A review published in Developmental Medicine & Child Neurology investigates the knowledge base of cannabis-based medicinal products in paediatric epilepsies, highlighting areas in need of additional research.
Following reports in the media of children with epilepsies apparently deriving benefits from medical marijuana (or cannabis-based medicinal products) accessed abroad, the UK government allowed clinicians to prescribe these products. A previous review found that there was some benefit in certain drug-resistant epilepsies in children.
In the review, the authors also looked at the prescribing environment surrounding these products. They found that the major obstacle to prescribing is a lack of quality evidence for efficacy and safety. The authors stress that unlicensed cannabis-based medicinal products should not circumvent the usual regulatory requirements before being prescribed. They are also concerned that children with epilepsy are at risk of being exploited as a “Trojan horse” for the cannabis industry, with widespread acceptance of medicinal cannabis accelerating the wider legalisation of marijuana and opening up a highly lucrative commercial market.
Scientists have found that significant amounts of THC and CBD, the two main components of cannabis enter the embryonic brain of mice in utero and impair the mice’s ability as adults to respond to fluoxetine (Prozac).
The study suggests that when the developing brain is exposed to THC or CBD, normal interactions between endocannabinoid and serotonin signaling may be diminished as exposed individuals become adults.
“Hemp-derived CBD is a legal substance in the US, and we are in a time of increasing state-level legalisation of cannabis. Therefore, use of cannabis components have increased across most levels of society, including among pregnant women. The study marks the beginning of an effort to understand the effects of THC and CBD on the endogenous cannabinoid system (ECS) in the developing brain and body,” explained Hui-Chen Lu, director of the Linda and Jack Gill Center and professor in the Department of Psychological and Brain Sciences in the IU Bloomington College of Arts and Sciences.
Researchers studied four groups of pregnant mice. Some received daily moderate doses of either THC, CBD, or a combination of equal parts THC and CBD; a control group had placebo injections throughout pregnancy. Using mass spectrometry, IU psychological and brain sciences professor Heather Bradshaw tested embryos and found that CBD and THC both could cross the placenta and reach the embryonic brain.
“The surprising part is that maternal exposure to CBD alone — a drug that is often considered as safe and harmless and is a popular ‘natural’ therapy for morning sickness — resulted in a lasting impact on adult mice offspring,” Lu said. “Both prenatal THC and CBD exposure impaired the adult’s ability to respond to fluoxetine. The results suggest taking a cautious approach to using CBD during pregnancy.”
There is however some evidence for CBD’s effectiveness in treating chronic pain and anxiety, though currently the only FDA-approved indication for CBD is the treatment of severe seizure disorders.
“We still know very little about the effects of CBD on the developing brain,” Prof Lu said.
The new paper is one of the first studies to see the potential negative impact of CBD on the developing brain and later behaviours. However observational studies in the 1980s saw increased anxiety and depression in offspring of mothers who used the lower-strength cannabis available at the time. Since women may take cannabis products for nausea and vomiting, this has relevance for public health awareness.
Study co-author Ken Mackie, Gill Chair of Neuroscience at IU Bloomington, said researchers know that prenatal cannabis exposure may increase the risk for anxiety and depression, so it is important to evaluate the response to a class of drug used to treat anxiety and depression.
Though normal mouse behaviours were seen in many tests, one test — to determine their response to stress — had a strongly atypical result. In all groups, the mice responded normally to a stressful situation. As expected, fluoxetine increased stress resilience in mice whose mothers had received the placebo. However, the drug was ineffective in mice whose mothers had received THC, CBD or their combination.
Fluoxetine works by increasing the amount of serotonin available at brain synapses, an effect known to require the endocannabinoid system. This internal system of receptors, enzymes and molecules both mediates the effects of cannabis and plays a role in regulating various bodily systems, such as appetite, mood, stress and chronic pain.
To test if maternal exposure to THC and/or CBD impaired endocannabinoid signaling in the adult offspring, the researchers tested whether boosting the ECS with a drug would restore fluoxetine’s effectiveness. They found that the ECS boosting restored normal fluoxetine responses in mice that had received THC or CBD while their brains were developing.
Journal reference: de Sousa Maciel, I., et al. (2021) Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition. Cannabis and Cannabinoid Research. doi.org/10.1089/can.2021.0015.
Scientists have uncovered an unexpected link between a synapse protein that has been implicated in neuropsychiatric disorders and the endocannabinoid pathway.
These findings suggest a role for the endocannabinoid system in conditions including bipolar disorder, according to Peter Penzes, PhD, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, professor of Physiology and Pharmacology, and senior author of the study.
“The endocannabinoid system could be disrupted in patients with bipolar disease, or it could be the opposite: medical marijuana could have therapeutic potential for these patients,” said Prof Penzes, who is also director of the Center for Autism and Neurodevelopment. “These are the questions that need to be answered.”
Cannabis mimics naturally occurring endocannabinoids in the brain, which is how it produces its effect in humans. Since the specific function of endocannabinoids is still not fully understood, the legalisation of marijuana in many US states has prompted more investigation into its biological pathways, Prof Penzes said. The endocannabinoid system is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults.
Endocannabinoids are produced by an enzyme known as diacylglycerol lipase alpha (DAGLA), which is concentrated in synapses. Endocannabinoids dampen synaptic strength, which is why marijuana has calming effects.
Prof Penzes and colleagues have previously studied ankyrin-G, another synapse protein which regulates transmission speed across synapses. Aberrant over- or under-expression of ankyrin-G has been associated with disorders such as bipolar disorder, schizophrenia and autism.
Studying mice with ankyrin-G genetically deleted, they made a surprising discovery: Ankyrin-G seemed to stabilise DAGLA at synapses, increasing the efficiency of DAGLA.
“It’s a delicate mechanism that regulates dendritic spine morphology,” said lead author Sehyoun Yoon, PhD, research assistant professor of Physiology.
These findings comport with another recent study, led by investigators at Icahn School of Medicine at Mount Sinai and published in Nature Genetics. The study showed that both DAGLA and ankyrin-G (ANK3) are risk genes for bipolar disorder in a genome analysis of over 40,000 patients.
“It’s almost like somebody who is leading a double life, Dr. Jekyll and Mr. Hyde,” Prof Penzes said. “Ankyrin-G has this entire separate function.”
The convergence of ankyrin-G with the endocannabinoid pathway opens up an entire new world of possibilities, both for investigating disease risk and possible therapies.
“Cannabis may contribute to increased risk for mental disorders, which has actually been shown in schizophrenia,” Prof Penzes said. “Conversely, cannabis could be beneficial in some brain disorders, which prompted trials of medical marijuana in patients with autism.”
Prof Penzes said in future he plans to examine the downstream effects of this biological pathway, both in normal subjects and in disease.
Cannabis use among young adults was associated with increased risks of thoughts of suicide (suicidal ideation), suicide plan, and suicide attempt, according to a population analysis.
These associations remained regardless of whether someone was also experiencing depression, and the risks were greater for women than for men. The study was conducted by researchers at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.
“While we cannot establish that cannabis use caused the increased suicidality we observed in this study, these associations warrant further research, especially given the great burden of suicide on young adults,” said senior author NIDA Director Nora Volkow, MD. “As we better understand the relationship between cannabis use, depression, and suicidality, clinicians will be able to provide better guidance and care to patients.”
The number of cannabis-using adults in the US more than doubled from 22.6 million in 2008 to 45.0 million in 2019. Over the same period the number of adults with depression also increased, as did those reported suicidal ideation or who committed suicide. However the link between cannabis and suicidality is not well understood.
Setting out to address, NIDA researchers examined data from the 2008-2019 National Surveys on Drug Use and Health (NSDUH). NSDUH collects nationally representative data among the US civilian population age 12 or older on cannabis use and use disorder, depression, suicidality, and other behavioural health indicators. In addition to determining the associations between these factors, the researchers examined whether the associations varied by gender. They examined data from 281 650 young adults ages 18 to 35 years, the age range where most mood and substance use disorders emerge.
Four levels of past-year cannabis use were compared: no cannabis use; nondaily cannabis use; daily cannabis use (use on at least 300 days per year); and presence of cannabis use disorder, assessed on specific criteria for a pattern of continued cannabis misuse. The prevalence of major depressive episodes based on specific diagnostic criteria measured through the survey was used to measure depression. To identify suicidality trends, the tean separately assessed the trends in the prevalence of past-year suicidal ideation, plan, and attempt as reported in the 2008-2019 NSDUH surveys.
The study found that even nondaily cannabis users were more likely to have suicidal ideation and to plan or attempt suicide than complete non-users. These associations remained regardless of comorbid depression. In people without a major depressive episode, about 3% of those who did not use cannabis had suicidal ideation, compared with about 7% of those with nondaily cannabis use, about 9% of those with daily cannabis use, and 14% of those with a cannabis use disorder. In people with depression, 35% of non-users had suicidal ideation, compared to 44% of nondaily cannabis users, 53% of daily cannabis users, and 50% of those with cannabis use disorder. Similar trends existed for the associations between different levels of cannabis use and suicide plan or attempt.
Additionally, the researchers found that women with any cannabis use were more likely to have suicidal ideation or report a suicide plan or attempt than men with the same levels of cannabis use. For example, among individuals without major depressive episode, the prevalence of suicidal ideation for those with vs without a cannabis use disorder was 13.9% vs. 3.5% among women and 9.9% vs. 3.0% among men. In individuals with both cannabis use disorder and major depressive episode, the prevalence of past-year suicide plan was 52% higher for women (23.7%) than men (15.6%).
“Suicide is a leading cause of death among young adults in the United States, and the findings of this study offer important information that may help us reduce this risk,” explained lead author Beth Han, MD. PhD, MPH, from NIDA. “Depression and cannabis use disorder are treatable conditions, and cannabis use can be modified. Through better understanding the associations of different risk factors for suicidality, we hope to offer new targets for prevention and intervention in individuals that we know may be at high-risk. These findings also underscore the importance of tailoring interventions in a way that take sex and gender into account.”
With reports of severe lung illnesses related to vaping making headlines in 2019, cannabis use skyrocketed among high school students were soaring.
Cannabis vaping involves inhaling evaporated oils, or vapours from heated concentrates known as dabs. Joseph J Palamar, PhD, of New York University reported on his study in the Journal of Adolescent Health.
The long-running Monitoring the Future study results showed that 4.9% (95% CI 4.3%-5.5%) of high school students reported “frequent” vaping of cannabis products — 10 times or more in the previous month — up from 2.1% in 2018 (95% CI 1.7%-2.6%). Rates of any cannabis vaping in the previous month also rose significantly, from 7.5% in 2018 (95% CI 6.7%-8.4%) to 14.0% in 2019 (95% CI 13.1%-14.9%).
These increases accompanied an unsettling outbreak of respiratory illnesses, until it was eclipsed by the COVID pandemic. Nearly 3000 Americans, mostly young adults, fell ill with EVALI — e-cigarette or vaping-associated lung injury — and 68 died, noted Dr Palamar. Epidemiological and lab research eventually identified vitamin E acetate as the likely cause. The substance is a common component of illicit cannabis vaping products, even though a substantial minority of victims denied use of such products.
Dr Palamar’s study drew on Monitoring the Future data on 4072 students in 10th and 12th grades in 2018 and 8314 in 2019. The study also highlighted other trends.
Cannabis vaping in the past month nearly tripled among female students from 2018 to 2019, while rates for students in general age 18 and older rose 2.5-fold. Social activity, as indicated by reports of “going out” four to seven times a week, was linked to increased rates of cannabis vaping. There were also small increases in cannabis vaping among students reporting other psychoactive drug use including opioids, cocaine, “tranquilisers”, and non-LSD hallucinogens.
The study did not address the extent to which school closures and social restrictions resulting from the COVID pandemic affected these trends, and it will be some before data from Monitoring the Future can answer this as the survey was stopped in March 2020 when the pandemic closed schools.
Nevertheless, the available 2020 data showed that the number of 10th graders saying cannabis was “fairly easy” or “very easy” to obtain had dropped sharply, accelerating a trend underway for more than 20 years. This was despite the spread of legal marijuana.
Dr Palamar noted several limitations to his study and to Monitoring the Future in general. Data on drug use was self-reported, and the survey took place at schools, meaning that students “chronically absent or who dropped out are underrepresented,” he wrote. There were also some subgroups such as those vaping cannabis daily, that were too small for analysis.
Older people who use cannabis to relieve or treat health conditions generally don’t discuss their substance use with doctors, according to a new study.
In this study of over 17 000 people aged 50 and over in the US, some use cannabis daily and others have mental health problems. The findings were published in peer-reviewed The American Journal of Drug and Alcohol Abuse.
The research is the first to identify where older users obtain cannabis, with the majority saying obtaining it was easy. Those who use cannabis for health reasons are more likely than non-medical (recreational) users to buy it at a medical dispensary (20% vs 5%) and less likely to get it for free (25% vs 46%) or from other sources such as parties (49% vs 56%).
According to the authors, the findings have significant clinical and policy implications especially as more US states are legalising cannabis, which is leading to a rapid rise in uptake among older people. This has implications for other countries such as South Africa, which has recently decriminalised it for personal use.
They urge that doctors should be routinely screening older people for cannabis and other substance use, as well as checking cannabis users for mental health problems, and recommending treatment when necessary. They add that education on the risks of obtaining cannabis and cannabis products from unregulated sources is also vital for this group.
“Cannabis is readily available and accessible to older cannabis users for medical or non-medical purposes,” said Namkee G Choi from University of Texas.
“The findings suggest that some medical users may be self-treating without healthcare professional consultation.
“All older people who take cannabis should consult healthcare professionals about their use. As part of routine care, healthcare professionals should screen for cannabis and other substance use, and for mental health problems.
“They should also recommend services or treatment when indicated. Given the increase in THC (tetrahydrocannabinol) potency, healthcare professionals should educate older cannabis users, especially high-frequency users, on potential safety issues and adverse effects.”
THC content has increased significantly over the past decades. Since 1995, the potency of illicit cannabis plant material seized in the US has consistently increased over time, from approximately 4% in 1995 to approximately 12% in 2014. Among older US adults, cannabis has more than doubled between 2008 and 2019. Reasons include pain relief and treating health issues. However, not much is known about where they obtain cannabis and how much they discuss their use with doctors.
Data for the research was drawn responses from the 2018 and 2019 National Survey on Drug Use and Health (NSDUH), with 17 685 men and women aged 50 and older. This annual national survey measures substance use and misuse and mental illness across the US.
The researchers analysed responses including those on frequency of cannabis use, reasons for taking it, where it was obtained, and how much they utilised healthcare services.
The study found that, overall, 9% used cannabis over the past year and of these, 19% used cannabis for a medical purpose to some extent, eg, to treat chronic pain, depression or diseases like arthritis, while the rest (81%) were recreational (non-medical) users.
The authors also found that people who reported cannabis use as being for medical reasons were over four times as likely than non-medical users to discuss their use with a healthcare professional. Nevertheless, only a minority of medical users did so, which implies that some are self-treating without consulting a doctor.
Medical users were also more likely than non-medical users to more frequently take cannabis, with 40% using it between 200 and 365 days a year.
A higher proportion of older cannabis users had mental illness, alcohol use disorder, and nicotine dependence compared with non-users of the same age, although medical users were less likely to have alcohol problems compared to recreational users.
As well as calling on doctors to do more, the study authors say the NSDUH needs updating to “reflect changing cannabis product commercialization”, such as including products available to older people like cannabidiols, topical solutions and edibles.
Limitations of the study included the relatively small number of medical users and the fact some respondents may have under-reported their cannabis and other substance use.
A comprehensive analysis of 80 scientific studies has identified a ‘window of impairment’ of between three and 10 hours caused by moderate to high doses of tetrahydrocannabinol (THC), the cannabis component that causes intoxication. According to the researchers, these results have consequences for drug-driving laws around the world.
How long the impairment lasts depends on the THC dose, whether it is taken orally or inhaled, on the usage habits of the cannabis user and the demands of the task. The psychoactive THC component of cannabis has potential medical applications in treating nausea, sleep apnoea, fibromyalgia and chronic pain, though these applications are controversial and currently difficult to study due to legal issues, though off-label use is common. Previous research by Dr Arkell and colleagues has shown that cannabidiol (CBD), one of the medically active components of cannabis, does not cause impairment in driving. CBD has analgesic and anti-inflammatory actions, as well as anxiolytic, antiemetic, antipsychotic, and neuroprotective antioxidant properties
Medical and non-medical legal cannabis use is on the rise worldwide. THC causes acute impairment in driving and cognitive performance, but there is uncertainty among users about the duration of this impairment and when they can start tasks such as driving after consuming cannabis. “Our analysis indicates that impairment may last up to 10 hours if high doses of THC are consumed orally,” said lead author Dr Danielle McCartney, Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney. “A more typical duration of impairment, however, is four hours, when lower doses of THC are consumed via smoking or vaporization and simpler tasks are undertaken (eg, those using cognitive skills such as reaction time, sustained attention and working memory). This impairment may extend up to six or seven hours if higher doses of THC are inhaled and complex tasks, such as driving, are assessed.”
A moderate THC dose is considered about 10 milligrams in this study, but could be higher for a regular user, said the researchers.
Co-author Dr Thomas Arkell, also from the Lambert Initiative, said: “We found that impairment is much more predictable in occasional cannabis users than regular cannabis users. Heavy users show significant tolerance to the effects of cannabis on driving and cognitive function, while typically displaying some impairment.”
Regular cannabis users might consume more to get the same effect, resulting in equivalent impairment, the authors noted.
In the case of oral use as in medical cannabis drops, tablets etc, the impairment takes longer to manifest and has a longer duration than the inhalation route.
The findings have implications for so-called drug-driving laws, the researchers said.
Professor Iain McGregor, Academic Director of the Lambert Initiative, said: “THC can be detected in the body weeks after cannabis consumption while it is clear that impairment lasts for a much shorter period of time. Our legal frameworks probably need to catch up with that and, as with alcohol, focus on the interval when users are more of a risk to themselves and others. Prosecution solely on the basis of the presence of THC in blood or saliva is manifestly unjust.
“Laws should be about safety on the roads, not arbitrary punishment. Given that cannabis is legal in an increasing number of jurisdictions, we need an evidence-based approach to drug-driving laws,” Prof McGregor said.
Journal information: McCartney, D., et al. (2021) Determining the magnitude and duration of acute Δ9-tetrahydrocannabinol (Δ9-THC)-induced driving and cognitive impairment: A systematic and meta-analytic review. Neuroscience & Biobehavioral Reviews. doi.org/10.1016/j.neubiorev.2021.01.003.
The effectiveness of cannabinoids as pain management has been brought into question by experts reviewing clinical evidence.
Researchers from the University of Bath’s Centre for Pain Research leading experts from around the world reviewed existing data into cannabinoids, including that on so-called ‘medicinal cannabis’ and ‘medicinal cannabis extracts’.
Their findings suggest that while preclinical data supports the hypothesis of cannabinoid analgesia, uncertainties especially in clinical evidence do not reach the certainty in efficacy and safety necessary for the IASP to endorse their general use for pain control. The studies and the statement from the IASP are limited to the use of cannabinoids to treat pain, and not for other conditions for which cannabinoids are used.
Dr Emma Fisher who led the review of the clinical evidence said: “Cannabis, cannabinoids, and cannabis-based medicines are becoming an increasingly popular alternative to manage pain. However, our review shows that there is limited evidence to support or refute their use for the management of any pain condition. The studies we found were poor quality (high risk of bias) and the evidence was of very low-certainty, meaning that we are very uncertain of the findings and more research is needed.”
Professor Christopher Eccleston, Director of the Centre for Pain Research / Department for Health, said: “Cannabis seems to attract strong opinions. If ever a field needed evidence and a rigorous scientific opinion it is this one. For many this will be an unpopular conclusion, but we need to face up to the fact that the evidence is simply lacking. Science is not about popularity but keeping people safe from false claims. The challenge in this field will be for governments to fund independent research, and to ensure balance and equipoise.
“Coming close on the heels of The Lancet Commission on children’s pain and the WHO guidelines on treating chronic pain, this further contribution also found no evidence to support the use of cannabis, cannabinoids, and cannabis-based medicines for children with chronic pain. We need to invest in real solutions to the very real problem of chronic pain in children.”
The study drew on data of more than a million people receiving primary care services throughout the VA Healthcare System in 2014 or 2015, of whom there were 135 703 with premature ASCVD.
A number of independent predictors for first-event ASCVD for men (from age 55) and women (from 65) were picked up. Tobacco (adjusted odds ratio [OR] 1.97) and alcohol use (OR 1.50) conferred significant additional risk, but the greatest risk increase of generally legal substances was cannabis use (OR 2.65). Cocaine use (OR 2.44), amphetamine use (OR 2.74) and other drug use (OR 2.53) all had very high risk increases.
Those using four or more substances had the greatest risk at nearly nine times normal. Women also had much stronger effect sizes for premature ASCVD than men.
In an accompanying editorial Anthony Wayne Orr, PhD, and colleagues at LSU Health Shreveport, wrote: “Substance use disorders have been associated with an acceleration of the ageing process. We are only young once, and we should do everything in our power to maintain that state as long as we can.”
The editorialists suggested a nationwide ASCVD education campaign targeting people with substance use disorders.
“In addition, clinicians and primary care providers should begin screening their adult and young adult patients with a history of a substance use disorder for symptoms of premature or extremely premature ASCVDs at earlier stages in their patients’ lives,” suggested the editorialists.
Limitations included it being an observational study, lack of socioeconomic data and the cohort being mostly white males, as well as not being able to discern between prescription and recreational amphetamine use. “Retrospective studies are limited by the available data. While this study supports the association between substance use disorder and early-onset ASCVD, the effect of substance use frequency, dose, and duration cannot be reliably ascertained in this patient sample,” the editorialists stated.
The editorialists recommended that specific biomarkers for substance use-associated cardiovascular disease be identified, and therapeutic window characterised to limit these chronic effects of substance use disorder.
Adding to a growing body of evidence as to its health benefits, medical cannabis may lower blood pressure in older adults, according to research from Ben-Gurion University of the Negev (BGU) and its affiliated Soroka University Medical Center.
This is the first such study to investigate cannabis’ effect on blood pressure, heart rate and metabolic parameters in hypertensive adults 60 and older.
“Older adults are the fastest growing group of medical cannabis users, yet evidence on cardiovascular safety for this population is scarce. This study is part of our ongoing effort to provide clinical research on the actual physiological effects of cannabis over time,” said Dr Ran Abuhasira, BGU Faculty of Health Sciences and BGU-Soroka Cannabis Clinical Research Institute
Before and three months after beginning medical cannabis therapy, patients in the study were evaluated using 24-hour ambulatory blood pressure monitoring, ECG, blood tests, and body measurements. Patients ingested cannabis either orally in the form of oil extracts or by smoking.
The findings included a significant drop in 24-hour systolic and diastolic blood pressure values, with the lowest point occurring three hours after ingesting cannabis. Both daytime and nighttime reductions in blood pressure were observed, with more greater changes at night. Higher nighttime than daytime blood pressure may also raise the risk of Alzheimer’s disease, so lowering it at night may offer that benefit.
The pain relief from taking cannabis, often a reason for prescriptions, may also have resulted in a reduction of blood pressure, the BGU researchers postulated.
“Cannabis research is in its early stages and BGU is at the forefront of evaluating clinical use based on scientific studies,” said Doug Seserman, chief executive officer of American Associates, BGU. “This new study is one of several that has been published recently by BGU on the medicinal benefits of cannabis.”
Journal information: Abuhasira, R., et al. (2021) Cannabis is associated with blood pressure reduction in older adults – A 24-hours ambulatory blood pressure monitoring study. European Journal of Internal Medicine.doi.org/10.1016/j.ejim.2021.01.005.
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