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Medical Marijuana for Autism

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Medical Marijuana for Autism

 

Although the research on cannabis and autism spectrum disorders is in its infancy, there has been much controversy and confusion. Over the years, more patients and their families are seeking guidance from doctors on using cannabis to alleviate symptoms. From preventing seizures to calming aggression, a slow trickle of research is suggesting that cannabidiol (CBD), a component of cannabis, may be the wonder drug families have been searching for. But does it hold up to this standard? Should we be recommending it to patients? How do we weigh the benefits and the risks?

Unfortunately, many clinicians lack adequate training on the subject, making them unprepared to have a meaningful discussion with patients and families. Efforts to advance research have been limited for technical and logistical reasons, often leaving doctors with just as many questions as patients.

Cannabis: An Overview

Cannabis is a genus of flowering plants belonging to the family Cannabaceae that includes 3 species: cannabis sativa, indica, and ruderalis. Marijuana specifically refers to the parts of the cannabis plant that contains high amounts of delta-9-tetrahydrocannabinol (THC). Medicinal use of the cannabis plant dates back thousands of years in cultures all around the world. Today, it is used to treat an assortment of conditions, such as arthritis, cancer, HIV/AIDS, glaucoma, seizures, and more.

Used recreationally, it produces a high or mind-altering effect when smoked or consumed. It is also used therapeutically. The National Institute on Drug Abuse defines medical cannabis as “using the whole, unprocessed marijuana plant or its basic extracts to treat symptoms of illness and other conditions.”1

The plant produces more than 500 different chemical substances. These include 100 unique cannabinoids, which bind to the CB1 and CB2 receptors in the body’s endocannabinoid system. CB1 receptors are more common in the central and peripheral neurons, while CB2 receptors are expressed only in peripheral tissues, predominating the immune system.2

THC and CBD are 2 cannabinoids found in cannabis that have particular clinical importance.3

In medical applications, THC is typically used to relieve pain, nausea, insomnia, and poor appetite. THC is a partial agonist of the CB1 and CB2 receptors.4 It produces the high, which is why it is included in so many recreational marijuana products.

CBD is less controversial than THC because it does not produce mind-altering or euphoric effects. It has low affinity for CB1/CB2, acting as an antagonist.5 It affects various receptor systems in the body (TRPV1, GPR55, PPAR.) Of note is its agonism on the 5HT1A (serotonin) receptor at high concentrations to help with anxiety, sleep, pain perception, and nausea.6 It also appears to be a partial dopamine receptor agonist, pointing toward its possible antipsychotic properties. Additionally, CBD appears to influence the glutamate-GABA system.7

Endocannabinoids are naturally occurring lipid mediators in the body that bind to the cannabinoid receptors. Unlike other neurotransmitters, they are produced on demand in the body and are quickly inactivated. The most common ones include: N-arachidonoylethanolamine (anandamide), 2-arachidonylglycerol (2-AG), and 2-arachidonylglyceryl ether.

Anandamide, also known as the “bliss molecule,” is currently one of the most-studied endocannabinoids.8 The cannabinoid receptor system has a very complex role in the body, which includes regulation of cell function, maintenance of homeostasis, motor coordination (basal ganglia), brain reward system, stress response, memory function (hippocampus), appetite, modulation of pain, and reduction of inflammation.

Anandamide causes inhibition of the release of neurotransmitters such as glutamate and gamma aminobutyric acid (GABA). It also affects norepinephrine, dopamine, serotonin, histamine, prostaglandins and opioids.9 An imbalance in the GABA and glutamate system is often linked with autism.

The Challenges of Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disability characterized by impairment in 3 major domains: social interaction, communication, and behavior patterns. It is called a spectrum disorder because it has a broad range of severity and symptom type. These usually appear within the first few years of life, although it can be diagnosed at any age.

In 2016, 1 in 54 children by the age of 8 was diagnosed with ASD, according to Centers for Disease Control and Prevention statistics. This was a 10% increase over 2014, when the estimate was 1 in 59. Boys are 4 times more likely than girls to be diagnosed.10

The causes of autism are not clearly understood. It is a complex disorder thought to be multifactorial in origin, involving genetic and environmental factors.11 It is associated with several conditions, such as Fragile X, Rett syndrome, tuberous sclerosis, phenylketonuria, and certain genetic conditions involving the deletion or duplication of chromosomes. Additionally, roughly 20% to 25% of individuals with autism are diagnosed with epilepsy at some point during their lives. Intellectual disability is also highly prevalent in autism, and there is a close association with seizure risk in autistic individuals.6

Environmental factors being explored by research include viral infections, air pollutants, dietary factors, medications, and perinatal complications. Other common risk factors include children born to older parents, siblings of affected children (especially in the case of identical twins), and a family history of autism.11,12

There are no medications that address autism’s core symptoms. Existing medications are used to target comorbid symptoms such as anxiety or mood symptoms and aggressive behavior. But these may not be very effective and often cause several side effects, limiting their use.

The Case for and Against

With autism cases on the rise, the need for effective treatments is rising too. Treatments in childhood carry special risks and potential rewards. Because a child’s brain is still developing, it is a good opportunity to make significant changes, but for the same reason, it is a dangerous time to experiment with certain compounds like THC and cannabis. Many of us have encountered desperate families who have found traditional treatments inadequate or resulting in undesirable side effects. At their wit’s end, they are willing to try just about anything. By not approaching the topic, patients and families may seek unsubstantiated advice on the Internet, leading them to use substandard and potentially dangerous products in an unregulated market.

Today, cannabis is easily accessible and popular with millions of Americans, but as noted, cannabis can be a mixture of many things. While the federal government considers cannabis a Schedule I drug, it has been legalized in 33 states and Washington, DC. Meanwhile, CBD is a schedule 5, the lowest degree of regulation by the US Food and Drug Administration. As a treatment for autism, cannabis has been prescribed in 14 states since 2019, according to the Autism Support Network.13

Whether we accept cannabis as a psychiatric treatment or not, our patients and their families are curious and interested in learning about all options. That is why it is vital for us as psychiatrists to educate ourselves on the use of cannabis to treat autism spectrum disorder (ASD), recognizing that the both the risks and benefits of use in ASD are indirect and insufficient. This might be the only way we can guide our patients to weigh all the facts before making a treatment choice.

Current Research Results

Research on cannabis’ impact on autism is still very much in its infancy, but there are several important studies to consider, with more on the way. In a 2018 Stanford University study, anandamide concentration was significantly lower in children with ASD as compared to controls.14 Research studies have suggested that anandamide produces effects similar to, but less intense than, those associated with THC.15 Because of this similarity, researchers theorize THC has therapeutic potential in the treatment of autism.

Another study in 2013 found an increased expression of CB2 receptors in peripheral blood mononuclear cells in autistic children, suggesting an imbalance in the endocannabinoid system.16 Oxytocin is a neuropeptide crucial for social behavior, and studies indicate the oxytocin-driven anandamide signaling system may be defective in autism patients, leading researchers to theorize whether CBD can correct this.17

Terpenoids are aromatic compounds present in the cannabis plant that give each strain its unique smell. Cannabinoids and terpenoids are thought to interact with each other as well as the brain in an entourage effect to produce synergistic results. This effect potentially increases the therapeutic value and tames the mind-altering effects of THC in a product. Similarly, there is some evidence proposing that the simultaneous use of THC and CBD is more effective than either alone. While still theoretical, it explains why both are often used together in medical applications.18 Further, the ratio of THC to CBD in a preparation determines the fine balance between its therapeutic use and mind-altering effects.

Epidiolex is the first CBD prescription approved by the US Food and Drug Administration (FDA) in 2018 to treat seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis (TS) in patients as young as 1 year old. It does not contain THC. This approval was based on 3 double-blind randomized controlled trials (RCT) and an open label extension study for LGS and DS, and one RCT for TS, all with positive findings.19-22 About 25% of children with treatment-resistant epilepsy have comorbid ASD. Both LGS and DS have been commonly linked to ASD.

It is important to note that medical cannabis has its own significant side effects (Table 1). A 2012 research study by Duke University found that persistent users of cannabis had reduced neuropsychological functioning, with adolescent onset users experiencing greater decline in IQ and executive functioning.23 These effects did not reverse fully on stopping cannabis use for one year or more, suggesting it has potential neurotoxic effects.

Another study shows that cannabis use in adolescence can significantly increase the risk of developing psychotic symptoms and persistent use can precipitate psychotic disorders in later life.24 Studies have also shown that cannabis use and the development of psychosis in adolescents is dose-dependent, with poorer outcomes associated with an earlier age and higher frequency of use.24

One 2015 to 2017 study conducted in Israel sought to gauge the safety and efficacy of cannabis.25 It observed 188 autism patients, most of whom were treated with an oil containing 30% CBD and 1.5% THC. It was not placebo controlled. After 6 months of treatment, parameters of activities of daily living, mood, and quality of life were assessed. It found that 30.1% of patients reported significant improvement, 53.7% moderate and 6.4% slight improvement, while 8.6% experienced no change to their condition. About 25% of self-reporting patients experienced at least 1 side effect from the treatment, the most common of which was restlessness. The study concluded that CBD and THC in autism patients appeared to be well-tolerated, safe, and effective.

In 2018, a study conducted at the Shaare Zedek Medical Center assessed the effect of a whole plant cannabis extract (20:1 CBD:THC ratio) on 60 autistic children with severe behavioral problems.26 Parents reported that 61% of behavioral symptoms in patients had either “much improved” or “very much improved,” 39% of children experienced improved anxiety level, and 47% improved in communication. Additionally, 24% of children were able to stop taking medication, 30% received either lower dose or fewer medications, while 8% had to increase medication intake. The incidence of side effects and adverse effects was quite high, reported by 57 parents. Common side effects included hypervigilance leading to sleeping difficulty (14%), irritability (9%), loss of appetite (9%), and restlessness (9%).

In another Israeli study published in 2019, 53 children with autism were given a 20:1 ratio CBD to THC dose for a median duration of 66 days in order to study its effect on comorbid symptoms with ASD.27 Symptoms were assessed every 2 weeks through phone call interviews with parents. Changes in individual symptoms cohorts were compared to available data from published studies. Of note, significant improvement was noted in self-injury and rage attacks (67.6%), hyperactivity symptoms (68.4%), sleep problems (71.4%), and anxiety (47.1%) within the groups of patients reporting these symptoms. The overall improvement in ASD comorbidities was calculated to be 74%. Common side effects included somnolence and reduced appetite.

It is important to note, however, that the aforementioned studies are limited because they were observational studies conducted without a placebo control group for comparison. Additionally, results were based on parental reports, which may have been heavily influenced by expectations, thus undermining results.

Adi Aran, MD, MSc, PhD, the Shaare Zedek study’s26 lead author, recently published a double-blinded, randomized placebo-controlled trial in February 2021 to study the role of cannabis in autism further.28 The study used 2 oral cannabinoid solutions (whole plant extract and purified forms of cannabis) with a 20:1 CBD to THC ratio along with a placebo. The purpose was to assess behavioral problems in 150 children and youth with autism with a unique crossover design that included 2 phases of 12 weeks, separated by a 4-week washout phase. It showed mixed results with no difference in one of the primary and secondary outcomes among the groups.

The study assigned 2 primary outcome measures to assess behavioral problems: the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale, with anchor points related to behavioral difficulties (CG-I). Secondary outcomes were measured by the Social Responsiveness Scale-second edition (SRS-2,) the Autism Parenting Stress Index (APSI) and modified Liverpool Adverse Events Profile. There was no difference in the total score of HSQ-ASD and APSI between the groups. However, disruptive behavior assessed by CGI-I scale was “much” or “very much” improved in 49% of participants who were given a whole-plant extract, versus 21% of participants on placebo (P = .005). The SRS-2 scale median score also improved by 14.9% on plant extract versus 3.6% placebo (P = .009). Common side effects included somnolence and decreased appetite. The study advised caution that while the CBD/THC solution was well-tolerated, the study had several limitations. The data on efficacy was mixed or insufficient, warranting more research.28

A study conducted by the Institute of Psychiatry, Psychology, and Neuroscience at King’s College in London used magnetic resonance spectroscopy to examine the effects of a single oral dose of CBD versus a placebo on the brains of 34 male participants, half of whom were diagnosed with autism.29 It is important to note that the study excluded any comorbid major psychiatric or neurological conditions, including traumatic brain injury, certain genetic disorders linked with autism, low IQ, and those receiving medicines with effects on glutamate-GABA pathways. The study found that while CBD affected the glutamate-GABA systems, the prefrontal-GABA systems responded differently in patients with autism. The authors were clear that the results did not apply to the efficacy of CBD.

Future Trials

There are other clinical trials currently underway that are worth following to see what they discover. Children’s Hospital of Philadelphia recently completed an observational study in collaboration with Zelda Therapeutics, an Australian biopharmaceutical company, to track children with autism who are independently using medical cannabis to address symptoms. Results have not been published yet.30 Another ongoing phase 2, 12-week double-blind, randomized, placebo-controlled trial study, funded by the US Department of Defense, is studying how behavior in children with autism might be affected by cannabidivarin, a nonpsychoactive phytocannabinoid, which is a safer alternative to CBD.31

The University of San Diego is conducting a phase 3 clinical trial in partnership with the Wholistic Research and Education Foundation through the Center for Medicinal Cannabis Research. It seeks to explore the role of CBD on behavioral symptoms in children with autism.32 The University of Colorado, Denver, is currently also recruiting participants for a randomized placebo-controlled study with a predetermined crossover design to assess CBD’s impact on common behavioral problems related to autism.33 All participants will receive CBD for at least 12 weeks. Some will receive CBD for the entire 27 weeks of treatment.

New York University’s Langone Health research facility is in the recruiting stage for a 6-week open trial to study CBD use in participants aged 7 to 17 with autism. It will assess dosing, symptoms changes, side effects, and primary and secondary outcomes to guide future controlled studies.34

Barriers to Research

While interest grows in cannabis, the medical community is eager for more research on how it might affect autism. In the United States, tight controls and a lack of adequate funding limits how cannabis is studied.

The National Institute on Drug Abuse (NIDA) contracts with the University of Mississippi, the only facility in the country registered with the Drug Enforcement Agency (DEA) to grow and supply the cannabis that scientists are allowed to study. However, these strains are often not the ones widely distributed to the public in states that have legalized medical cannabis.

Different strains of cannabis have diverse chemical variations, according to Donald Abrams, MD, an integrative oncologist at Zuckerberg San Francisco General Hospital and Trauma Center.35 Products with higher amounts of THC, for example, are often used to treat cancer-related nausea and poor appetite, while CBD tends to be used for chronic pain, inflammation, and insomnia. Abrams also pointed out that NIDA’s supply included mostly low-THC, zero-CBD strains, which can challenge researchers struggling to move with the times and study emerging products on the market. NIDA’s focus on substance abuse also means it is more focused on the negatives of cannabis, rather than any potential benefit.

Even NIDA has acknowledged federal limitations on cannabis research. In 2015, Nora Volkow, MD, NIDA’s director, spoke before the US Senate Caucus on International Narcotics Control.36 She acknowledged application barriers to research and the lack of well-controlled clinical trials. She also noted CBD’s potentially positive effect on a variety of symptoms, including children with drug-resistant epilepsy.

Approval to conduct cannabis research comes from both the FDA and the DEA. The process takes more than a year, with some researchers waiting even longer. Strict protocols govern how cannabis is stored, requiring limited access in an alarm-controlled, locked container physically attached to a floor or wall, according to the UCSF report.35 These obstacles create a catch-22 for medical marijuana research, according to the State of Cannabis Research Legislation in 2020, a report led by Ali Zarrabi, MD, associate director of outpatient support and palliative care at Emory University.37

“Investigators cannot conduct research on cannabis until they demonstrate that it has a medical use, and they cannot show that it has a medical use until they conduct research,” the report states.37

Treading With Caution

The American Academy of Child and Adolescent Psychiatry discourages the use of marijuana and cannabinoids in children with autism, a stance that has not changed despite the FDA’s approval to use cannabidiol to treat seizures. The American Academy of Pediatrics holds a similar stance, although it acknowledges it may provide an option for children with life-limiting or severely debilitating conditions when current therapies are inadequate.

Despite these cautions, individuals with any number of ailments are flocking to cannabis for treatment. But there is a huge gap between the desire for treatment and the research needed for doctors to give approval. Additionally, it is rare for any cannabis curriculum to be included in residencies and fellowships, but this is changing.

We are taught to practice evidence-based medicine as psychiatrists, placing the highest importance on meta-analysis and well-designed double-blinded RCT in research. Most psychiatrists try to adhere to the established standards of evidence-based medicine. However, there are times when we prescribe medications for off-label purposes based on clinical experience, often with reasonable or good results. Could CBD be used in the same way, especially in cases where we are hitting a dead end with existing treatment strategies?

There is some anecdotal evidence that cannabis can positively affect autism. But there is a lack of well-designed clinical trials with adequate sample sizes to study its efficacy and assess for safety. We need to study pure CBD separate from pure THC, without the confounding unknown effects of other molecules present. At this time, however, clinical trials of THC in individuals under the age of 20 are probably unwise.

As of today, we lack evidence-based recommendations to support CBD and cannabis use in children with autism. We lack guidelines on overall safety and efficacy, as well as factors like dosage, the required ratio of CBD to THC, symptoms that will likely respond, and the duration of treatment. We also lack guidance on how to discuss this sensitive topic with our patients, who may be asking for advice and are ready to pursue it on their own. See Table 2 for some tips on how to advise patients.

Therefore, psychiatrists must direct patients and families in their approach toward this treatment option with exercised caution to its risks, benefits, and costs. Additionally, they must understand the data that does exist, and then explain that current data, with its significant lack of evidence-based results, to our patients and their families.

Dr Parmar is a double board-certified adult and child psychiatrist with Community Psychiatry based in Newark CA. She earned her medical degree at Terna Medical College & Hospital in Mumbai, India.

References

1. National Institute on Drug Abuse. Marijuana as medicine. Drug Facts. Accessed May 21, 2021. https://www.drugsandalcohol.ie/18946/1/marijuanamedicinedrugfacts_july2019_.pdf

2. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.

3. Freeman TP, Hindocha C, Green SF, Bloomfield MAP. Medicinal use of cannabis based products and cannabinoids. BMJ. 2019;365:1141.

4. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.

5. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol. 2011;163(7):1411-1422.

6. Hrdlicka M, Komarek V, Propper L, et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry. 2004;13:209-213.

7. Agarwal R, Burke SL, Maddux M. Current state of evidence of cannabis utilization for treatment of autism spectrum disorders. BMC Psychiatry. 2019;19:328.

8. Scherma M, Masia P, Satta V, et al. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin. 2019;40(3):309-323.

9. Fišar Z. Cannabinoids and monoamine neurotransmission with focus on monoamine oxidase. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):68-77.

10. Centers for Disease Control and Prevention. Data & statistics on autism spectrum disorder. Accessed May 21, 2021. https://www.cdc.gov/ncbddd/autism/data.html

11. Chaste P, Leboyer M. Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci. 2012;14(3):281-92.

12. Durkin MS, Maenner MJ, Newschaffer CJ, et al. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol. 2008;168(11):1268-1276.

13. Buglione N. Marijuana madness. Autism Support Network. Accessed May 21, 2021. http://www.autismsupportnetwork.com/news/autism-treatment-marijuana-madness-8763721

14. Karhson DS, Krasinska KM, Dallaire JA, et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018;9:18.

15. Justinova Z, Solinas M, Tanda G, et al. The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys. J Neurosci. 2005 ;25(23) :5645-5650.

16. Siniscalco D, Sapone A, Giordano C, et al. Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord. 2013;43:2686-2695.

17. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A. 2015;112(45):14084-14089.

18. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.

19. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897.

20. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096.

21. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020.

22. US Food and Drug Administration. FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease. July 31, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare#:~:text=Today%2C%20the%20U.S.%20Food%20and,year%20of%20age%20and%20older

23. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109(40):E2657-64.

24. Kuepper R, van Os J, Lieb R, et al. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ. 2011;342:d738.

25. Bar-Lev Schleider L, Mechoulam R, Saban N, et al. Real life experience of medical cannabis treatment in autism: Analysis of safety and efficacy. Sci Rep. 2019;9(1):200.

26. Aran A, Cassuto H, Lubotzky A, et al. Brief report: Cannabidiol-rich cannabis in children with autism spectrum disorder and severe behavioral problems-a retrospective feasibility study. J Autism Dev Disord. 2019;49(3):1284-1288.

27. Barchel D, Stolar O, De-Haan T, et al. Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and comorbidities. Front Pharmacol. 2019;9:1521.

28. Aran A, Harel M, Cassuto H, et al. Cannabinoid treatment for autism: a proof-of-concept randomized trial. Mol Autism. 2021;12(1):6.

29. Pretzsch CM, Freyberg J, Voinescu B, et al. Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. 2019;44(8):1398-1405.

30. Children’s Hospital of Philadelphia. Medical cannabis registry and pharmacology (Med Can Autism.) Updated January 27, 2020. https://clinicaltrials.gov/ct2/show/NCT03699527

31. Hollander E. Cannabidivarin (CBDV) vs. placebo in children with autism spectrum disorder (ASD). Updated February 18, 2021. https://clinicaltrials.gov/ct2/show/NCT03202303

32. Trauner D. Trial of cannabidiol to treat severe behavior problems in children with autism. Updated August 18, 2020. https://clinicaltrials.gov/ct2/show/NCT04517799?term=epidiolex&cond=Autism&draw=1&rank=1

33. University of Colorado, Denver. Cannabidiol study in children with autism spectrum disorder (CASCADE). Updated Febrauary 26, 2021. https://clinicaltrials.gov/ct2/show/NCT04520685

34. NYU Langone Health. Cannabidiol for ASD open trial. Updated January 14, 2021. https://clinicaltrials.gov/ct2/show/NCT03900923

35. Wells J. Dazed and confused: marijuana legalization raises the need for more research. University of California San Francisco. June 20, 2017. https://www.ucsf.edu/news/2017/06/407351/dazed-and-confused-marijuana-legalization-raises-need-more-research

36. Volkow N. The biology and potential therapeutic effects of cannabidiol. National Institute on Drug Abuse. June 24, 2015. https://archives.drugabuse.gov/testimonies/2015/biology-potential-therapeutic-effects-cannabidiol

37. Zarrabi AJ, Frediani JK, Levy JM. The state of cannabis research legislation in 2020. N Engl J Med. 2020;382(20):1876-1877.

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CBD

Royal Blend CBD Gummies Review – Scam or Effective Gummy Product?

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Are you still experiencing stress, anxiety, body aches and pains? Tired of going to the doctor or therapist, or taking prescribed pills that don’t have long-term effects? Then, you’re not alone; This article can help you. Many people around the world struggle with various physical and psychological problems that affect their daily activities and lifestyle. However, medications are not really effective and can have negative effects on the body system due to frequent use. Why not choose natural solutions that are unlikely to have any adverse effects?

Recently, cannabinoid (CBD) products have gained popularity in the health and wellness industry as a famous natural remedy for correcting physical and mental problems, particularly body pain, depression, stress and anxiety. As people continue to adopt CBD as a cure for many health problems due to its effectiveness, they yearn for the best CBD products on the market for the best possible effects. Royal Blend CBD gummies have been rated as one of the best CBD products on the market with numerous health claims combined with the delicious taste of the gummies. This CBD product promises to supply the body system with enough cannabinoids to improve the working condition of the endocannabinoid system; This can help improve overall body condition, relieve pain, and improve mental health.

Royal Blend CBD Gummy is a natural nutritional supplement in the form of a fruit-flavored candy enriched with CBD oil to offer delicious and tasty cannabinoid pills. These pills are designed to help manage the stress of taking CBD oils or capsules, which some people find difficult. These CBD gums purportedly contain all-natural ingredients that have been scientifically proven and clinically tested to help alleviate the body’s physical and mental problems. According to the manufacturer, Royal Blend CBD gummies can help relieve chronic body aches and pains, anxiety, depression, stress, and others. In addition, the ingredients in this supplement can help improve joint flexibility, reduce the risk of obesity, high blood sugar and pressure, cardiovascular disease, and promote healthy sleep.

Royal Blend CBD gummies are not said to contain any psychoactive THC effects; therefore they are not addicting and take getting used to. The manufacturer said these CBD gums contain no chemical additives or stimulants and are unlikely to cause any side effects.

Overall, this product is designed to improve human physical and mental health.

As with many other CBD products, the main ingredient in this dietary supplement is CBD. It is said to contain 100% organic hemp oil extract to improve body condition and eliminate inflammation. You have no reason to worry about using this dietary supplement; The manufacturer said all components are all natural and have no adverse effects.

The main target of this supplement is the human endocannabinoid system (ECS), which is responsible for many activities in the body, such as regulating mood, sleep, pain relief, and others. When used, Royal Blend Gummies go straight into the system to provide CBD to the endocannabinoid system, increase cannabinoids in the body, and improve ECS function. This will help improve the body’s working conditions, relieve muscle and joint pain, and improve mood and sound sleep.

The producer said Royal Blend Gummies could help you feel good all day without getting high.

Royal Blend gummies promise different benefits depending on age, weight and state of health, among other things. Each bottle of Royal Blend Gummies contains 100% organic, fruit-flavored CBD for great taste. Unlike pain relievers and prescribed pills, which can have side effects later on, Royal Blend gummies are purported to do no harm to the body. Below are some of the benefits of this supplement.

Pain and Pain Relief: This supplement is a natural pain reliever that can help you relieve aches and pains in the joints, muscles, and other parts of the body. This supplement works by supplying CBD to the endocannabinoid system to help relieve body pain. Royal Blend Gummies can lubricate the joint for maximum flexibility. According to the manufacturer, you can do without painkillers with Royal Blend Gummies.

Reduced inflammation: Inflammation is a common problem in people that puts them at risk of disease, infection, damage to arteries, joints, and organs. Royal Blend Gummies promise to reduce inflammation in the body to keep you healthy and safe.

Control of blood sugar: According to the official website, Royal Blend Gummies can help regulate blood sugar to prevent diabetes and obesity. Hence, the body’s immune system becomes stronger and more effective.

Mood and anxiety reduction: With the ability to supply CBD to the ECS, Royal Blend Gummies can help improve mood, reduce anxiety, and calm the nerves by helping the ECS to calm the brain. Anxiety, depression, and stress are among the most common problems people face; You can alleviate these problems with Royal Blend Gummies.

Improved healthy sleep: Once the brain is calm and calm, you can sleep better. Royal Blend Gummies can help you enjoy a longer, healthy sleep that is better at invigorating your cells.

Improved blood circulation: Royal Blend Gummies can stimulate blood flow to the body system, allowing cells to receive more nutrients and reducing exposure to many diseases such as stroke and high blood pressure.

First of all, it is important to know the people who cannot use this supplement. Royal Blend CBD gummies are only suitable for adults. Pregnant women and women who are breastfeeding should not take this supplement, and it is not recommended for people with certain health problems.

Using Royal Blend CBD Gummies is very simple and straightforward. According to the manufacturer, you should start taking this dietary supplement with one CBD gum per day. Depending on your age, weight, and health status, you can increase the dosage to work perfectly for you. Seek advice from your doctor if you think it is necessary.

Royal Blend CBD Gummies can be purchased from the official website. To avoid buying counterfeits, do not buy from a third party website. Below are the prices and deals to buy Royal Blend CBD Gummies.

  • 2 x bottles cost $ 234.72 (free shipping)
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CBD

Does It Have an Effect?

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High blood pressure or high blood pressure can lead to serious health problems like a heart attack or stroke. But because high blood pressure doesn’t usually cause symptoms, many people don’t even know they have it. This is why it is so important to check your blood pressure regularly.

If you have high blood pressure, you may have heard that cannabidiol (CBD) can help lower blood pressure. Here’s what the research says plus tips on how to find a few products to explore.

Blood pressure is defined as the pressure of blood against the walls of the arteries. While it is normal for blood pressure to go up and down over the course of a day, persistently high blood pressure levels are a problem.

There are two types of high blood pressure:

  • Primary hypertension is the most common. It develops gradually for no apparent cause, but it may be related to genetics, physical changes in the body, or being high in body weight.
  • Secondary hypertension comes quickly and can be more serious. It has a number of causes, including kidney disease, congenital heart defects, thyroid problems, alcohol use, and certain drugs and stimulants such as cocaine and amphetamines.

Because high blood pressure is often a silent condition, symptoms may not appear until the severity of the condition develops. At this point, symptoms can include:

  • headache
  • Nosebleeds
  • shortness of breath
  • dizziness
  • Chest pain
  • Flushing
  • Changes in vision
  • Blood in the urine

If you have these types of symptoms, it is important to see a doctor right away.

CBD is one of the active ingredients in the cannabis plant. In contrast to tetrahydrocannabinol (THC), it has no intoxicating properties or creates a “high”. Instead, there is a lot of focus on the potential therapeutic benefits of CBD. It can be helpful for everything from pain relief and improved sleep to anxiety and even addiction.

CBD is available in a few different types: full spectrum, broad spectrum, and isolate.

While full-spectrum and broad-spectrum both contain other compounds from the cannabis plant – like flavonoids, terpenes, and other cannabinoids – full-spectrum CBD is the only type that has some THC in it (usually less than 0.3 percent).

CBD isolate is pure CBD. However, it’s important to know that any type of CBD can contain traces of THC that could be detected in a drug test.

These three forms of CBD are made into a wide variety of products, including:

  • Oils and tinctures. These liquids have been fortified with CBD. You can either place them under the tongue or add them to food and drinks.
  • Edibles. Sometimes CBD is added to foods like gummy bears or beverages like teas. Edibles are one of the most popular methods of consumption because they are discreet and easy to dose.
  • Capsules. CBD can be taken in tablet or capsule form.
  • Subjects. Topical CBD is applied directly to the skin for targeted relief.
  • Vape juices. These products are designed to be inhaled with a vape pen. The effects are very quick, but there have been reports of lung injuries related to vaping. Currently, we don’t know if vaping CBD carries the same risks.

CBD interacts with the body’s own endocannabinoid system (ECS), a complex system that helps regulate a number of processes in the body.

As our understanding of the ECS continues to evolve, we know that it has three components:

  • Endocannabinoids, which are molecules that are made in the body
  • Endocannabinoid receptors found throughout the body; the main receptors are called CB1 and CB2 receptors
  • Enzymes that break down endocannabinoids once they have finished their function

Currently, researchers believe that the main role of the ECS is to maintain homeostasis in the body. The ECS is associated with a number of processes in the body, including:

  • Appetite and digestion
  • metabolism
  • pains
  • mood
  • sleep
  • Engine control

Cannabinoids, including THC and CBD, interact with the ECS by attaching to receptors in the same way as endocannabinoids.

While THC can bind to both CB1 and CB2 receptors, researchers don’t yet understand how CBD interacts with the ECS. One theory is that CBD prevents endocannabinoids from breaking down and gives them greater effects on the body. Another theory is that CBD binds to a receptor that researchers have not yet identified.

There is research from 2011 suggesting that ingesting both THC and CBD along with the other compounds in the cannabis plant may be more effective than using a single cannabinoid on its own. This theory is known as the entourage effect, and this is why some people say that full-spectrum CBD works better than broad-spectrum or isolate.

There is some evidence that CBD products might help lower blood pressure, but the research is somewhat contradicting.

A 2017 study of nine male participants found that a single dose of CBD in healthy participants lowered blood pressure in those at rest and those who were under stress.

Another 2017 study in mice found that CBD significantly reduced stress-related increases in blood pressure and heart rate.

However, a 2020 study in rats found that CBD was not effective in lowering blood pressure, despite having antioxidant effects. Another 2020 study was more promising, the results of which showed that CBD could lower blood pressure in stressed patients.

Researchers recognize the beneficial effects of CBD in cardiovascular disease, but note that additional study is needed to fully understand how it could help.

Both the Food and Drug Administration (FDA) and the World Health Organization (WHO) recognize the potential benefits of CBD.

A report by the WHO from 2017 describes CBD as generally well tolerated with a good safety profile and no effects that could indicate a potential for abuse or dependence.

The FDA notes that more research is needed and notes that many questions about the safety of CBD remain unanswered. In addition, it should be noted that some CBD products are inaccurately labeled and of questionable quality.

If you decide to give CBD a try, be aware that some people experience side effects, including:

  • diarrhea
  • Changes in weight or appetite
  • fatigue

2012 research on cannabinoids and anxiety suggests that some cannabinoids can have two-phase effects, meaning that they have different effects depending on the dose taken.

Specifically for high blood pressure, a 2011 study found that THC alone or in combination with CBD sometimes increased blood pressure and sometimes decreased it.

Finally, it’s important to keep in mind that CBD can interact with some drugs, including those used for high blood pressure. If you are considering using CBD to treat high blood pressure, speak to a doctor first.

Although CBD comes in many forms, the best option for high blood pressure is likely to be an oil or tincture rather than a topical or edible one. Oils tend to offer higher bioavailability, which means a higher rate of absorption for greater effectiveness. Sublingual products also have a full body effect.

The FDA does not regulate CBD products in the same way as diet supplements and medications, which means consumers need to be careful about the brands they use. To find a high quality CBD product, there are a few things that are important to check.

Certificate of Analysis

Avoid buying CBD products that don’t have a Certificate of Analysis (COA). A current COA means that a product has been tested for safety and purity by an external laboratory. Many brands make these reports available through a QR code on the product packaging or on the website.

When you review the COA, double-check that the amount of CBD and THC the lab found matches the advertised. Also, look at the pollutant test results to make sure there are no unsafe amounts of pesticides, heavy metals, or mold.

Warning letters and lawsuits from the FDA

When a CBD company makes unaudited health claims, the FDA sends out a warning letter. You can check online whether a company has received such a letter and whether it has been involved in any litigation. If you find that a company received one, it might be best to avoid it.

Customer rating

Look for customer feedback on both the company and the product you are considering to get an idea of ​​its effectiveness. However, be aware that some brands:

  • only publish positive reviews on their pages
  • Remove reviews mentioning specific health conditions to comply with FDA regulations

transparency

Always read a brand’s website that you’re interested in. Some brands will be very open about where they get their CBD from and how they make their products. These are the brands you will want to buy from.

Don’t rely on CBD alone to lower blood pressure. It is important to speak to a doctor and follow their prescriptions. This can include medication.

There are also home remedies that can help treat the condition. Eating a nutritious diet high in fruits, vegetables, whole grains, and lean proteins is important, as is weight control and regular exercise. It is also recommended that you maintain a low-sodium diet.

Coping with stress is also important. Things like meditation, massage, yoga, and even deep breathing are worth exploring to relieve stress.

Finally, smoking can also affect blood pressure. Chemicals in tobacco smoke damage tissues in the body and harden the walls of blood vessels. Alcohol can also increase blood pressure, so limiting consumption can be helpful.

Before trying CBD for treating high blood pressure, it is important to speak with a doctor. Regular checkups are also a good idea, as symptoms of high blood pressure often don’t show up until the condition becomes more severe.

If you experience symptoms or if you can’t remember the last time your blood pressure was measured, it’s a good idea to speak to a doctor.

High blood pressure can be dangerous, and it’s a condition that may not be noticeable until it’s serious. Fortunately, there are medications and lifestyle changes that can help, and there is some evidence that CBD is another option worth exploring. Before doing this, however, consult a doctor.

Jessica Timmons has been a freelance writer since 2007, and covers everything from pregnancy and parenting to cannabis, chiropractic, stand up paddling, fitness, martial arts, home decor and much more. Her work has appeared in mindbodygreen, Pregnancy & Newborn, Modern Parents Messy Kids and Coffee + Crumbs. Check out what she’s doing at jessicatimmons.com.

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CBD

Comparing THC compounds: What we know about THC-O versus delta-9 & delta-8

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THC-O-acetate is even stronger than regular THC. Here’s what you need to know to try it safely.

From Delta-8 to Delta-10, cannabinoids made from hemp have a moment. And now there’s a new kid on the block that’s about to be taken over: THC-O. But while the Deltas are gentler versions of the classic THC or Delta-9 of cannabis fame, THC-O can be three times more potent than its mainstream cousin.

Because it is made from hemp, THC-O has a different legal status than cannabis products, especially in many states that do not yet have a recreational market. That being said, there is still some debate over whether THC-O is “synthetic THC” under federal law, which is still a controlled substance and illegal, even if it’s made from hemp. So proceed with caution.

We are still learning a lot about THC-O, although there is research on it that dates back to the 1940s. As its popularity grows, it’s important to keep up with the facts – and how to find safe, effective, and reputable products.

Related

Meet THC-O, a hemp-derived compound that is three times stronger than THC

Here’s what we know about THC-O, and how to make sure it’s from a trusted source before trying it out.

THC-OCourtesy of five ™

What is THC-O and where does it come from?

The full name of THC-O is THC-O-acetate, and the earliest research we have on it dates back to American military experiments involving non-lethal incapacitated agents in the 1940s. Researchers tested the compound on dogs. At the end of the experiment, the dogs had clearly lost control of their motor skills.

In order to obtain THC-O from hemp, CBD is first converted into Delta-8 or a similar THC modification. But it goes one step further. Adding acetic anhydride to the mixture turns it into an acetate – especially THC-O.

But don’t try this at home! Acetic anhydride is highly corrosive and flammable and is dangerous to your health, safety and the environment unless it is manufactured in a strictly controlled laboratory environment. This is one of several reasons why you should only buy THC-O if you know it is from a reputable source.

How do you take THC-O?

When it’s done, THC-O-acetate is a kind of thick brown liquid. You can take it in a vape cartridge, tincture, or edible. It takes about 20-30 minutes for it to set in.

THC-OCourtesy of five ™

How does THC-O feel? How is it different from Delta-8, -9 and -10?

Delta-8 and Delta-10 are both milder and generally less intoxicating than regular Delta-9 THC. Delta-8 is known for its more sedative effects, while Delta-10 has a reputation for being a more active, sativa-like high.

THC-O is significantly stronger than not only Delta-8 and -10, but also normal THC. Some users have reported a more spiritual high with powerful effects that can even border on hallucinogenic effects. As with any drug, the effects and tolerability vary from person to person.

How to Buy THC-O Safely

Because THC-O is largely unregulated, buying THC-O from a mysterious source carries many risks. Cannabis researcher James Stephens told Leafly that sometimes producers don’t even know or claim they don’t know what’s in their own product: “I ask, ‘What’s the rest?” And they say,’ We don’t know. ‘ .. That’s what usually ends the conversation. “

There’s also the possibility that THC-O-Oil contains toxic additives – and we’ve already seen sketchy additives cause serious health problems. Since it’s so much stronger than other forms of THC, you’ll want accurate potency most of all.

You want to buy from a company that is completely transparent, with clear laboratory results and a high level of responsibility towards its customers. five has been making trustworthy, transparent, full-spectrum products that combine CBD with other beneficial hemp compounds for years, and they were one of the first companies to offer products with Delta-9 and Delta-10. They know how to make perfect blends of cannabinoids – and they have experience making them safely, with the consumer’s experience in mind. They even offer certificates of analysis from third party laboratories so you know what it says on the bottle matches the contents of the product.

THC-OCourtesy of five ™

five has worked hard to develop THC-O products that meet their high standards. Right now, you can get to know them through their fan favorite offers – and if THC-O appeals to you, you know you have a producer you can trust for a great experience.

At the moment five has a special offer for Leafly readers. Click the link below to try a full size product for free. You only pay for shipping and five covers the rest.

Daily buzz gummies: Five’s flagship gummies are both delicious and powerful, with a full range of beneficial botanicals and 5 mg of Delta-9 THC per gummy bear. Like all of their gummies, they’re vegan too. * Availability is subject to local laws.

Sleeping rubbers: Five’s Recovery Gums add the natural sleep aid melatonin to their perfect blend of hemp cannabinoids – with up to six times more cannabinoids than other brands.

THC + CBD liquid capsules: Get all of the benefits of full-spectrum hemp in one easy-to-use capsule with CBD, THC, CBN, and CBC.

Full spectrum THC + CBD chocolate: For a more luxurious edible experience, five offers their signature blend of cannabinoids in two chocolate flavors: milk chocolate and dark sea salt chocolate.

Full spectrum THC + CBD oil: It all started with this oil. Two flavors of tinctures, citrus and mint chocolate, are packed full of CBD, THC, CBN, CBC, and terpenes.

THC-OCourtesy of five ™

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