The complexities and public health risks of attempting to regulate marijuana.
Marijuana whether in its highly variable “natural” form or in its hybrid or engineered forms is highly problematic when it comes to the full range of its harmful side effects.
Even when thorough and exhaustive clinic research and trials are undertaken before attempting to bring cannabis-based product to market, there is no way of ensuring that there will not be unpredictable harmful effects, whether mental or physical.
There are a plethora of pot-propagandist claims on the ‘panacea potential’ of various potions, tinctures and formulations of the largely unregulated cannabis ‘supplement’ market, that are unleashing already evident and arguably untold harms moving forward, even approved medicines have risks, as indeed most medicines can have.
The sale of Dr Poppy’s Wonder Elixir started in the late 1800’s and sold in Australia up until the end of WW2, this sign dates to 1946 and was found in Alice Springs, Australia
There are those who would argue that even the cannabis-based epilepsy preparation Epidiolex ®. which has been deemed a “clinically approved “ medicine not only has a limited range and narrow efficacy, it can be argued that the full range of the harmful effects and risks involved in its use have not been fully acknowledged. This is the reality of trying to bring cannabis to the market: there are an extremely wide range of harmful effects that will persist and pose a danger to public health that potentially cannot be remedied.
"No state can ever successfully regulate the use of marijuana owing to the fact that it has such idiosyncratic and unpredictable effects on users and those exposed to its use. No state can prevent the predictable as well as unpredictable genotoxic, arteriopathic, and teratogenic effects and other deleterious mental, psychological, physical, and spiritual effects of marijuana use and exposure to marijuana use. Biochemical individuality and differences in the psychopharmacological effects that marijuana use has and exposure to marijuana use has, all make regulation an impossibility."
The American Society of Addiction Medicine - Public Policy Statement on Cannabis: 2020
Following is an excerpt
Cannabis & Medical Purposes – The Evidence
Cannabis use has been shown to be associated with cognitive decline, impaired education or occupational attainment, risk of other substance use disorders, and poor quality of life.10 It has also been shown to be associated with impaired driving and fatal vehicle crashes, cannabis-related emergency room visits, psychosis, and psychiatric comorbidity.11 CUD has been associated with disability11 and strongly and consistently associated with other substance use and mental disordres.10 Use of high potency cannabis has been associated with increased frequency of use, cannabis use-related problems and increased likelihood of anxiety disorder.12
In 2013-2014, 9.8% of U.S. adults who used cannabis in the past year reported doing so for medical purposes, and 21.2% of adults who reported using cannabis for medical purposes resided in states that had not legalized cannabis use for such purposes.15 Over 75% of those who use cannabis for medical purposes also report using it for non-medical purposes.16
States have approved various indications for cannabis use, despite a lack of sufficient scientific evidence for its effectiveness as a medicine for many of these indications. A 2017 review by the National Academies of Sciences, Engineering, and Medicine found conclusive or substantial evidence that cannabinoids are effective in only three conditions: chemotherapy-induced nausea and vomiting, multiple sclerosis-related spasticity, and chronic pain.17 According to a Cochrane review, the effectiveness of cannabis-based medicines for neuropathic pain was small and may be outweighed by potential harms.18 A systematic review of 43 randomized controlled trials found that cannabis-based medicine might be effective for chronic pain based on limited evidence, primarily for neuropathic pain, and that, due to small effect sizes, the clinical significance is uncertain.19
Although some states include mental health disorders as indications for cannabis for medical purposes, cannabis use may be particularly harmful to populations with or at risk for mental health disorders. A 2019 meta-analysis of 83 studies reported scarce evidence that cannabis or any type or formulation of medicinal cannabinoids improve depressive disorders, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder (PTSD), or psychosis.20 In 2019 the American Psychiatric Association stated that “there is no current scientific evidence that cannabis is in any way beneficial for the treatment of any psychiatric disorder. Current evidence supports, at minimum, a strong association of cannabis use with the onset of psychiatric disorders.”21 Cannabis has been shown to contribute to risk factors for the onset and symptom severity of substance-induced psychosis and bipolar disorder as well as the onset of depression and anxiety disorders; there is preliminary evidence that ongoing cannabis use in persons with a history of trauma increases the odds of developing PTSD.22
A widely publicized study found lower opioid overdose rates in states that legalized cannabis use for medical purposes compared with other states through 2010.23 This led some states to include opioid use disorder (OUD) as a possible indication for cannabis used for medical purposes.24 However, a subsequent analysis extended through 2017 and using similar methods with additional controls found the opposite association.25 Studies of individuals show an association between cannabis use and increased rates of non-medical opioid use and OUD.26 There is no current evidence that cannabis is effective for the treatment of OUD.27 Further, due to its mechanism of action, cannabis would not be expected to reduce opioid overdose rates, unlike the existing FDA-approved medications for OUD. There has been a preliminary finding of an effect of CBD in reducing opioid cue-induced craving,28 but this requires further research to assess the clinical significance.
Cannabis use during pregnancy is associated with a host of negative outcomes.
The recent paper by Stanciu discussing cannabis use in pregnancy1 makes several useful and highly salient points. With a more complete understanding of the published literature further important patterns in the data emerge. They aid our understanding of the pathobiology of in utero cannabis exposure and thereby powerfully inform the community on the most appropriate manner in which to regulate cannabis and cannabinoids from an improved evidence base.
It is well known that cannabis use has been liberalized across the United States as a result of well-financed and orchestrated campaigns.2 Stanciu is correct that most epidemiological studies point towards harmful associations, that cannabis use in pregnancy is becoming more common, that it is widely recommended in pregnancy by cannabis dispensaries, and that increased rates of low birth weight, premature and stillbirths, and increased neonatal intensive care admission are well recognized associations. It is correct that all 4 longitudinal studies of children born after prenatal cannabis exposure (PCE) show increased adverse neurodevelopmental outcomes including impaired executive function, visuomotor processing deficits, heightened startle responses, impulse control, heightened susceptibility to addiction in later life, emotional behaviors, and motor defects.3-5 Well-documented impacts on the glutamatergic, GABAergic and dopaminergic signaling in the brain are of concern as they represents major neurotransmitters in the central nervous system [CNShttps://pubmed.ncbi.nlm.nih.gov/17162495/">A large Hawaiian study found an increased incidence of microcephaly (R.R. = 12.80, 95%C.I. 4.13-36.17)8 and the CDC have twice reported elevated rates of anencephalus (adjusted O.R. 1.7, C.I. 0.9-3.4) and (posterior O.R. 1.9 (C.I. 1.1, 3.2).9,10 This sets up a clear spectrum of severity from mild neurodevelopmental impairment, to microcephaly, to anencephalus and then fetal death. In the context of dose-response relationships and strong geotemporospatial associations issues of causality necessarily arise.
Stanciu’s observation that preclinical studies in experimental animals are important to understand the likely effects of PCE in individuals, not least due to the problem of the frequent exposure to multiple substances clinically, is also correct. This issue was studied in detail long ago in the 1960s and 1970s, and succinctly summarized by Graham’s telling observation: “oedema, phocomelia, omphalocoele, spina bifida, exencephaly, multiple malformations including myelocoele. This is a formidable list.”11
However, a reasonable question might be: “Why don’t we see such a broad teratological spectrum clinically?”
Stanciu’s remark that there are “no overt birth defects” is an oft-repeated myth and is in error, as well as obviously being at odds with several preclinical studies, especially in the most predictive species for human teratology (ie, hamsters and white rabbits).12,13
A recent paper from the Centers for Disease Control (CDC) noted that 4 defects, anencephalus, gastroschisis, diaphragmatic hernia and esophageal atresia were more common following PCE.9 The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) issued a joint position statement that both ventricular septal defect (VSD) and Ebsteins anomaly were also elevated by PCE.14
The review of 17 years of birth defects from Hawaii found 21 defects to be elevated after PCE and featured prominently cardiovascular defects (atrial septal defect (ASD), VSD, hypoplastic left heart syndrome, tetralogy of Fallot (ToF) and pulmonary valve atresia or stenosis), chromosomal defects such as Downs syndrome, body wall defects such as gastroschisis, limb defects including syndactyly and upper limb reduction defects, facial, bowel and genitourinary system defects with calculated rate ratios ranging from 5.26 (C.I. 1.08-15.46) to 39.98 (C.I. 9.03-122.29).8
In September and October 2018 Colorado released 2 datasets of congenital anomalies across the period of its cannabis legalization program from 2000 to 2013 and 2000 to 2014 and reported 87,772 and 64,463 major defects respectively (which are obviously contradictory).15 Based on 4830 and 4026 major anomalies in the year 2000 this represents a case excess of 20,152 (29.80%) or 11,753 anomalies (22.30%) respectively. During this period the use of tobacco and alcohol was declining and other drug use was not rising. Only cannabis use rose. Importantly, models quartic in time indicated a non-linear response of total birth defects to rising cannabinoid exposure. Estimated exposure to several cannabinoids including cannabinol, THC, and tetrahydrocannabivarin was shown to be positively associated with major defect rates and to be robust to adjustment for other drug use. CNS defects (microcephalus, neural tube defects), cardiovascular defects (ASD, VSD, patent ductus arteriosus (PDA)), total chromosomal anomalies including Downs syndrome, musculoskeletal, respiratory and genitourinary anomalies all rose dramatically.
Defects described as being cannabis-related (by the Hawaiian, CDC, AAP and AHA investigators) rose more quickly than cannabis-unrelated defects (P<0.003). As fetal cardiac tissue and the central great vessels have high numbers of cannabinoid receptors from early in fetal life it is easy to understand why this pattern might emerge. Since ASD, VSD and PDA are the most common cardiovascular congenital anomalies it is understandable that total cardiovascular anomalies increased in Colorado.
A recent review of total congenital anomalies in Canada showed that they were 3 times more common in the northern territories which consume more cannabis, and that these effects were robust to adjustment for other drug exposure and for socioeconomic variables.16 Total cardiovascular defects, Downs syndrome and gastroschisis were noted prominently in this series. Neural tube defects including anencephalus and spinal bifida and meningomyelocoele were falling across Canada from 1991 to 2007, although it was not clear whether the decline was due to dietary folate supplementation or increased antenatal early termination of pregnancy for anomalies (ETOPFA).17 Notwithstanding this it was recently shown that within each of 3 periods (the pre-folate period, the transitional period and the post-folate period) neural tube defects across Canada were becoming more common.17
An Australian dataset found greatly elevated relative rates of cardiovascular (PDA, ASD, VSD, ToF, transposition of great vessels), body wall (gastroschisis, exomphalos, diaphragmatic hernia), chromosomal (Downs syndrome, Turners syndrome, Edwards Syndrome (trisomy 18)), genitourinary, hydrocephalus, neural tube defects, and bowel defects with borderline results for anencephalus (ETOPFA data unavailable) in a high cannabis use area in Northern New South Wales compared to Queensland state-wide data.18
Transposition of the great vessels was previously linked with paternal cannabis exposure.19
The presence of Downs syndrome on the list of cannabis-associated anomalies in Hawaii, Colorado, Canada and Australia is important as it necessarily implies megabase-scale genetic damage.8,15,16,18 Since cannabis interferes with tubulin metabolism and thus the separation of the chromosomes which occurs in mitotic anaphase it is easy to see how PCE-induced chromosomal mis-segregation errors might occur.20 Studies of PCE in rodents show that cannabis induces major alterations of gene expression widely with 8% alteration in DNA sperm methylation patterns, changes which are transmissible to subsequent F1 generations.21
Stanciu’s comment about a so-called “cannabis phenotype” is provocative. It is true that a “fetal cannabis syndrome” (FCS) has not been described in the way that a “fetal alcohol syndrome” (FAS) has. Fetal alcohol syndrome of course is a very diverse and pleomorphic group of clinical presentations and a wide spectrum of presentations is described. Importantly the fetal alcohol has been described as being mediated by the cannabinoid type 1 receptor (CB1R’s) and is mediated epigenetically.22-26 The suggestion that alcohol can work epigenetically via CB1Rs but cannabinoids cannot defies the bounds of credulity. Moreover, as noted above, there is as yet no objective marker of gestational cannabinoid exposure. Once such a biomarker has been derived (say epigenetically and / or glycomically27) then an objective measure will exist to allow genotype-epigenotype-phenotype correlative studies to be performed so that we can usefully investigate if a fetal cannabis syndrome phenotype spectrum might exist. However, if researchers do not believe it might exist then it is clear that one will not be described. It is our view that once an objective biomarker is established it will only be a matter of time before a diverse and highly variable FCS is also defined and enters the clinical diagnostic compendium.
Cannabidiol and Abnormal Liver Chemistries in Healthy Adults: Results of a Phase 1 Clinical Trial
Liver safety concerns were raised in randomized controlled trials of cannabidiol (CBD) in patients with Lennox‐Gastaut and Dravet syndromes but the relevance of these concerns to healthy adults consuming CBD is unclear. The objective of this manuscript is to report on liver safety findings from healthy adults who received therapeutic daily doses of CBD for ~3.5 weeks and to investigate any correlation between transaminase elevations and baseline characteristics, pharmacogenetic, and pharmacokinetic data. Sixteen healthy adults were enrolled in a phase 1, open‐label, fixed single‐sequence drug‐drug interaction trial to investigate the effect of repeated dose administration of CBD (1500 mg/day) on cytochrome P450 (CYP) 1A2 activity. Seven (44%) participants experienced peak serum alanine aminotransferase (ALT) values greater than the upper limit of normal (ULN). For 5 (31%) participants, the value exceeded 5× ULN, therefore meeting the international consensus criteria for drug‐induced liver injury. There was no correlation between transaminase elevations and baseline characteristics, CYP2C19 genotype, or CBD plasma concentrations. All ALT elevations above the ULN began within 2–4 weeks of initial exposure to CBD. Among the 6 participants with ALT elevations who were discontinued from the protocol, some had symptoms consistent with hepatitis or hypersensitivity.
We conclude that healthy adults consuming CBD may experience elevations in serum ALT consistent with drug‐induced liver injury. Given the demonstrated inter‐individual variation in susceptibility, clinicians should be alert to this potential effect from CBD, which is increasingly available in various non‐prescription forms and doses to consumers.