Systematically Testing the Evidence on Marijuana

Cannabis Basics

This is meant to be a very broad, high-level evidence-based overview of a very complex topic. There are undoubtedly subtleties and nuances to the information presented that are not adequately captured in this overview. The information presented here is based on our current understanding of a rapidly evolving body of evidence; readers are referred to the bibliography at the end for more details.

Cannabis plant

The cannabis plant contains over 550 chemical compounds

Cannabinoids

The two best–studied cannabinoids are:

Delta-9-tetrahydrocannabinol (THC)

  • Produces much of the intoxicating effect or “the high” associated with cannabis
  • Popularly thought to contribute to various potential therapeutic benefits

Cannabidiol (CBD)

  • No significant intoxicating effect
  • Potential anxiolytic and therapeutic benefits, but not well-studied
  • May decrease the intoxicating effects of THC

Other cannabinoids

There are over 100 identified cannabinoids. Several notable ones that have received recent attention include:

  • Delta-8-tetrahydrocannabinol (Δ8)
    • Psychoactive in humans
    • Synthetically derived from CBD since the 1940s
    • Regulatory status is controversial
      • Does not qualify for legal definition of marijuana under the Agriculture Improvement Act of 2018 (the “Farm Bill”), but still a controlled substance as a synthetic cannabinoid
      • 14 states have blocked the sale of Δ8 due to lack of research into the compound’s psychoactive effect
      • Quasi-legal status has increased sales, including where THC Δ9 is not permitted
    • Δ8 vs Δ9
      • Same chemical makeup with different structures (ie, THC isomers)
      • Similar pharmacology
      • Available research suggests that Δ9 may be more potent, but sufficient clinical data is lacking
  • Cannabigerol (CBG)
    • Non-Psychoactive
    • Not thought to act at the same receptors as THC and CBD
      • May modulate the endocannabinoid system itself
    • Potential therapeutic applications for nausea, glaucoma, and colitis
  • Cannabinol (CBN)
    • A product of THC degradation/oxidation
    • Shows weak affinity to CB1-receptor, the target of THC’s effects
      • Unclear if CB2-receptor agonist or inverse agonist
    • Some mouse-model evidence in ALS, otherwise weakly psychoactive

Terpenes

Terpenes are naturally occurring organic compounds that are responsible for the aromas and flavors in cannabis and other plants and may influence the intoxicating effects of cannabinoids in whole-plant products. These may be part of the reason that different cannabis products with the same THC and CBD content can have differing effects. Terpenes have been suggested to have various therapeutic properties including anti-inflammatory, analgesic, antiviral, antioxidant, and anxiolytic. However, research regarding terpenes is still in early stages. Over 100 have been identified in cannabis. More high-quality studies are needed to better understand the health impacts of different terpenes.

Some commonly referenced terpenes include: b-caryophyllene, b-pinene, Humulene, Limonene, Linalool, and Myrcene.

Sativa or Indica?

These terms are used colloquially to characterize the expected effects of a given product: Sativa products are purported to have energizing, uplifting, and creative effects (a “mind high”), while Indica products tend to be sedating, and relaxing physically and mentally (a “body high”). While these terms are commonly used, it may be difficult to obtain a pure indica or sativa strain, and these terms are not scientifically grounded. Rather, it is likely that the cannabinoid and terpene profiles account for the observed differences in effects.

The degree to which a product will have energizing, intoxicating, or relaxing effects is most likely determined by the relative amounts of THC and CBD and its terpene profile.

The endocannabinoid system

The Endocannabinoid System is a complex neuromodulatory system that largely serves to promote homeostasis. Scientists are still working to fully understand the endocannabinoid system, but it is thought to play in role in regulating a wide range of processes, such as:

  • Pain
  • Appetite and digestion
  • Inflammation and immune responses
  • Mood
  • Memory
  • Reproduction and fertility
  • Motor control
  • Cardiovascular function
  • Liver function
  • Bone remodeling and growth
  • Reproductive system function

The Endocannabinoid System is comprised of four parts:

  1. Cannabinoid receptors
  2. Endocannabinoids (endogenous cannabinoids)
  3. Enzymes responsible for the formation and degradation of the endocannabinoids

Cannabinoid receptors

The effects of cannabinoids are primarily mediated through two receptors: cannabinoid receptor type 1 and 2 (CB1 and CB2)

  • CB1 receptors:
    • Found in particularly high levels in the cortex, basal ganglia, hippocampus, and cerebellum
    • Also found in many extra-neural sites such as adipose tissue, liver, testis, eye, vascular endothelium, and spleen
    • Δ9-tetrahydrocannabinol (Δ9-THC), the main psychotropic cannabinoid of cannabis sativa, is a partial agonist at CB1
    • CB1 mediates most of the psychotropic effects of Δ9-THC
    • Cannabidiol (CBD) has many known targets. Among them, CBD is a partial inverse agonist/antagonist and negative allosteric modulator at CB1. This is why CBD is thought to potentially attenuate some of the negative effects of THC. However, findings from studies have been inconsistent, with some even showing that CBD can enhance the effects of THC.
  •  CB2 receptors:
    • Typically considered the “peripheral” cannabinoid receptor, however functional CB2 receptors are present in the central nervous system (CNS)
    • CB2 receptors are found peripherally in the circulating immune cells, the spleen, and on macrophage-derived cells including osteocytes, osteoclasts, and hepatic Kupffer cells.
    • CB2 receptors are upregulated in neuroinflammatory conditions
    • Primarily expressed postsynaptically, as opposed to the presynaptic expression of most CB1 receptors
    • Δ9-THC is a partial agonist at CB2
    • CBD is a partial inverse agonist/antagonist at CB2
    • Δ9-THC and CBD binding at CB2 is thought to lead to anti-inflammatory effects

There are other receptors that interact with endogenous and exogenous cannabinoids:

  • Transient receptor potential cation channel subfamily V member (TRPV1)
    • Involved in synaptic transmission and pain regulation
  •  G protein coupled receptor 55 (GPR55)
    • Sometimes referred to as the 3rd cannabinoid receptor (CB3)
    • Expressed in the CNS and immune/gastrointestinal (GI) systems
    • Linked to bone development and cancer cell proliferation
  •  Peroxisome proliferator-activated receptor family (PPAR-a, g)
    • Expressed on bone, muscle, liver, and heart

Endocannabinoid receptor signaling

  • 2-AG primarily works as a retrograde signaling molecule
    • Activation of a receptor, or increased calcium, triggers the release of 2-AG that travels to presynaptic terminals and binds to CB1 receptors
    • In most cases, presynaptic CB1 receptor then suppresses the release of neurotransmitters by inhibiting voltage gated calcium channels or inhibiting adenylyl cyclase and the cAMP/PKA pathway. In at least one case, presynaptic CB1 can enhance the release of the neurotransmitter glutamate by regulating the presynaptic secretory machinery.
  • Anandamide primarily acts as a volume transmitter, regulating the activity of cells at a short distance from its sites of production.

Endocannabinoids (endogenous cannabinoids)

  • Anandamide (AEA)
    • AEA is a partial agonist for CB1 receptors, with high affinity, and largely mimics THC binding
    • Has little affinity for CB2 receptors
    • Also interacts with TRPV1 and GPR55 receptors
    • AEA is involved in the regulation of stress-coping responses, sociability, and pain.
    • CBD has been shown to inhibit the uptake of AEA and inhibit AEA degradation, and thus increase AEA levels
  •  2-Arachidonoylglycerol (2-AG)
    • 2-AG is a full agonist at both CB1 and CB2 receptors, with moderate to low affinity
    • More abundant in the CNS than AEA
    • 2-AG is thought to be involved in a wide array of functions, such as emotion, cognition, energy balance, pain sensation,and neuroinflammation.

Enzymes responsible for endocannabinoid synthesis and degradation

  • Endocannabinoids are synthesized on-demand in response to receptor activation or increased intracellular calcium concentration
  • After endocannabinoids are taken up by cells, they can be degraded via hydrolysis and/or oxidation
    • AEA is degraded by fatty acid amide hydrolase (FAAH)
    • 2-AG is primarily degraded by monoacylglycerol lipase (MAGL)
Dosing

THC

The potency of a cannabis product is typically defined by the amount of THC in the product; the potency of cannabis has increased several-fold over the last several decades. There is no clear definition of a single “dose” of THC. A few states have standardized the definition of a single dose as 5-10 mg of THC, and the NIH recently defined a dose as 5mg of THC for study purposes. However, cannabis dosing is complicated by variations in bioavailability across formulations and across individuals, and by the complex interaction among the different compounds present in whole plant and plant extract products. Individuals may also develop tolerance with regular use which affects the maximum dose. Recent consensus and expert recommendations for dosing medical cannabis for chronic pain treatment recommend a CBD-predominant variety, a starting THC dose of 0.5 to 3 mg/day, and titration to a maximum of 30 to 40 mg/day.

In studies

  • Nabiximols is an oromucosal spray which has been effective in improving neuropathic pain in some studies. A single dose of nabiximols contains 2.7 mg THC and 2.5 mg CBD. Participants in these studies used an average of 25 mg or less of THC over 24 hours.
  • Dronabinol is a synthetic form of THC that has been FDA-approved for treatment of AIDS-related cachexia, and refractory chemotherapy-induced nausea and vomiting (CINV). The recommended starting dose is 2.5 to 5 mg daily, with a maximum divided daily dose of 20 mg THC. For CINV it can be dosed up to 15 mg/m2 at 4-6 doses daily.

In dispensaries

  • The concentration of THC in cannabis has been increasing over time and the amount of THC in dispensary products is much higher than the amount of THC in products studied in clinical trials.
  • In one study, the median amount of THC in a 1.5 gm edible product in dispensaries was 54 mg, and the median THC:CBD ratio was 36:1. Of note, labeled cannabinoid content was often modestly different than measured content.
  • Of note, there is also a burgeoning, unregulated market for CBD products derived from hemp at other retailers such as grocery and online stores. Studies that have tested the cannabinoid concentrations in these products have found inaccurate labeling of CBD content, and some of these products have been found to contain small amounts of THC despite it not being reported on the label.

Calculating the dose of THC

  • Multiply the weight of the product by the percentage of THC in the product
  • According to estimates, the average joint weighs about 0.32 to 0.66 grams. A high-potency cannabis product might contain 25% THC
    • Joint is 320 mg x 0.25 = 80 mg THC/high-potency joint
    • Joint is 660 mg x 0.25 = 165 mg THC/high-potency joint

Routes of administration and dose

Certain formulations and routes of administration will deliver a higher effective dose (i.e., will be more potent) than others. For instance, first-pass metabolism of ingested products yields a metabolite that is more potent than THC, and dabbing delivers a very high dose of THC. Other characteristics of use such as breath-holding after cannabis inhalation can also influence the dose delivered. See the Cannabis Formulations and Routes of Administration sections below.

Overdose potential

While lethal overdose with THC is very unlikely in humans and potentially impossible via traditional routes of administration (e.g. smoking, oral, vaping), at very high doses tachycardia, acute mental effects such as psychosis, and seizures can occur, particularly in children. Because of individual variability in tolerance to THC, what is considered a threshold dose leading to these effects is unclear. In a case series of five adults who used smoked cannabis daily, they sought emergency treatment for cannabis-induced psychosis after consuming cannabis edibles with doses equating to greater than 100mg THC.

CBD

Due to its lack of psychogenic properties, less attention has been paid to potency concerns regarding CBD. In clinical trials, CBD has been used in doses ranging from anywhere < 1mg/kg to 50mg/kg per day (1mg/kg/day is equivalent to 62mg/day using the global average body mass). The recommended maximum daily dose of nabiximols contains 30mg CBD, while Epidiolex (FDA-approved CBD extract) is up to 20mg/kg/day for seizure prevention. A recent US consensus recommendation for dosing medical cannabis for chronic pain treatment recommended titrating to a maximum of 40mg/day of CBD. The Australian government Therapeutic Goods Administration categorizes a low dose range as ≤1 mg/kg/day, medium as 1 to 10 mg/kg/day, and high as 10 to 50 mg/kg/day.

Cannabis formulations

Form

Other Terms

Development

Route of Administration

Plant

Flower, bud

The highest concentration of cannabinoids are found in the flower, not the leaf, of the female plant; topical preparations and rectal suppositories can be made with dried flower or plant extract

Smoking Vaporization Topical Rectal

Edibles

Brownies, cookies, candy, beverages Typically butter or oil used to extract cannabinoids and put into a variety of edible products including beverages

Oral

Tincture

Golden dragon, green dragon

Alcohol or glycerin used to extract active ingredients*

Oral Sublingual Oromucosal

Oil

Vape cartridges, Droppers

CO2 or organic solvents used to extract active ingredients, or live resin

Vaporizing
Sublingual
Topical

Resin

Hash, dry sift, kief

Concentrate made by mechanically separating trichromes (hair like protrusions on flower with high concentration of cannabinoids) from the plant

Smoking Vaporization

Rick Simpson oil

RSO

Alcohol used to make highly viscous concentrated extract

Oral
Topical
Suppository

Nabiximols

SativexTM

Pharmaceutically prepared whole plant extract in spray form; 1:1 THC:CBD concentration; approved for prescription use in many countries outside the US

Oromucosal

Dab

Wax, shatter, butane hash oil (BHO)

Ultraconcentrated extract made with solvents such as butane; very high levels of THC

Dabbing (concentrate placed on very hot metal rod and inhaled)

Pharmaceutical cannabinoids

Dronabinol (MarinolTM; SyndrosTM), Nabilone (CesametTM), EpidiolexTM

Dronabinol and nabilone are synthetic THC (FDA-approved for chemotherapy induced nausea/vomiting and AIDS-related cachexia); Epidiolex is a highly purified CBD plant extract (FDA-approved for the treatment of two rare epilepsy syndromes)

Oral

*Some dispensaries have been known to sell oils extracted using CO2 or other chemicals as tinctures

Common routes of administration: compare & contrast

Route

Smoking

Vaporization (“Vaping”)

Oral/Edibles

Topical

Dabbing

Description
Combustion of dried cannabis flower using several methods: cigarettes (joints, spliffs), pipes, water pipes (bongs) Vaporizer is used to heat dried flower or concentrated extract (oil, resin) and the resultant vapor is inhaled Variety of edibles available; often sold in multi-dose/serving packages; beverages also fall in this category Many forms available: creams, ointments, patches, poultices, oils Ultraconcentrated formulation placed on a hot metal implement and vapor inhaled, often through water
Pharmacology

Notes

 Rapid onset and peak Rapid onset, peak, and duration similar to smoking No inhalation; broad range of products; slower onset (liquids likely to be absorbed more quickly) and longer duration of action None of the pulmonary effects associated with inhalation; probably much less intoxicating; presumably works by a local interaction Can deliver very high potency with over 90% THC.  Rapid onset and peak.

Time to peak effect (THC)

 2-30 minutes (usually within 10) Similar to smoking 1-6 hours (usually 2-4) Unclear Similar to smoking

Duration (THC)

 45-180 minutes (dose-dependent) Similar to smoking Duration 3-8 hours (dose-dependent) Unclear Similar to smoking

Distribution (THC)

90% plasma protein bound

10% bound to red blood cells

1% gets into the brain

 Unclear Similar to smoking

Bioavailability

THC 10-40% (average 35%)

CBD 11-45% (average 31%)

 Similar to smoking, although THC levels can vary depending on product (e.g., oil, dab, vape cartridge)

THC 4-12%

CBD 13-19%

Overall 6-20%

 Unclear Likely similar to smoking but no comparative data available at this time
Cautions
Bronchial irritation; cough; sputum; production contains carcinogens; potential for adverse effects on lung function with heavy use over many years Substantially higher blood THC concentrations achieved at a given dose than with smoking; higher risk of adverse effects in novice users; long-term lung safety is unknown; need for potentially costly equipment; potentially fatal vaping-related pulmonary illness† Onset and peak are delayed, and effects can last many hours which makes it more difficult to titrate dose; oral metabolite of THC (11-OH-THC) may have four-fold more powerful psychoactive effect; risk of overdose; caution especially in novice users Very little is known about topical preparations; unknown systemic absorption Very high levels of THC; risk of overdose and acute psychosis

*Other modes of administration include suppositories and sublingual applications
†In response to the outbreak of severe vaping-related pulmonary illness cases in 2019-2020, cartridges sold in dispensaries have been reformulated to remove Vitamin E Acetate, which was implicated in these cases. However, vape cartridges sold outside of dispensaries do not have this assurance and providers should advise against their use.

The pharmacology of cannabis

Note: The graph is meant to illustrate relative differences in time to peak concentration. The actual concentration of THC at different time points varies markedly across individuals and is influenced by patient characteristics, dose, and frequency of use. Low levels can persist for days to weeks in frequent users.  Chronic users may have different pharmacokinetics.

Cannabis-drug interactions

Cannabis has the potential to compound the sedative effects of different drug classes, including anticholinergics and CNS depressants. The sedative effect of cannabis combined with antidepressants or lithium is unpredictable.

Cannabinoids can induce or inhibit CYP enzymes and can, therefore, decrease or increase the levels of pharmacologic drugs.

For example:

  • THC may reduce levels of the following drugs: aminophylline/theophylline, clozapine, ropinirole
  • CBD may increase levels of the following drugs: clobazepam, diazepam, proton pump inhibitors, phenytoin/fosphenytoin

Since THC and CBD are substrates of different CYP enzymes, their levels can also be increased by certain drugs.

For example:

  • Boceprevir, Ritonavir, Clarithromycin, Conivaptan, Ketoconazole, Posaconazole, and Voriconazole can increase levels of CBD and THC
  • Carbamazapine, Phenobarbitol, Phenytoin, Rifampin, and St. John’s Wort can increase levels of THC and CBD
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We thank the following content experts for their extensive input and editorial suggestions:

Jacci Bainbridge, PharmD, FCCP (Professor, Department of Clinical Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus)

Kendall Browne, PhD (Former Core Investigator, Center of Excellence in Substance Abuse Treatment and Education (CESATE), VA Puget Sound.  Former Assistant Professor of Psychiatry and Behavioral Sciences, University of Washington)

Joseph Bubalo, PharmD, BCPS, BCOP (Assistant Professor of Medicine, Oregon Health and Science University)

Michelle Cameron, MD, PT, MCR (Associate Professor, Department of Neurology, Oregon Health and Science University Co-Director, MS Center of Excellence-West, VA Portland Health Care System)

Kim D Jones, RNC, PhD, FNP (Professor of Nursing, Oregon Health and Science University Dean, Linfield-Good Samaritan School of Nursing)

Salomeh Keyhani, MD, MPH (Core Investigator, Center for Healthcare Improvement and Medical Effectiveness (CHIME), San Francisco VA Health Care System.  Professor of Medicine, University of California, San Francisco)

Mark S. Kindy, PhD, FAHA (Professor, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida.  Senior Research Career Scientist, James A. Haley VA Medical Center)

Emily Lindley, PhD (Assistant Professor, Department of Orthopedics, University of Colorado Anschutz Medical Campus)

Owen Miller, PhD (Postdoctoral Fellow, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus)

Douglas Rice, MD, PhD (Resident Physician, Department of Internal Medicine, Oregon Health and Science University)

Andrew Saxon, MD (Director, Center of Excellence in Substance Abuse Treatment and Education (CESATE), VA Puget Sound Professor of Psychiatry and Behavioral Sciences, University of Washington)

Special thanks to Lynn Kitagawa, MFA at the VA Portland Health Care System for the illustration, Daniele Piomelli, PhD for critical review of the Endocannabinoid System section, and to Julia Haskin, MA, and Alison Eckhardt, LAc, MAOM at the VA Portland Health Care System, for editorial support.