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Cannabis & THC Emerging Research, Risks, Side Effects

Written by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Marijuana

Tetrahydrocannabinol (THC) is one of the main active compounds in cannabis. It may reduce pain in MS and is also being researched in people with nausea, insomnia, and seizures. The use of cannabis is illegal under federal law in the US, but policies across states vary. Does any solid science support the use of THC and what are the side effects and risks? Read on to find out.

What is Tetrahydrocannabinol (THC)?

Overview

Tetrahydrocannabinol (THC), also known as delta9-tetrahydrocannabinol, is the primary component of cannabis responsible for its psychoactive properties [1].

ThC is considered a secondary metabolite of the marijuana plant. Scientists think that it serves as the plant’s defense mechanism – it repels animals and insects and prevents them from eating the plant [1].

A Brief History of Cannabis

According to some estimates, medical use of cannabis dates back as far as the 16th century B.C. in ancient Egypt [2].

Documents suggest that it was also subsequently used by the Greeks and Romans [2].

Another line of evidence suggests its use more than 5,000 years ago in what is now Romania [3].

Yet other sources claim that cannabis was used before the Christian era in India. Archeological and historical findings indicate that the plant was cultivated for fibers since 4.000 B.C. in China [4].

A cannabis extract containing THC metabolites was found inside a tomb in Israel on the remains of a young woman who appeared to have died giving birth. The archeologists who discovered the tomb speculated that the cannabis was used to facilitate the birth process [2].

Current Uses in Medicine & Controversy

Some research points to the medical potential of cannabis.

However, its use remains controversial because of the high risk of addiction, dependence, side effects, and withdrawal syndrome. This is particularly true for non-medical use of cannabis and makes it difficult to stop using.

Relapses in people attempting to quit are relatively common. If you’re struggling with cannabis addiction or relapses, find an addiction center near you to get medical help and support.

Nabiximols (Sativex) is a cannabis extract formulated as a spray that contains similar amounts of THC and CBD (2.7 mg THC and 2.5 mg CBD per spray). It has been approved in Canada and the UK as an add-on treatment for the symptomatic relief of neuropathic pain in adults with treatment-resistant multiple sclerosis [5, 6].

Sativex may also be used to relieve pain in advanced cancer patients who don’t respond to high doses of opioid painkillers [5].

Sativex is an oromucosal spray that should be applied under the tongue, as directed by a healthcare professional.

CBD, the non-psychoactive compound from cannabis, has become more popular than THC recently. It was legalized in many parts of the world and is mainly sold as a supplement.

On the other hand, a synthetic form of THC called dronabinol (Marinol) is FDA-approved for AIDS-related anorexia and chemotherapy-induced nausea and vomiting [7].

Legality

The use and possession of cannabis is illegal under federal law for any purpose in the US.

THC in cannabis is classified as a Schedule I controlled substance, defined as having a high potential for abuse, no currently accepted medicinal use, and a lack of accepted safety data for use under medical supervision [8].

Nonetheless, cannabis laws across different US states vary and many states conflict with federal law. States such as California, Colorado, Washington, Oregon, New York, Arizona, and others have legalized or decriminalized cannabis for medical and/or recreational use.

Canada permits the use of both recreational and medical cannabis.

Cannabis should never be used as a replacement for approved medical therapies. Speak with a doctor before taking medical cannabis if THC/cannabis is legal in your state.

In states where cannabis is illegal, possession and use can result in felony charges.

Potential THC Uses & Emerging Research

Possibly Effective for:

Spasms in Multiple Sclerosis

Sativex, a specific spray containing cannabis extract has been shown to improve self-reported symptoms of muscle stiffness and spasticity, urination frequency, and neuropathic pain associated with multiple sclerosis in several clinical trials involving thousands of patients in total [9, 10, 11, 12, 13].

Evidence about other cannabis extracts is conflicted. One small clinical trial suggests that oral cannabis extract (Cannador) reduces muscle stiffness and spasms and improves sleep, compared to placebo. The daily dose was titrated up to THC 25 mg and cannabinol 8 to 18 mg/ Larger trials suggest that cannabis extract does not objectively improve spasticity in MS [14, 15].

In another study of 50 MS patients, those who took a different CBD/THC combination (2.5 mg THC and 0.9 mg CBD per capsule) reported somewhat reduced muscle tightness and improved sleep. Lower doses had a weaker association; the authors suggested that some MS patients in the study needed higher doses to get relief [16].

Better-designed trials on different cannabis extracts are needed to determine the effects of THC/CBD combinations on MS symptoms.

Additionally, some epidemiological studies have suggested that smoking cannabis may reduce self-reported muscle spasms, pain in arms and legs, and tremors associated with multiple sclerosis. The effects of smoking cannabis on MS symptoms have not been evaluated in clinical trials [17].

Neuropathic pain

An analysis of five small clinical studies concluded that inhaled cannabis (providing 1.6-96 mg THC daily) reduces the intensity of neuropathic pain caused by HIV, trauma, diabetes, chemotherapy, and other conditions in up to 2 weeks [18].

In one small clinical trial, inhaled cannabis (containing 2.9% or 6.7% THC) reduced neuropathic pain due to spinal cord injury. The effect was immediate and lasted less than 2 hours [19].

Some human studies showed mixed results regarding THC’s effectiveness for other types of pain, as is the case with sunburns and capsaicin-triggered pain and inflammation in healthy volunteers [20, 21].

Insufficient Evidence for:

The following purported benefits are only supported by limited, low-quality clinical studies. There is insufficient evidence to support the use of cannabis/THC for any of the below listed uses.

Decreased Appetite and Nausea

In Life-threatening Diseases

HIV, cancer, and other life-threatening diseases often lead to decreased appetite and muscle wasting. THC and cannabis extract has been studied for stimulating appetite and mitigating cachexia in these patients. However, there are not enough data to rate its effectiveness [22].

In one study, a standardized cannabis extract (THC 2.5 mg and CBD 1 mg twice daily) did not seem to increase appetite compared to placebo in patients with cancer-related anorexia-cachexia [23].

This study had several major limitations, however. The placebo response was exceptionally high, as was the drop-out rate.

Better-designed trials are needed to determine the effects of cannabis extracts and CBD on decreased appetite, nausea, and muscle wasting in people with life-threatening diseases.

In another small study on HIV patients, inhaling THC reduced the levels of peptide PYY (an appetite suppressant), while increased levels of leptin and ghrelin [24].

Nausea and Vomiting Related to Chemotherapy

So-called delayed nausea and vomiting induced after completing chemotherapy (also called delayed CINV) is an issue for many cancer patients.

In a small clinical study, a spray containing standardized cannabis extract (Sativex) prevented delayed chemotherapy-related nausea and vomiting. It helped 71% of patients, compared with 22% of patients who responded in the placebo group [25].

The spray was used 3-5 times daily for up to 5 days after completing a chemotherapy cycle. Larger clinical trials should confirm these findings [25].

Glaucoma

Despite anecdotal claims, it’s still unknown whether cannabis/THC improves glaucoma.

Smoking cannabis or Sativex spray seems to reduce eye pressure in people with glaucoma, but the effect may last for only three to four hours [26, 27].

Another older study suggests that smoking cannabis reduces both eye pressure and blood supply to the eye. Reduced eye blood flow has been linked with vision loss in some types of glaucoma [27, 28].

Better-designed studies are needed to clarify these findings.

Insulin Sensitivity

We don’t yet know how THC and cannabis affect insulin sensitivity and weight.

An epidemiological study found that current marijuana use is associated with 16% lower fasting insulin levels in comparison to past marijuana users and 26% in comparison to people who never used marijuana. This trend was also similar for other insulin resistance metrics. However, clinical trials are needed to determine whether THC increases insulin sensitivity [29].

On the other hand, limited human studies suggest that Rimonabant, a mild cannabinoid receptor 1 blocker (inverse agonist), increases insulin sensitivity in an adiponectin-dependent manner.

Rimonabant is an anti-obesity drug that mainly acts to reduce appetite, which may explain these effects. This drug is not approved in the US due to its risk for psychiatric side effects like depression and suicidal thoughts [30, 31, 32, 33].

Clinical trials are needed to determine the effects of cannabis, THC, and other cannabinoids on insulin sensitivity, appetite, and obesity.

Possibly Ineffective for:

Insomnia & Deep Sleep

Many studies suggest that marijuana has profound effects on sleep, which may be detrimental in the long run. However, most of the data comes from epidemiological studies and surveys. We’re in need of proper clinical research.

According to one study, THC and smoked marijuana seem to decrease the time it takes to fall asleep and increase stage 4 sleep (deep sleep). But they decrease REM sleep, which is the phase associated with dreaming. People who stop using cannabis often report difficulty sleeping and strange dreams for a short period of time [34].

Lacking Evidence (Animal Research)

No clinical evidence supports the use of cannabis or THC for any of the conditions listed in this section.

Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

Pain Pathways

Based on studies in mice, scientists think that THC might reduce pain by potentiating the glycine receptor [35, 36].

In mice, THC activated CB1 receptors and increased the release of agmatine. Agmatine seemed to increase pain tolerance and overall body temperature [37, 38].

Neuroscience

Chronic THC exposure in mice results in increased brain-derived neurotrophic factor (BDNF) in the hippocampus, but not in the frontal lobe [39].

THC appears to reduce seizures in rats, but CBD has been more thoroughly researched for this effect in people with epilepsy [40].

Marijuana smoking seems to increase cerebral blood flow for up to 2 hours afterward [41, 42].

Scientists are investigating whether THC can reduce amyloid plaque levels and inflammation, and improve mitochondrial function in cells [43, 44].

Some researchers think that THC causes a euphoric state by increasing dopamine, although the chronic use of THC may blunt dopamine receptors (coded by DRD1 and DRD2 genes) [45]. The effects of THC on the dopamine system appears to be dependent on dose and duration of use, but human studies would need to determine this [45].

Heart Health

On the one hand, recreational marijuana use has been associated with other unhealthy behaviors such as a high-calorie diet, smoking, and other drug use [46].

However, studies drawing these associations were limited. Simply put, not all people who use marijuana recreationally lead unhealthy lives. Additionally, have in mind that this study dealt only with recreational, not medical marijuana use [46].

On the other hand, mechanistic studies are investigating the effects of THC (without those unhealthy lifestyle factors) on reducing cardiovascular disease risk. No human studies have been carried out so far, though, so it’s still unknown how THC/cannabis affects heart health [46].

Atherosclerosis Plaque Progression

Studies show that patients with atherosclerosis or hardening of arteries have increased levels of foam cells in the major arteries, which lead to the buildup of cholesterol and fatty plaque [47].

Scientists believe that CB2 receptors are present on the surface of foam cells and that THC may activate them, which would theoretically prevent them from depositing fatty streaks in the heart. However, this hypothesis has never been verified [48, 49].

Other research teams are looking at the following pathways that THC may act on:

  • Inhibiting 15-lipoxygenase, an enzyme that oxidizes low-density lipoprotein [50].
  • Reducing platelet accumulation and promoting immune function, which might block atherosclerosis [51].

These mechanisms remain unexplored in humans.

Some rat studies suggest that small amounts of THC might reduce atherosclerosis in lab animals without psychoactive effects. Clinical trials are lacking [52].

Cancer Research

The internet is full of unsubstantiated claims about the alleged anti-cancer effects of THC.

Cannabis has not been shown to treat cancer.

No proper clinical trials have tested cannabis or THC on cancer progression.

In one small experimental study, direct injection of THC into the glioblastoma tumors in two patients was safe. It was also hypothesized to have some effects on tumor cells [53].

Glioblastoma multiforme is a form of brain cancer with limited treatment options and a low life expectancy. Future clinical trials need to determine the effectiveness and safety of THC brain injections in people with this type of brain cancer [53].

Scientists are investigating the effects of THC on certain types of cancer and pathways in cells and animals, such as on:

  • In combination with CBD on brain cancer cells [54].
  • On ErbB2, Akt, and mTOR on breast cancer cells and mice [55, 56].
  • On EGF in lung cancer cells and mice [57].
  • Prostate cancer cells [58].

Let’s keep in mind that many substances have anti-cancer effects in cells, including downright toxic chemicals like bleach. This doesn’t mean that they have any medical value. Most substances (natural or synthetic) that are researched in cancer cells fail to pass further animal studies or clinical trials due to a lack of safety or efficacy.

In a survey of people who are habitual THC users but not cigarette smokers, the use of THC did not increase the incidence of lung cancer, although negative outcomes from smoking THC were not ruled out [59].

Side Effects & Safety of THC

Side Effects

The most common adverse effects caused by smoking cannabis or using Sativex oromucosal spray containing cannabis extract are [6]:

  • Headache
  • Dizziness
  • Drowsiness
  • Fatigue
  • Dry mouth
  • Nausea
  • Paranoid thinking and dissociation

Other (less common or experimental)

THC has been reported to cause schizophrenia-like symptoms, altered perception, increased anxiety, delayed recall time, impaired mental performance, and increased cortisol in some people [60].

After ingesting a high dose of THC, increased levels of adrenaline were detected after 2 hours but then returned to normal after 4 hours in one study [61].

Cannabinoid is hypothesized to impair working memory through the CB1 receptor in astroglial cells [62].

One study linked the chronic consumption of Cannabis with increased the odds of getting bipolar disorder and manic episodes. These findings have not been properly verified [63].

THC may reversibly block synaptic neuroplasticity in the nucleus accumbens and hippocampus [64].

Chronic THC usage in humans is hypothesized to reduce overall dopamine synthesis, which may theoretically reduce motivation [65].

According to one study, highly potent cannabis may impair creativity and divergent thinking [66].

Repeated use of cannabis might result in intolerance due to a reduction in CB1 receptors [67].

Prior THC exposure makes nicotine more addictive in rats [68].

Safety and Drug Interactions

Cannabis extract may be safe when used for up to two years in the form of Sativex, a spray that should be applied into the mouth. This product is available as a prescription drug in the UK and Canada. It is an investigational new drug in the US that is not approved by the FDA.

Inhaling cannabis is likely unsafe. Smoking cannabis can cause respiratory problems such as coughing, wheezing, and inflammation.

Cannabis use has been associated with health complications, addiction, cognitive and mood issues, and withdrawal syndrome.

Cannabis use during pregnancy is unsafe. Cannabis passes through the placenta and can reduce fetal growth. It has also been linked with other abnormalities and health complications in newborns [69].

Breastfeeding women should not use cannabis. THC passes into breast milk and has been linked with delayed motor development [70].

Drug Interactions

THC and cannabis extract (Sativex) can interact with many drugs. Interactions with the following groups of drugs are possible [6]:

  • Hypnotics and sedatives
  • Opioid painkillers
  • Anesthesia drugs
  • Anti-seizure drugs
  • Blood-thinners
  • Certain antibiotics and antifungal drugs
  • Statins
  • Certain antidepressants

Alcoholic beverages should be avoided while using Sativex [6].

Your doctor will take into account all the medications and supplements you are taking when prescribing Sativex.

Clearance of THC involves CYP450 in phase II liver detoxification [71].

Pharmacokinetics

Many different routes of THC administration have been described in the scientific literature, with varying absorption and elimination rates [72].

  • Smoking or absorption of THC via the lungs seems to result in rapid absorption with 2 – 56% bioavailability of THC and its metabolites. Peak levels in the blood are detected after 12 minutes. Smoking cannabis can cause other side-effects from smoke exposure.
  • Oral or ingestion of THC results in a lower, more gradual and blunted peak in serum concentration of THC. Serum levels peak at around 1.5 – 2 hours. Chocolate cookies with cannabis have ~6% bioavailability 1 – 5 hours post-ingestion. Absorbed cannabis is also subject to first-pass liver metabolism.
  • Sublingual, rectal, and skin uses of THC bypass the digestive system and first-pass liver metabolism. In addition, the THC metabolites may stay longer in the system.

THC is a highly fat-soluble substance, which means that it may stay longer in lipid-rich tissues such as the lungs, heart, brain, and liver [72].

Studies suggest that brain levels of THC are almost always higher than blood levels, and there may be THC in the brain even when it is absent in the blood. Chronic use of THC may result in THC accumulation in fat tissues [72].

Want Better Ways to Improve Your Mood?

If you’re interested in natural and more targeted ways of improving your mood, we at SelfHacked recommend checking out this mood wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.

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About the Author

Ana Aleksic

Ana Aleksic

MSc (Pharmacy)
Ana received her MS in Pharmacy from the University of Belgrade.
Ana has many years of experience in clinical research and health advising. She loves communicating science and empowering people to achieve their optimal health. Ana spent years working with patients who suffer from various mental health issues and chronic health problems. She is a strong advocate of integrating scientific knowledge and holistic medicine.

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