckberg index”) which is limited to the diastolic phase of the cardiac cycle.77, 78  Hence this scenario combines both an adverse mechanical and electrical profile in the context of reduced coronary perfusion, and an altered endothelial, coagulation, angiogenic79 and inflammatory milieu. 

 

Cannabis has also been linked with elevated rates of cardiac arrhythmias in several case reports.80  Generally these are supraventricular and trivial,81-83 but well documented cases of lethal ventricular arrythmias do exist57 and one such was recently reported from a man who survived, and whose episode was recorded on his implantable defibrillator.84 

 

Elevated plasma concentrations of the endocannabinoid 2-arachidonylglycerol status have been associated in an Italian study of 62 patients with an exacerbation of the cardiovascular risk profile with worse concentrations of total cholesterol, HDL-cholesterol, body mass index, intra-abdominal obesity, and adiponectin. 85 

 

Bones

 

Cannabinoid receptors are present on bones. Physiological studies have shown that cannabinoids have an important role in the regulation of bone density;86 blockade or modulation of CB1 cannabinoid activity protects from bone loss.87  Heavy cannabis use in humans is associated with substantial bone loss.54  Interestingly, CB2 stimulation appears to be causally associated with stimulation of both endosteal and periosteal bone growth by mechanisms involving inhibition of osteoclastogenesis, osteoblast stimulation, favourable modulation of the RANKL (receptor activated NF-kB ligand) – osteoprotegerin system, matrix metalloproteinase inhibition, inhibition of adrenergic sympathetic signalling to bone and inhibition of bone marrow monocyte-directed haemopoiesis88-99 (the bone marrow derived monocyte is believed to be the immediate precursor of the multinucleate osteoclast).  Cannabis use is also known to be associated with profound loss of alveolar bone from the jaws,100-103 often in the context of severe erosive periodontitis.104, 105 

 

Maternal cannabis use and fetal development

 

Not all the studies in this field have returned results confirming a link between maternal cannabis use and later deleterious changes in the offspring. 106   However, maternal cannabis use has been shown to reduce body weight at birth. 107  Many birth abnormalities were identified in a large Hawaiian sample over six years.  Of 54 birth defects studies, 39% were noted in cannabis exposed babies. 108  Many of these defects were major and involved the brain (encephalocoele, hydrocephaly, microcephaly, anophthalmia / microphthalmia), cardiovasculature (tetralogy of Fallot, VSD, ASD, and right and left heart atretic syndromes), gastrointestinal system (pyloric stenosis, intestinal atresias and stenoses and gastroschisis) and limbs (polydatyly, syndactyly and reduction deformities of the upper and lower limbs); oro-facial clefts were also reported.   One large American study found a somewhat elevated risk of anencephaly (O.R. = 1.7, C.I. 0.9-3.4). 109 The association with gastroschisis has been confirmed by other investigators. 110

 

The dominant theme to emerge from studies of perinatal exposure is that of impaired executive cortical functioning reflected in reduced attention and analytical behaviour, and visuospatial analysis and hypothesis testing, 111 parent rated behavioural problems, language comprehension, distractibility 112 inattention, hyperactivity, impulsivity and substance use disorders. 113 Indeed, close agreement between human and animal studies of perinatal exposure has been shown. 113  Such changes emerge from as early as the first weeks of life and persist in children in longitudinal studies into the school ages.  Importantly, cannabis seemed to potentiate other causes of disadvantage such as smoking, low protein nutrition, and early age of first maternal pregnancy, and child sexual abuse implying that cannabis use by disadvantaged groups compounds other functional deficits. 112, 114  Lower school age child IQ was also noted in another large longitudinal follow-up study. 115  It is important to note however that such reductions in intellectual performance, executive function, memory, sustained attention and verbal ability are also seen in samples of low risk upper middle class children of school age. 116 Equally it is important to note that careful studies controlling for such pertinent confounding psychosocial variables find strong persistent effects of cannabis exposure. 117

 

Maternal prenatal cannabis use has been found to predict later cannabis use during adolescence both as age of onset and frequency of use, a relationship which persisted after adjustment for many other risk factors. 118 

 

Genotoxicity, mutagenicity and oncogenesis 

 

Cannabis use is associated with cancer of the lung30-32 (O.R. = 2.3, 4.1, 5.7), head and neck44, 119 (O.R. = 4.1, 2.6, 3.1), larynx (O.R. = 1.7, 2.3) prostate (O.R. = 3.1)120, cervix (O.R.=1.4)120, testes (O.R. = 1.7)121 and brain (O.R. = 2.8).122  Cannabis has also been linked with tumours of the urothelial tracts.123-125   Several authors have also found evidence of a dose response relationship, either with dose, duration, or the combined life time total duration of cannabis consumption.31, 32, 44, 126   A report from Tunisia showed an eight-fold rise in lung cancer risk, but initially did not demonstrate a dose-response relationship; tobacco is frequently mixed with cannabis in that country.30  A later expanded revision of these data from the same area in northern Africa was able to demonstrate a relationship with the total dose-duration of cannabis exposure. 126 

 

Of great concern is the evidence of inheritable tumours such as childhood neuroblastoma (O.R. = 1.8, 4.7),127 rhabdomyosarcoma45 and leukaemia (O.R. = 11), particularly non-lymphoblastic leukaemia,128 in cannabis exposed pregnant mothers. 

 

It should be noted that not all epidemiological studies have been positive,129 with some studies failing to demonstrate such a link, possibly because cannabis exposure in the study population was limited.45 For example, a study conducted in Los Angeles did not observe an association with lung cancer, which the authors attributed to the relatively few cases exposed to significant amounts of cannabis.130  Similarly, a New Zealand study of head and neck cancer was recently found to be negative, a finding attributed by the authors to uncontrolled confounding and inadequate sampling of the New Zealand population. 129 

 

Cannabinoids liberate radical species both at receptor binding (nitrogen centred species 131-133 ) and by uncoupling mitochondrial oxidative phosphorylation via stimulation of the matrix protein uncoupling protein 2 (UCP2). 134, 135  Nitric oxide generation at the cell membrane occurs via both CB1 131 and non-CB1/2 receptor mediated 132 mechanisms.  Indeed it has been shown that oxidation 136 of the DNA base guanosine to oxo-guanosine is a normal part of endocannabinoid signalling.  This potentially very serious and inherently mutagenic defect is overcome during normal signalling by activation of the base excision DNA repair pathway within cells.  The capacity of such DNA repair pathways is well known to be limited, so the possibility exists that with pathological over-stimulation, as might occur during substantial cannabis use, the resulting major genetic defects would become fixed and eventually translated into altered mRNA’s, micro-RNA’s, genetic expression and protein sequences. 

 

Cannabis is known to stimulate the oncogenic MAP kinase pathway,137  which is potently oncogenic, and to be involved particularly in the genesis of non-lymphocytic leukaemias.138  A strongly positive association between cannabis consumption and this tumour has been found.128 Cannabinoids block topoisomerase II, an enzyme which untwists and makes accessible the dominant coding DNA strand and plays a vital role in DNA repair, meiotic chromosomal replication, mRNA transcription and DNA hypermutation in prelymphocytes.139, 140 Cannabinoids also impair RAD-51 another enzyme involved in the accurate repair of DNA breaks.  Mice chromosomal studies imply that cannabinoids also interfere with the normal maintenance of the ends of chromosomes. 141

 

Chromosomal ends or telomeres are made up of many copies of a 6 nucleotide repeat structure (T-T-A-G-G-G) and are protected by a complex of proteins collectively called “shelterin”.142, 143 Telomeres are maintained by an enzyme called telomerase which is absent from most cells, but is present in stem cells, gonads (testes and ovaries) and cancers.144, 145  The length of the telomeres has been shown recently to be proportional to the age, health and reproductive fitness of stem cells in a variety of in vivo tissue niches.146   It is of concern that the chromosomal damage was shown in mice not only for tetrahydrocannabinol, but also for cannabidiol (and cannabinol),141 a non-psychoactive cannabinoid which has been added to commercial cannabis sprays supposedly to confer safety!147

 

The involvement of cannabinoids with at least three enzymes involved in DNA repair raises questions about their potential genetic toxicity, a subject which remains largely uninvestigated.  Gonadal, stem cell and genetic toxicity have implications for cell growth inhibition, fetal malformations and inheritable defects including cancers.  Indeed, evidence of cannabis-induced altered DNA expression,148 a higher incidence of 21 birth defects108 and an 11-fold rise in inherited leukaemias in the offspring of cannabis users128 have been documented.  Other studies have produced similar findings,149 including in tissues of the germ line.150  The presence of such major chromosomal abnormalities in sperm cells but not in circulating white blood cells150 is consistent with the inhibition by cannabinoids of telomerase, which is well known to be present in stem cells, germ cells and cancer cells, but not in the nuclei of normal tissue.151-153

 

Conclusions

 

In summary there is now evidence for the implication of cannabis in various psychiatric, respiratory, cardiovascular and bone pathologies. 154, 155  The reports of social disruption, disorganization and deprivation consequent on widespread heavy cannabis use from a number of communities around the world is of substantial concern. The features associated with chronic cannabis use imply that a clear public health cautionary message is warranted along the lines employed for other environmental intoxicants such as tobacco, which should be targeted strategically to young and otherwise vulnerable populations. 

 

Conflict of interest

 

There is no conflict of interest to declare.

 

Acknowledgements

 

Nil.

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