Bortezomib And Endocannabinoid/Endovanilloid System: A Synergism In Osteosarcoma.

Pharmacological Research

“Osteosarcoma is the most common primary malignant tumor of bone in children and adolescents.

Bortezomib (BTZ) is an approved anticancer drug, classified as a selective reversible inhibitor of the ubiquitin-dependent proteasome system, that leads to cancer cell cycle arrest and apoptosis reducing the invasion ability of Osteosarcoma cells in vitro. It also regulates the RANK/RANKL/OPG system, involved in the pathogenesis of bone tumors and in cell migration.

A side effect of BTZ is to induce painful sensory peripheral neuropathy which lead to cessation of therapy or dose reduction.

Recently BTZ has been evaluated in combination with Cannabinoids targeting CB1 receptor, demonstrating a promising synergic effect.

The Endocannabinoid/Endovanilloid (EC/EV) system includes two G protein-coupled receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel and their endogenous ligands and enzymes.

CB1 and CB2 are expressed mainly in Central Nervous System and Immune Peripheral cells respectively. TRPV1 is also expressed in primary sensory neurons and is involved in pain modulation.

EC/EV system induces apoptosis, reduces invasion and cell proliferation in Osteosarcoma cell lines and is involved in bone metabolism.

We analyzed the effects of BTZ, alone and in combination with selective agonists at CB2 (JWH-133) and TRPV1 (RTX) receptors, in the Osteosarcoma cell line (HOS) on Apoptosis, Cell Cycle progression, migration and bone balance. We observed that the stimulation of CB2 and TRPV1 receptors increase the efficacy of BTZ in inducing apoptosis and reducing invasion, cell cycle progression and by modulating bone balance.

These data suggest the possibility to use BTZ, in combination with EC/EV agonists, in Osteosarcoma therapy reducing its dose and its side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30267762

https://www.sciencedirect.com/science/article/abs/pii/S1043661818310387

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Cannabinoid Delivery Systems for Pain and Inflammation Treatment.

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“There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions.

The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety.

The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes.

Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.”

https://www.ncbi.nlm.nih.gov/pubmed/30262735

https://www.mdpi.com/1420-3049/23/10/2478

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Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

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“This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products.

The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers.

The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months).

Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/223, 36%), with statistical significance (p < 0.0001).

Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.56) between treatments with CBD-rich extracts (97/255, 38%) and purified CBD (94/223, 42%).

Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346, p < 0.0001) and severe (23/285 vs. 77/346, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts.

CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30258398

https://www.frontiersin.org/articles/10.3389/fneur.2018.00759/full

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Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

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“The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner’s attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available.

Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy.

Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018.

Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1-35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient’s quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option.

Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30258395

https://www.frontiersin.org/articles/10.3389/fneur.2018.00731/full

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Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats.

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“Methamphetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects.

Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on methamphetamine addiction.

AIMS:

The current study investigated whether cannabidiol administration reduces the motivation to self-administer methamphetamine and relapse to methamphetamine-seeking behavior following abstinence.

RESULTS:

Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer methamphetamine and attenuated methamphetamine-primed relapse to methamphetamine-seeking behavior after extinction.

CONCLUSION:

This is the first demonstration that cannabidiol can reduce the motivation to seek and consume methamphetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for methamphetamine dependence.”

https://www.ncbi.nlm.nih.gov/pubmed/30260267

http://journals.sagepub.com/doi/abs/10.1177/0269881118799954?journalCode=jopa

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Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.

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“Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction.

Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control.

Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity.

The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment.

The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/29686308

https://www.nature.com/articles/s41386-018-0050-8

“Unique treatment potential of cannabidiol for the prevention of relapse to drug use” https://www.nature.com/articles/s41386-018-0218-2

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A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

 Annals of Clinical and Translational Neurology banner

“Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects.

Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy.

Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.

RESULTS:

Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.

CONCLUSIONS:

TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/30250864

https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.621

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Association of Cannabinoid Administration With Experimental Pain in Healthy Adults A Systematic Review and Meta-analysis

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“Patients have reliably endorsed the belief that cannabis is helpful in alleviating pain.

Cannabinoids (the collective term for all of the drugs examined in this study, including plant-based cannabis, which can contain multiple compounds) have long been considered effective for reducing pain and are frequently proposed as treatment options in pain management.

Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes.

Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain.”

“Cannabinoid drugs make pain feel ‘less unpleasant, more tolerable'”  https://www.sciencedaily.com/releases/2018/09/180919111454.htm

“Medical marijuana increases pain threshold for patients”  https://www.upi.com/Health_News/2018/09/19/Medical-marijuana-increases-pain-threshold-for-patients/1771537292969/?rc_fifo=1

“Study reveals cannabinoid drugs make pain feel ‘less unpleasant, more tolerable'”  https://medicalxpress.com/news/2018-09-reveals-cannabinoid-drugs-pain-unpleasant.html

“Cannabinoid drugs reduce perceived unpleasantness of painful stimuli and increase tolerance” https://www.news-medical.net/news/20180919/Cannabinoid-drugs-reduce-perceived-unpleasantness-of-painful-stimuli-and-increase-tolerance.aspx

“Cannabinoids appear to increase pain tolerability”  https://www.healio.com/psychiatry/practice-management/news/online/%7B7626bb3f-ce35-4968-99bc-50ecdaac79b7%7D/cannabinoids-appear-to-increase-pain-tolerability

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At 70, Singer Olivia Newton-John​ Using Cannabis To Treat Cancer.

“At 70, Singer Olivia Newton-John​ Using Cannabis To Treat Cancer. Olivia Newton-John says she has been diagnosed with cancer for the third time in three decades. Newton-John says she’s “treating it naturally and doing really well.” The “Grease” star says she is taking cannabis oil, made from marijuana her husband John Easterling grows on their ranch in Santa Barbara. She said, “I believe I will win over it.”” https://sanfrancisco.cbslocal.com/2018/09/10/olivia-newton-john-cannabis-cancer/

“Grease star Olivia Newton-John is battling her breast cancer with cannabis. Grease star Olivia Newton-John is offering an update on her third battle with cancer and revealing how cannabis has become a key component in her treatment plan.”   http://www.digitalspy.com/showbiz/news/a865881/grease-olivia-newton-john-battling-breast-cancer-with-cannabis/

Olivia Newton-John Says She’s Managing Breast Cancer with Cannabis. Newton-John explained that she uses cannabis oil to treat the pain and help her sleep, much of which her husband John Easterling (who runs Amazon Herb Company) grows for her. “I’m very lucky that I live in a state where it’s legal and that I have a husband who is a plant medicine man,” she said. “How lucky is that?” Newton-John also advocated for legalizing cannabis in her home country of Australia, adding, “My dream is that it will be available to all the cancer patients or people going through cancer or any kind of disease that causes pain.” Newton-John turns 70 on September 26.” http://exclaim.ca/music/article/olivia_newton-john_says_shes_managing_breast_cancer_with_cannabis

“Olivia Newton-John diagnosed with cancer for a third time but believes she ‘will win’ health battle with homegrown cannabis treatment. The Grease actress is using homegrown cannabis as part of her treatment to fight the disease. She drinks a cannabis mixture made by her herbalist husband to control the illness.” https://www.mirror.co.uk/3am/celebrity-news/olivia-newton-john-diagnosed-cancer-13220595

“Olivia Newton-John uses medical marijuana to treat cancer”  https://www.buzz.ie/celebs/olivia-newton-john-drinks-cannabis-extract-numb-pain-cancer-253796

“Olivia Newton-John reveals marijuana helping her beat cancer”   http://www.9news.com.au/national/2017/09/03/08/58/olivia-newton-john-backs-medicinal-cannabis

“Olivia Newton-John’s cancer battle is going well… Thanks to cannabis oil!”  https://closeronline.co.uk/celebrity/news/olivia-newton-john-daughter-chloe-lattanzi-cannabis-oil-cancer/ 

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Olivia Newton-John ‘Feeling Great’ as Source Denies ‘False’ Report Her Cancer Has Spread Further. “This is just false,” a source close to Newton-John tells PEOPLE. “She’s feeling and looking great. Everything that’s being reported about her diagnosis is the same news she released last year.” https://people.com/music/olivia-newton-john-denies-false-report-cancer-spread/

“Olivia Newton-John Reveals Secret Cancer Battle in 2013: ‘I Just Decided to Keep It to Myself.” Last year, Newton-John announced she’d been diagnosed with stage 4 breast cancer that had metastasized to her back, but the 69-year-old actress has been treating the illness with natural wellness therapies, including medicinal marijuana. A source close to Newton-John tells PEOPLE that she’s been feeling fine and healthy as of late.” https://people.com/music/olivia-newton-john-secret-cancer-battle-decided-keep-myself/

Olivia Newton-John: It’s not just cancer sufferers needing help, carers do too. The mum-of-one discovered she had a tumour in the base of her spine last year. She had previously overcome breast cancer in 1992 after undergoing surgery and chemo, before secretly beating the disease again in 2013. Praising both husband John and her daughter Chloe, Olivia said: “Of course they’ve been a huge support, I think it’s hard for people on the outside – the care takers – because they have to be taken care of too sometimes, because it is hard for them.” John grows cannabis plants for Olivia, as she has chosen natural therapies such as cannabis oil to help ease her pain from the disease, instead of opioids and other drugs such as chemo this time round. He grows the plants in California where the couple live, as it is legal there.” https://startsat60.com/entertainment/tv-movies/olivia-newton-john-cancer-sufferers-carers-husband-john-help

“‘I use cannabis’: Olivia Newton-John talks cancer treatment” https://startsat60.com/health/i-use-cannabis-olivia-newton-john-opens-up-on-cancer-treatment

“Olivia Newton-John using cannabis oil as she battles cancer for the third time”  https://www.hellomagazine.com/healthandbeauty/health-and-fitness/2018091162192/olivia-newton-john-using-cannabis-oil-battles-cancer-third-time/

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“Olivia Newton-John Is Using Cannabis Oil To Treat Her Cancer”  https://www.inverse.com/article/32780-cannabis-oil-cancer-treatment-cannabinoid-chemotherapy

“Olivia Newton John’s cannabis oil for cancer treatment” https://www.msn.com/en-nz/health/medical/olivia-newton-johns-cannabis-oil-for-cancer-treatment/ar-AAoTvE3

“‘I believe I will win’: Olivia Newton-John, 69, reveals the tragic cancer diagnosis she kept secret… as she fights the disease for a third time with the help of her husband” https://www.dailymail.co.uk/tvshowbiz/article-6148177/Olivia-Newton-John-69-reveals-tragic-cancer-diagnosis-kept-secret.html

“Olivia’s husband grows her medical marijuana”  https://au.be.yahoo.com/entertainment/celebrity/a/37038356/john-easterling-home-grows-olivia-newton-johns-medical-marijuana/

“Olivia Newton-John Admits to Using Home-Grown Medical Marijuana to Battle Cancer” http://popculture.com/2017/09/11/olivia-newton-john-medical-marijuana-breast-cancer/

“Olivia Newton-John Reveals She Was Unable to Walk After Cancer Relapse – and She’s Using Marijuana to Ease Pain. The 68-year-old said that the “hardest thing” has been her pain level, admitting that trying to do shows was “really agonizing.” Now, she’s been treating the pain with medical marijuana her husband John Easterling grows. “I’ll be fine,” said Newton-John.” https://people.com/music/olivia-newton-john-cancer-update-couldnt-walk-australian-60-minutes/

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“Olivia Newton-John on Being a Cancer ‘Thriver’ and Using Weed to Cope with Her Relapse: It’s a ‘Healing Plant’. The actress also shared that she’s been treating the pain with medical marijuana her husband John Easterling grows. “People have this vision from the ’60s of people just sitting around and getting stoned,” she said. “It’s not about that. This plant is a healing plant. I think we need to change the vision of what it is because it helped me greatly and it helps with pain and inflammation.”” https://people.com/music/olivia-newton-john-cancer-relapse-weed/

Olivia Newton-John reveals she is on medical cannabis for cancer” https://www.dailymail.co.uk/health/article-6171365/Olivia-Newton-John-reveals-medical-cannabis-breast-cancer.html

“‘It’s a magical miracle plant:’ Olivia Newton-John reveals husband John Easterling grows marijuana to aid her breast cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-4869940/Olivia-Newton-John-benefits-medical-marijuana.html

“‘It’s really important and should be available’: Olivia Newton-John speaks about how ‘medical cannabis’ is helping her beat breast cancer” https://www.dailymail.co.uk/tvshowbiz/article-4846664/Olivia-Newton-John-talks-cannabis-use-time.html

“Olivia Newton-John voices her support for medical marijuana after revealing her husband grows the plant to aid her breast cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-4891760/Olivia-Newton-John-voices-support-medical-marijuana.html

“‘Medical cannabis has helped me a lot’: Olivia Newton-John speaks candidly about the ‘healing remedies’ that have helped CURE her pain during her agonising cancer battle” https://www.dailymail.co.uk/tvshowbiz/article-5181401/Olivia-Newton-John-speaks-candidly-medical-cannabis.html

“Let’s Get Physical! Olivia Newton-John beams in green as she dazzles Melbourne crowds at charity walk to raise funds for her cancer research centre… after speaking candidly about her attempts to ‘win over’ the disease” https://www.dailymail.co.uk/tvshowbiz/article-6172857/Olivia-Newton-John-beams-green-dazzles-crowds-cancer-research-charity-walk.html

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Olivia Newton-John leads the biggest ever Wellness Walk and Research Run! With participant numbers up by over 50 per cent from last year, the beautiful grounds at La Trobe University were filled with a vibe of family, community, love and hope. Olivia Newton-John was an enthusiastic participant enjoying the sunshine, along with her husband John Easterling, her niece Tottie Goldsmith (herself an ONJ Centre Goodwill Champion) and other family members. She was grateful for the large crowd of people who were there to support her ONJ Centre.“It’s very moving actually, to see so many people turn out,” says Olivia. “It looks like there are more people than last year which is fantastic, people with their dogs and their children and their friends. It’s wonderful.”” https://www.onjcancercentre.org/news/article/2018/09/18/biggest-ever-wellness-walk-and-research-run

“Well over half a million dollars has been raised so far and while the event itself is over for this year, fundraising is still open until the 30 September. You can continue to support family and friends by donating to their page, or you can donate to Olivia’s page here: https://secure.artezpacific.com/registrant/FundraisingPage.aspx?registrationID=1213890&langPref=en-CA

“The Olivia Newton-John Cancer Wellness & Research Centre is at the frontier of cancer medicine, with over 200 ongoing clinical trials.” https://www.onjcancercentre.org/patients-family/clinical-trials

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http://www.thctotalhealthcare.com/olivia-newton-john-champions-the-use-of-magical-miracle-medicinal-cannabis/

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Recreational Cannabis Reduces Rapes and Thefts: Evidence from a Quasi-Experiment

 

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“An argument against the legalization of the cannabis market is that such a policy would increase crime. Exploiting the recent staggered legalization enacted by the states of Washington (end of 2012) and Oregon (end of 2014) we show, combining difference-in-differences and spatial regression discontinuity designs, that recreational cannabis caused a significant reduction of rapes and thefts on the Washington side of the border in 2013-2014 relative to the Oregon side and relative to the pre-legalization years 2010-2012.”

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2841267

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