While there are strong links between excessive usage of THC, especially in adolescents, with triggering psychosis and schizophrenia, CBD has been found to have the opposite effect. Can you successfully use cannabis, particularly the non-intoxicating CBD, to treat schizophrenia? Does THC actually cause the condition? Prepare for several mind-blowing facts about CBD, cannabis, and schizophrenia. Scientists are studying CBD oil for schizophrenia and dozens of other health conditions. Here’s what to know if you have schizophrenia and are thinking of trying CBD.
CBD Fights Schizophrenia, but with Different Dose Range for Different Symptoms
In journalism and media industry for more than twenty years, worked for a number of media companies. Business editing, research and PR specialist. Covering industry and science news for Ilesol Pharmaceuticals.
CBD Fights Schizophrenia, but with Different Dose Range for Different Symptoms
Have you wondered about CBD and its effect in treating schizophrenia? Schizophrenia is a chronic and in many cases permanently disabling mental disorder that affects about one percent of the world’s population. According to the World Health Organization, more than 26,3 million people suffer from the disease, 16,7 million are disabled and it is accounted for 30.000 fatal outcomes a year, half of which take place in South East Asia.
Schizophrenia is characterized by episodes of psychosis between periods of a blunted emotional state and stupor. Symptoms that occur during episodes of psychosis are called ‘positive symptoms’ and include impaired mental activity, a delirium that consists of false beliefs, and is often accompanied by paranoia; and hallucinations, most commonly in the form of hearing prying voices. These symptoms are accompanied by anxiety, depression, and excessive activity, e.g. constant movement and agitation.
Negative symptoms of schizophrenia include blunted emotions, a decrease in the frequency of speech, a deterioration in the ability to plan, start or continue any activity, and a reduction in the perception of positive emotions or interest. These symptoms can cause severe problems in social interaction and daily life.
The third group – cognitive symptoms of schizophrenia include disorganized thinking, slow thinking, difficulty understanding, poor concentration, poor memory, difficulty expressing thoughts, and difficulty integrating thoughts, feelings, and behavior.
The opposite effects of THC and CBD
While there are strong links between excessive usage of THC, especially in adolescents, with triggering psychosis and schizophrenia, CBD has been found to have the opposite effect . Nonetheless, a significant proportion of patients don’t respond to traditional antipsychotics , that only target the positive symptoms, with little effect on negative or cognitive symptoms. On top of that, dopamine-acting antipsychotics are associated with a number of side effects, some of which can be severe.
These understandings have driven the attention of scientists to provide more scientific evidence on the effects of CBD on patients who suffer from schizophrenia.
In 1982, a study of the interactions between THC and CBD in healthy volunteers provided the first evidence that CBD might have antipsychotic properties. This finding was confirmed in 1995 when a study published in the Journal of Clinical Psychiatry concluded that CBD has an atypical antipsychotic profile.
Lately, in 2018, at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, a clinical trial was conducted where 33 antipsychotic medication–naive participants at clinical high risk of psychosis and 19 healthy control participants were studied. The scientists used functional magnetic resonance imaging to inspect the effects of CBD on parahippocampal, striatal, and midbrain function – the three brain functions active in schizophrenia. Observing the level of activation in the left parahippocampal brain cortex, the study concluded that a single dose of CBD may partially normalize dysfunction in the medial temporal lobe, striatum, and midbrain in the individuals at clinical high risk of psychosis.
Very recently, in May this year, Antonio Waldo Zuardi an d José Alexandre Crippa from the University of São Paulo published an article in the Psychiatric Times, where they discuss the current stage of scientific evidence that supports the use of cannabidiol in schizophrenia, anxiety, and Parkinson disease.
The article underlines the connection between cannabis and psychosis as having a centuries-long history, that goes back to 2700 BC, when Shen-nung pen ts’ao ching ( Divine Husbandman’s Materia Medica ) , the world’s oldest pharmacopeia attributed to Chinese emperor Shen-Nung, stated that “. . . ma-fen (the fruit of cannabis), if taken in excess, will produce visions of devils . . . over the long term, it makes one communicate with spirits.”
In the 19th century, French psychiatris t Jacques-Joseph Moreau started using cannabis as an experimental psychotomimetic, a drug that mimics the symptoms of psychosis, and, apparently, it’s been used for that purpose in Western medicine to this day. Consistent scientific evidence indicates that the chronic and intense use of the plant, especially if started in adolescence, contributes to the occurrence of schizophrenia.
Great results with intermediate doses of CBD in schizophrenia
After the study in 1982, which provided the first evidence that CBD might have antipsychotic properties, the same observation was confirmed in a study with THC administrated intravenously after oral pretreatment with CBD or placebo. In addition to blocking the psychotic symptoms induced by THC, CBD and THC demonstrated opposite effects.
This led the scientists to carry out a pioneering study to test the effects of CBD on laboratory animals. The stereotypy induced in rats was clearly reduced by CBD, without producing catalepsy, the study has found. The next step was to evaluate the effects of CBD in a patient with schizophrenia. The patient was a chronically psychotic young female who has experienced many adverse effects from traditional antipsychotics, which presented the ethical justification for the first clinical test. After four weeks of treatment, the patient had a marked reduction in her psychotic symptoms.
The patient was given up to 1500 mg per day in two divided doses, with weekly reducing diazepam dose, which was being given for periods of great agitation and anxiety. The dose of diazepam was reduced from 16,3 to 5,7 mg per day. The improvements of her condition were observed in all the symptoms closely related to the psychosis, including thought disturbance and hostility-suspiciousness.
To date, three randomized controlled trials have evaluated the therapeutic effects of CBD in schizophrenia patients. The first one included 39 patients treated with either CBD (800 mg/d; n = 20) or the atypical antipsychotic amisulpride (800 mg/d; n = 19) for four weeks. Both drugs led to a similar significant reduction in both positive and negative psychotic symptoms, but fewer adverse effects were seen in the CBD group.
In the other two trials, the results were contradictory. Treatment with a dose of 1000 mg per day significantly reduced positive symptoms , while the other study with 600 mg per day found no significant symptomatic differences between CBD and placebo. It is possible that the explanation for the contradictory results lays in the difference in CBD doses.
The CBD dose-response relationship appears to have a particular feature, Zuardi and Crippa point out. In 1990, CBD was tested in a range of doses in rats with the elevated plus-maze model and was found to act according to a bell-shaped dose-response curve. CBD induced an anxiolytic-like effect only at intermediate doses. At a dose of 20,0 mg/kg, it was no longer effective.
The dose-response curve was also observed in healthy volunteers subjected to anxiety induced by the simulation of public speaking test and by public speaking in real settings. In the first situation, volunteers were asked to speak for a few minutes in front of a video camera, while in the second each subject had to speak in front of a group of other research participants. In both situations, treatment with CBD 300 mg was associated with significant decreases in anxiety symptoms, but this effect was not observed with lower or higher doses.
Zuardi and Crippa observed the same response pattern in preclinical tests using other models of induce d anxiety, cognitive impairment, and schizophrenia-like behavior. The findings suggest that this inverted U-shaped curve response pattern may be extended to other therapeutic effects of CBD, with different effective doses and therapeutic windows for each condition.
The data from all three studies in schizophrenia patients suggest that the dose range to reduce psychotic symptoms (probably between 800 and 1000 mg/d), but not cognitive symptoms, should be higher than that used to induce anxiolytic effects (between 200 and 400 mg/d). However, the scientists point out that precise dose ranges for each condition or symptom are yet to be determined.
Reviewed by Sasha Bajilo, founder of ILESOL Pharmaceuticals, an industrial scale producer of CBD products and formulations. Expert on Hemp/Cannabis policy, member of the Croatian Ministry of Health regulatory commission for medical cannabis.
CBD for Schizophrenia: Can Hemp Oil Help with Schizoaffective Disorder?
Although cannabis has got a bad rap when it comes to psychotic disorders such as schizophrenia, the latest research findings indicate that the plant has been largely misunderstood. Studies suggest CBD may actually offset the development of schizophrenia and curb the episodes of psychosis. Better yet, it appears that the other major cannabinoid, THC, may not necessarily trigger the condition — at least not as a direct cause.
Today we’ll focus on the potential CBD treatment for schizophrenia. We’ll cover the recent studies on this subject, explain the mechanism of action, and debunk a few myths about cannabis and mental health.
Using CBD for Schizophrenia: Does It Make Sense?
Cannabis is a complex plant with 115 identified cannabinoids. Depending on the chemotype, cannabis strains may be THC-dominant and CBD-dominant.
Marijuana is known for significant amounts of THC, while hemp boasts higher concentrations of CBD and only traces of the intoxicating cannabinoid.
There are also terpenes, which influence the effect profile of each strain.
The majority of CBD oils available for sale are made from hemp, so their effects revolve around the benefits of CBD supported by other compounds in the plan. A growing body of scientific evidence suggests CBD may relieve anxiety, inflammation and pain, sleep disturbances, and balance mood.
The FDA has recently approved the first cannabis plant-derived medication, Epidiolex. It contains pure CBD and is recommended for treatment-resistant seizures. However, doctors may prescribe Epidiolex off-label for other conditions, such as schizophrenia.
What to Know About CBD and Schizophrenia?
There is a clear link between cannabis use and psychosis, as noted by epidemiological studies. However, a higher risk of schizophrenia has been associated with strains that have high THC content, and studies have notoriously mentioned a dose-response relationship for the risk of schizophrenia in cannabis users. This isn’t the case for high-CBD strains.
THC produces acute psychotic-like symptoms in healthy individuals after a certain dosage threshold is breached — but CBD decreases the THC-induced psychosis and cognitive impairment.
Patients with schizophrenia suffer from cognitive deficits — they affect up to 85% of the sufferers, so the potential positive effects of CBD on cognition have critical importance.
Below we shed more light on how CBD may help with schizophrenia.
Antipsychotic Properties of CBD
A case study published by Zuardi and colleagues found that CBD may successfully treat schizophrenia. The authors tested a dose of CBD up to 1500 mg daily for 4 weeks, which improved the acute psychotic symptoms (1).
Findings from a 2006 study that analyzed the efficacy of CBD as monotherapy for treatment-resistant schizophrenia in three individuals show that only one patient responded positively to the treatment, but the dosage might’ve been inadequate (2). A later study on the benefits of CBD for schizophrenia tested flexible doses up to 400 mg daily on 6 patients with Parkinson’s disease, finding improvement of psychotic symptoms in all participants over the course of 4 weeks.
Since then, CBD has been investigated for its antipsychotic properties in three clinical studies with contradictory results.
For example, a 2012 double-blind randomized controlled trial on the therapeutic effects of CBD showed that the cannabinoid was as effective as amisulpride, a common antipsychotic drug, in treating the symptoms of schizophrenia. On top of that, CBD had fewer side effects; it caused no weight gain and resulted in less extrapyramidal symptoms (4).
CBD was also tested as an adjunctive medication in the treatment of acute psychosis in people with schizophrenia and non-affective psychotic disorders. After 6 weeks of taking 1000 mg of CBD daily, the CBD group showed greater improvement of positive psychotic symptoms compared to the placebo group. At the end of their therapy, more patients in the CBD group were evaluated as “improved” on the CGI-I scale compared with the controls. Patients who took CBD also showed trend-level improvements in their cognitive performance and motor speed (5).
A similar 2018 study investigated the therapeutic effects of 600 mg CBD daily — divided into two doses — in comparison with placebo in a 6-week double-blind placebo-controlled randomized clinical trial. However, the lower dose didn’t have a significant impact on the psychotic symptoms and cognitive performance of the participants compared to the placebo group (6).
How Does CBD Work for Schizophrenia?
Despite being supported by several epidemiological and clinical studies, the mechanism of action behind the antipsychotic properties of CBD remains unknown. Unlike other antipsychotics, CBD doesn’t directly affect dopaminergic neurons. It also doesn’t bind to cannabinoid receptors like THC.
However, CBD does indirectly increase the CSF levels of anandamide, one of the main endocannabinoids, by blocking its metabolizing enzyme, fatty acid amine hydrolase (FAAH). Interestingly, anandamide levels show a negative correlation with the severity of psychotic symptoms, whereas increased levels of anandamide have been found to improve them clinically after a CBD treatment.
This may hint to CBD as the potential mediator in the management of psychosis through the aforementioned boost of the endogenous levels of anandamide. However, further research is needed to confirm this theory.
Over the past few decades, medical researchers have been exploring the endocannabinoid system as the potential therapeutic target for mental disorders (7). The current pharmacological treatment for schizophrenia is only partially effective and doesn’t tackle the negative symptoms. This has led scientists to search for new pharmacological targets — and the findings from the ECS studies are very promising.
However, there’s a discrepancy in clinical results regarding CBD’s efficacy in treating schizophrenia and psychotic episodes. They could stem from different doses of CBD, stages of psychosis, and heterogeneity of the condition.
Risk and Side Effects: Can CBD Cause Psychosis?
There’s currently no evidence that CBD can cause psychosis. In order to do that, the cannabinoid would have to induce intoxication, elevating anxiety, and paranoia in the dose-response pattern. CBD has been repeatedly shown to reduce anxiety, help with the symptoms of PTSD, addiction, and improve people’s response to stress. CBD has a balancing effect on the nervous system, reducing the hyperactivity and increasing the hypoactivity of neurotransmitters when needed.
CBD is a safe substance. Studies have tested doses as high as 1,500 mg daily without dangerous side effects. That being said, there are a few mild reactions you may experience when you take too much CBD at a time:
- Changes in appetite
- Dry mouth
There’s also a risk of CBD-drug interactions, so make sure to consult your doctor prior to buying CBD oil if you want to avoid them.
The relationship between cannabis use and schizophrenia refers to how THC affects the brain.
But are you sure you have been taught the truth? Let’s take a brief look at the effects of THC on people predisposed to schizophrenia.
Does THC Cause Schizophrenia?
THC is an anti-inflammatory compound with antidepressant-like properties. In low and moderate doses, it also has a relaxing effect on top of inducing an altered state of mind, such as euphoric mood, giggles, and tranquility. However, doses of THC that score higher than your tolerance may aggravate anxiety and trigger bouts of paranoia, especially in those who are sensitive.
Studies conducted in the past have shown a correlation between cannabis use and a faster onset of schizophrenia in people with a family history of the condition. However, the conclusion might have been too hasty, as the latest research shows.
A study performed by Harvard University has analyzed all contributing factors besides cannabis use, pointing to the hereditary burden as the main trigger of schizophrenia in cannabis users. According to the research team, cannabis can only spur the onset of schizophrenia, but it’s not a trigger per se.
In other words, if a person is predestined to have schizophrenia, they will develop it sooner or later.
According to Dr. Musa Sami, a researcher and psychiatrist from King’s College in London increased cannabis use would need to positively correlate with the severity of psychosis, which hasn’t been proven by any study to this day.
Finally, Italian scientists from the University of Calgary have recently tested whether cannabis use will further harm the brain structure of rats that were prenatally exposed to an inflammatory agent that disrupts dopamine signaling and causes behavioral symptoms of schizophrenia. To their surprise, exposure to THC during adolescence seemed to protect the rats’ brains. The authors of the study hypothesized that THC’s anti-inflammatory effects were responsible for offsetting schizophrenia (8).
How Much CBD to Take for Schizophrenia?
The studies we’ve covered above have tested how pure CBD affects the mental health of the participants. However, most people use full-spectrum CBD products, where CBD is only one of over 400 compounds. These compounds influence the way CBD affects the body and brain, so doses may vary between people. Whole-plant extracts require a lower dose than CBD isolates, for which most studies have used a daily dose of 600 to 1,000 milligrams.
If you’re using a full-spectrum or broad-spectrum CBD oil, it’s best to start with a low dose, say, 15 mg once or twice a day with food. If you don’t feel a difference in your symptoms after one week, increase by 10–15 mg and reassess the effects. Once you’ve found your optimal dosage, you can stick to it — there’s no risk of increasing your tolerance to CBD over time.
Do Your Research Before Buying CBD for Schizophrenia
The CBD market is regulated due to the current classification of hemp-derived products. As health supplements, CBD extracts aren’t subject to any standardization when it comes to quality and labeling. Although the market has positively evolved over the years, there are still many fly-by-night vendors churning out poor quality products with less CBD than advertised. Some of them may contain more than 0.3% THC; others may be contaminated with pesticides, solvent residue, and other impurities.
For this reason, you should always check how the company grows, tests, and processes its CBD products.
The best source of CBD is organically grown hemp. Hemp plants are dynamic bio accumulators, so they easily absorb everything from the environment they grow in. Organic farming ensures that you only get the good substances in the source material.
Another important factor on your checklist should be the extraction method. Premium-quality CBD oils are extracted using pressurized CO2; this method produces pure extracts with consistent potency throughout the batches. It doesn’t use additional heat or solvents, so you’re getting a product with a complete cannabinoid profile.
Last but not least, look for certificates of analysis or COA. This shows that each batch is tested by a third-party laboratory. Independent laboratories analyze the potency of the product and look for common contaminants, such as heavy metals, pesticides, or solvent residue.
Summarizing the use of CBD for Schizophrenia
CBD can be used to manage schizophrenia thanks to its therapeutic effects on psychotic symptoms. It may also have a role in preventing or treating cannabis-induced psychosis in vulnerable individuals who consume high-THC strains.
High CBD content may positively affect our mental health — not only by curbing psychosis but also by reducing anxiety and improving the body’s response to stress. Studies investigating the efficacy of CBD in mental disorders have found that the cannabinoid has a calming effect on the nervous system but without the dangerous side effects of commonly prescribed antipsychotic medications.
Clinical trials on CBD and schizophrenia have brought mixed results, most likely due to the discrepancy in dosages. If you’re considering taking CBD oil to improve the symptoms of your condition, make sure to consult a holistic psychiatrist who will have a good understanding of CBD and cannabis in general. Doing so will help you determine the effective dosage and avoid negative CBD-drug interactions.
- Zuardi, A W et al. “Antipsychotic effect of cannabidiol.” The Journal of clinical psychiatry vol. 56,10 (1995): 485-6.
- Zuardi, Antonio Waldo et al. “Cannabidiol monotherapy for treatment-resistant schizophrenia.” Journal of psychopharmacology (Oxford, England) vol. 20,5 (2006): 683-6. doi:10.1177/0269881106060967
- Zuardi, Antonio Waldo et al. Op. Cit.
- Leweke, F M et al. “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.” Translational psychiatry vol. 2,3 e94. 20 Mar. 2012, doi:10.1038/tp.2012.15
- McGuire, Philip et al. “Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial.” The American journal of psychiatry vol. 175,3 (2018): 225-231. doi:10.1176/appi.ajp.2017.17030325
- Boggs, Douglas L et al. “The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo-controlled trial.” Psychopharmacology vol. 235,7 (2018): 1923-1932. doi:10.1007/s00213-018-4885-9
- Leweke, F Markus et al. “Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention.” CNS drugs vol. 32,7 (2018): 605-619. doi:10.1007/s40263-018-0539-z
- Lecca, Salvatore et al. “Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.” Frontiers in behavioral neuroscience vol. 13 202. 6 Sep. 2019, doi:10.3389/fnbeh.2019.00202
Livvy is a registered nurse (RN) and board-certified nurse midwife (CNM) in the state of New Jersey. After giving birth to her newborn daughter, Livvy stepped down from her full-time position at the Children’s Hospital of New Jersey. This gave her the opportunity to spend more time writing articles on all topics related to pregnancy and prenatal care.
Does CBD Oil Help With Schizophrenia?
Many people say CBD helps them manage health issues like pain, anxiety, sleep trouble, and PTSD. CBD is short for cannabidiol, a natural compound in cannabis (also known as marijuana) and hemp plants. It has the same chemical makeup as cannabis but doesn’t cause a high.
In 2018, the FDA approved a form of CBD to treat seizures in children. Scientists are also studying CBD oil — the most concentrated form — for dozens of other health conditions, including schizophrenia.
What the Experts Say
Joseph Pierre, MD, a psychiatrist and professor at the University of California, Los Angeles, says CBD’s potential role in schizophrenia treatment starts with tetrahydrocannabinol (THC), the compound in cannabis that causes a high. THC can cause psychotic symptoms in some people, he says. And long-time cannabis users, especially those who start when they’re young, may be more likely to get a disorder like schizophrenia.
“Since CBD opposes some of the effects of THC in the brain, it makes sense it could be useful in treating psychotic disorders,” Pierre says. “There’s also some evidence that CBD has properties similar to antipsychotic drugs.”
But Pierre says people with schizophrenia shouldn’t try CBD on their own. The risks and benefits aren’t clear, and products sold without a prescription don’t always contain what they claim.
He also notes that the FDA doesn’t regulate CBD products.
“We have many FDA-approved medications from plant sources,” Pierre says. “For example, the heart medication digoxin is derived from the foxglove plant. But if someone needs digoxin, I wouldn’t recommend they go pick some foxglove, bake it into a brownie, and eat it.”
Peter Bongiorno, ND, a naturopath and acupuncturist in New York, recommends CBD for some people as part of an approach that includes lifestyle changes, balanced hormones, and lower levels of inflammation. He urges those who take other medicines or who have mental health conditions to “work with someone who has experience with CBD.”
What to Know About CBD and Schizophrenia
If you have schizophrenia but antipsychotic medications don’t work for you or have serious side effects, you might be tempted to give CBD oil a try. But there are some important things to keep in mind.
Because of its link to schizophrenia or psychotic episodes, THC is strictly off-limits if you have schizophrenia or if it runs in your family. So it’s crucial to know what you’re getting. That’s not easy, because the market is flooded with products. Many don’t contain what the label claims, and the terms may be confusing.
- Full-spectrum CBD oil comes from the whole hemp plant. It contains all the compounds called cannabinoids, including traces of THC (0.3% or less). It’s a small amount, but you should still skip this one.
- Broad-spectrum CBD oil doesn’t contain THC but has all the other cannabinoids. Bongiorno says they may help CBD work better.
- Pure CBD oil means 100% CBD. “Pure CBD products are supposed to only have CBD, but unfortunately, even those sold in dispensaries sometimes contain THC or don’t contain any CBD at all,” Pierre says.
- Hempseed oil is tricky. To avoid legal trouble, some manufacturers label CBD oil as hemp oil. Hempseed oil is made from hemp seeds and contains no CBD.
Do your research
Find out how the company grows, tests, and processes its CBD products.
- Check the certificate of analysis, or COA. This shows that each batch is tested by an independent lab. It should say exactly what’s in the product and what isn’t, like toxic metals and pesticides. You can find the CoA online, by email, or with the product. If not, steer clear.
- Ask about sources. The best CBD usually comes from organic plants grown on small farms in the U.S. and Canada.
How much to take
“If you’re going to use CBD for mental health, ask your practitioner for a high-quality version,” Bongiorno says. The amount you take can vary. “The studies tend to use pure CBD, which requires a higher dose. I use CBD with other cannabinoids at lower doses.”
CBD is normally very safe but can have side effects in some people. The most common are dry mouth, feeling dizzy or irritable, anxiety, diarrhea, and nausea. There’s a chance of liver damage at very high doses.
CBD can affect how your body handles other medicines. This means you may have higher or lower amounts in your blood than you should. Penn State University researchers found 60 drugs that interact with CBD or cannabis. Be extra careful if you take blood thinners, heart medicine, or drugs that weaken your immune system after transplant surgery. Pierre says that even some psychiatric medicines, including antipsychotics, could interact with CBD. You should ask your doctor if CBD is safe to use.
Gallup.com: “14% of Americans Say They Use CBD Products.”
Joseph Pierre, MD, acting chief of Community Care Systems at the VA West Los Angeles Healthcare Center and clinical professor in the Department of Psychiatry and Behavioral Sciences, UCLA.
National Center for Complementary and Integrative Health: “Cannabis (Marijuana) and Cannabinoids: What You Need to Know.”
Kendra Mark, founder 2Rise Naturals.
Peter Bongiorno, ND, naturopath and acupuncturist, InnerSource Natural Health and Acupuncture, New York City and Long Island.
Epidiolex.com: “Epidiolex: A treatment innovation.”
Journal of Clinical Medicine Research: “Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.”
Pennsylvania State University, College of Medicine, Department of Pharmacology: “NTI Meds to be Closely Monitored when Co-administered with Cannabinoids.”