Updated: Feb 03, 2022
Author: George T Griffing, MD; Chief Editor: George T Griffing, MD 


Humans and animals alike naturally synthesize endocannabinoids, chemical compounds that activate the same receptors as delta-9-tetrahydrocannabinol (THC), the active component of marijuana (Cannabis sativa). Marijuana, as smoked in cigarettes, has many names both formal—cannabis, hashish, hemp, sinsemilla—and informal—pot, dope, grass, weed, Mary Jane, bud, hash, bhang, kef, ganja, locoweed, reefer, doob, spliff, toke, roach.

Marijuana is famous for its significant psychoactive effects. Its ability to provide relief of chronic pain, to induce an increase in appetite, to alleviate nausea, and to ease anxiety are only some of the common uses for it. The interest in cannabis has risen in the United States, and its medical use is currently legal in 37 states, as well as the District of Columbia, Guam, Virgin Islands, and Puerto Rico.[1]

Medical use of marijuana is allowed in the following states (as of February 2022):

  • Alabama
  • Alaska
  • Arizona
  • Arkansas
  • California
  • Colorado
  • Connecticut
  • Delaware
  • Florida
  • Hawaii
  • Illinois
  • Louisiana
  • Maine
  • Maryland
  • Massachusetts
  • Michigan
  • Minnesota
  • Mississippi
  • Missouri
  • Montana
  • Nevada
  • New Hampshire
  • New Jersey
  • New Mexico
  • New York
  • North Dakota
  • Ohio
  • Oklahoma
  • Oregon
  • Pennsylvania
  • Rhode Island
  • Utah
  • Vermont
  • Virginia
  • Washington
  • West Virginia

Marijuana has been legalized for recreational use in Washington DC and the following states:

  • Alaska
  • Arizona
  • California
  • Colorado
  • Connecticut
  • Illinois
  • Massachusetts
  • Maine
  • Michigan
  • Montana
  • Nevada
  • New Jersey
  • New Mexico
  • New York
  • Oregon
  • Vermont
  • Virginia
  • Washington

Voters in South Dakota approved nonmedical use of marijuana. However, that intiative was overturned by the state's courts.[1]  


Abbreviations used in the discussion of cannabinoids and in this article are as follows:

  • THC: Δ9-Tetrahydrocannabinol
  • AEA: Anandamide
  • 2-AG: 2-Arachidonoylglycerol
  • AA: Arachidonic acid
  • EC: Endocannabinoids
  • ECS: Endocannabinoid system
  • CB1-R: Cannabinoid binding receptor-1 (predominantly in brain)
  • CB2-R: Cannabinoid-binding receptor-2 (predominantly in immune system)
  • PE: Phosphatidylethanolamine
  • NAT: N -acyltransferase
  • NAPE: N -acyl-phosphatidylethanolamine
  • NAPE-PLD: NAPE-specific phospholipase D
  • MGL: Monoacylglycerol lipase
  • FAAH: Fatty acid amide hydrolase

Further investigation

Endocannabinoids are crucial to bioregulation. Their main role is in cell-signaling, and, because they are hydrophobic, their main actions are limited to paracrine (cell-to-cell) or autocrine (same cell), rather than systemic, effects. Unique characteristics of the endocannabinoids are as follows[2] :

  • Lipid structure, making it lipophilic
  • Hydrophobic with limited mobility in an aqueous environment
  • Local cell-signaling (paracrine or autocrine)
  • Retrograde transmission in the brain; travels backward from postsynaptic to presynaptic cells
  • Formed from the internal lipid constituents of cellular membrane
  • Synthesized “on demand” and not stored
  • Very short half-life
  • Degradation by fatty acid aminohydrolase (FAAH) may regulate endocannabinoid system bioactivity
  • Two G-protein–coupled receptors in the brain (CB1-R) and immune system (CB2-R)

Scientific evidence suggests that endocannabinoids have a role in inflammation, insulin sensitivity, and fat and energy metabolism. Consequently, inhibition of endocannabinoids may be a tool in reducing the prevalence of metabolic syndrome and augmenting the benefits of physical exercise.[3, 4] Furthermore, modulation of the endocannabinoid system may be a cure for more chronic neurologic and immune conditions. Research in animal models suggests the possible use of cannabinoids as anticancer drugs.[5, 6]

The endocannabinoid system (ECS) is a unique and ubiquitous cell-signaling system that is just beginning to be understood. The biochemistry of endocannabinoid synthesis, metabolism, and bioactivity has been difficult to study in the past. Newer techniques such as genetically modified animals, pharmacologic probes, and molecular biology promise to reveal some of these mysteries. The greater promise is that with this understanding, the ECS will yield insights into the mechanisms of health and disease and provide important new therapeutic options.



History of endocannabinoid research

When Mechoulam and colleagues isolated THC in 1964, they made it possible to further understand the complex nature of the endocannabinoid system.[7] Other important events in endocannabinoid research are as follows:

  • 2000-650 BCE: Cannabis (azaluu or gurgurru) mentioned in Assyrian pharmacopoeia at the library of Assurbanipal
  • 1964: THC isolation and structure elucidation
  • 1988: Cannabinoid-binding sites in rat brains identified
  • 1991: Human CB1-R receptor successfully cloned
  • 1992: Endogenous CB1-R ligand (EC), anandamide (AEA; name based on Sanskrit for “supreme joy”), discovered in the brain
  • 1993: CB2-R receptor, found in the immune system, successfully cloned
  • 1995: Second EC, 2-AG discovered; more abundant in the brain than AEA

In the 21st century, new discoveries of other endocannabinoids, their site distributions, and roles are deepening scientists' understanding of the endocannabinoid system.


Chemical Structure

Although the first EC to be identified was AEA, 2-AG is the most abundant in the brain.[8] Several other ECs have been identified, but their function and role in ECS physiology remain to be determined. Five of the best-known ECs are shown in the figure below. Note that all of them share the same 19-C backbone structure but differ in the R-group constituents.

The five best-known endocannabinoids showing the c The five best-known endocannabinoids showing the common 19-C backbone structure and specific R-group constituents.

Endocannabinoid System Roles

Multiple human and animal studies support that endocannabinoids play a key role in memory, mood, brain reward systems, drug addiction, and metabolic processes, such as lipolysis, glucose metabolism, and energy balance.[9]

Several competing pathways for AEA biosynthesis have been described. The best-described pathway is shown in the figure below. AEA biosynthesis is initiated following a postsynaptic neuronal depolarization and an influx of calcium. The calcium then activates N- acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and diacylglycerol (DAG) lipase, each of which forms AEA and 2-AG, respectively.[8, 10] The anterograde neurotransmitter transmission and retrograde EC modulation form the closed signaling loop.

This figure depicts the neuromodulatory signaling This figure depicts the neuromodulatory signaling loop between anterograde neurotransmitter release and the retrograde inhibition by postsynaptic anandamide (AEA). More specifically, it shows the biosynthesis of AEA and activation of the cannabinoid binding receptor-1 (CB1-R) receptor pathway (2-arachidonoylglycerol [2-AG] pathway is similar but not shown here). The initiation of AEA biosynthesis differs from 2-AG. Important to note is that these two processes are mutually exclusively so that AEA and AG cannot be co-synthesized. The endocannabinoid system (ECS) steps shown are as follows: (1) the initiation of AEA biosynthesis starts with activation of N-acyltransferase (NAT), which transfers an acyl group to the membrane phospholipid, phosphatidylethanolamine (PE), forming N-acyl-phosphatidylethanolamine (NAPE); (2) a NAPE-specific phospholipase D (NAPE-PLD) next cleaves NAPE to produce AEA; (3) once synthesized, AEA is susceptible to degradation by fatty acid amide hydrolase (FAAH), possibly an important point of regulation; (4) the AEA that escapes FAAH degradation can diffuse across the synaptic cleft to activate the presynaptic G-coupled membrane bound CB1-R receptor; (5) this activation results in inhibition of anterograde neurotransmitter release. It is obvious that one of the purposes of this ECS is to enable postsynaptic neuron control over neurotransmitter action.

Owing to their lipophilic nature, the endocannabinoids act locally and are not synthesized until needed. Central nervous system messengers that act in a retrograde fashion, the endocannabinoids, are agonists to CB1-R and CB2-R.[11, 12]

Endocannabinoid receptors (CB1-R and CB2-R)

CB1-R and CB2-R are membrane-bound G-protein receptors that activate cyclic adenosine monophosphate (AMP), like other classic G-protein receptors. A non–CB1-R/non–CB2-R has been theorized, based on indirect data, but has yet to be characterized.

CB1-R and CB2-R are G-protein receptors. CB1-R receptors are abundant in the brain, specifically the mesocorticolimbic system, the spinal cord, and the peripheral neurons. CB1-R receptors are particularly concentrated on both gamma-aminobutyric acid (GABA)–releasing neurons (inhibitory neurons) and glutaminergic-releasing neurons (excitatory). Hence, activation of CB1-R leads to retrograde suppression of neurotransmitter release, which may be excitatory or inhibitory depending on the location in the brain.[11, 13] Interestingly, CB1R gene polymorphisms have been described but their functional effects are not well-characterized. Some are associated with anxiety and depression.[14]

CB2-R receptors are located peripherally, with a high density on immune-modulating cells, including microglia in the brain. It is believed the CB2-R may have a protective effect on autoimmunity and inflammation.[3, 14] CB2-R may have some relationship to depression based on animal studies and the finding of a high-incidence of CB2-R polymorphisms in a depressed Japanese population.[14]

Table. Comparison of EC Receptors CB1-R AND CB2-R Characteristics (Open Table in a new window)




Principal Endogenous Ligands

AEA and 2-AG

2-AG (AEA partial agonist)

Major Tissue Locations

Brain and peripheral nervous system

Immune system

Other Tissue Locations

Pituitary, thyroid, and adrenal glands; male and female reproductive system; liver, adipocytes, lungs, kidney

Spleen, tonsils, thymus gland, gastrointestinal tract, osteocytes

Cellular Location

Presynaptic glutamate and GABA neurons

Monocytes, macrophages, microglia, B-cells, and T-cells




General Action

Inhibits release of glutamate and GABA

Modulates cytokine release and immune response

Physiologic Actions



Gastrointestinal System

Decreases gut motility

Reduces bowel inflammation

Peripheral Nervous System Analgesic Effects

Nociceptive interneurons in the dorsal horn of the spinal cord

Anti-inflammatory action mast cells in spinal cord

Reproductive System

Male – Leydig cells

Female – Ovary, ducts, uterus, placenta, embryo implantation

Placenta, embryo, T-cell cytokine release


Promotes fibrosis, increases steatosis

Inhibits fibrosis, decreases steatosis

Cardiovascular System

Hypotension, bradycardia

Atherosclerotic plaque inflammation

Drug-Seeking Behavior




CB1-R CB2-Rphysiologic and pathophysiologicroles in the body

Chronic stress

Although stress responses can be life-saving in the face of a threat, chronic stress often has negative health effects. The endocannabinoid system (ECS) is the central mediator of the stress response. The ECS regulates the release of stress-induced neurotransmitters, including the systemic release of norepinephrine and cortisol. The ECS plays a role in the stress alterations of mood, cognition, and activation of the hypothalamic-pituitary-adrenal axis. The ECS may also mediate some of the dysmetabolic effects of glucocorticoids on lipid metabolism that lead to hepatic steatosis and potentially contribute to the metabolic syndrome.[15] Therefore, the ECS is an important control point and therapeutic target to reduce the deleterious effects of chronic stress.[16]


CB1-R is important for energy balance in the body. With fasting or starvation, AEA and 2-AG levels increase in the limbic forebrain and, to a less significant extent, in the hypothalamus. CB1-R activation increases food intake and effects energy metabolism through coordination of the mesolimbic reward system and the hypothalamus’ appetite control pathway.[13, 17] This receptor also promotes food intake by increasing odor detection via stronger odor processing in the olfactory bulb.[18]

Some obese people may have excess CB1-R activation. Obese and overweight individuals may have a mutation in FAAH, the enzyme that degrades AEA. This can lead to increased levels of AEA (15-fold increase in FAAH “knock-out” mice) and stimulation of the hypothalamic appetite control center.[17]

It is uncertain whether there is a regulatory feedback loop between the ECS and obesity. Wild-type mice that develop diet-induced obesity have a hyperactive ECS, with an increase in receptor availability and an increase in circulating ECs. In presatiated mice, an intrahypothalamic injection of AEA induced substantial hyperphagia. Inactivation of CB1-R receptors decreases plasma insulin and leptin levels, ultimately leading to more efficient energy metabolism.[19, 20]

Nervous system

The ECS obviously plays a significant role in the normal functioning of the brain, spinal cord, and peripheral nervous system. Therefore, the ECS can either cause or become altered by diseases of the neurologic system. For example, hyperactivity of the ECS reduces dopaminergic tone in the basal ganglia, contributing to the pathophysiology of Parkinson disease.[21] Other diseases with potentially significant ECS interactions include multiple sclerosis, seizure disorders, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and psychiatric diseases such as schizophrenia.[22, 23]


Pain is already a well-established and important therapeutic target for ECs. CB1-R agonists act on nociceptive interneurons in the dorsal horn of the spinal cord to alleviate pain. In addition, CB2-R–selective agonists have proven to be helpful in reducing inflammation and undoing established inflammation hypersensitivity involved in peripheral pain and skin disorders.[24, 3]

Heart and blood vessels

CB1-R activation aids in vasodilation and cardiac contractility, regulating blood pressure and improving left-sided heart function. CB2-R has been implicated in the inflammation in atherosclerotic plaques. In this regard, CB2-R activation is a therapeutic strategy for reducing atherosclerotic plaque inflammation and reducing vulnerability to rupture and thrombosis.[25]


Both marijuana and ECs are anti-inflammatory, antiproliferative, anti-invasive, antimetastatic, and proapoptotic in most cancers, in vitro and in vivo, in animals. In some cancers, ECs are proproliferative and antiapoptotic, but in the majority they promote cell cycle arrest, autophagy, apoptosis, and tumor inhibition. At present, cannabinoid cancer therapy is limited to nausea and pain, but future studies are needed to determine its full chemotherapeutic potential.[24, 26, 27]


Activation of CB-1 receptors and, to a lesser extent, CB2-R receptors, by AEA also reduces gastrointestinal motility and secretions. CB1-R receptor activation inhibits proinflammatory responses in the colon.[28, 29]


CB1-R receptors aid in modulating hepatic lipogenesis. Activation in the liver leads to fatty acid synthesis, causing hepatic steatosis and diet-induced obesity. In addition, the CB1-R promotes hepatic fibrosis and contributes to the hemodynamic abnormalities in cirrhosis. By reducing inflammatory cell infiltration and lipid peroxidation, CB2-R receptor activation is protective against hepatic ischemia-reperfusion injury. Targeting the hepatic ECS may have therapeutic potential in a variety of liver diseases.[30]

Reproductive system

The ECS has a role in reproduction. The CB1-R is found in the male (Leydig cells) and the female (ovary, ducts, uterus). Furthermore, normal folliculogenesis and spermatogenesis may require the ECS. The CB1-R is also present in the placenta and is necessary for embryo implantation.[26] The use of cannabis is associated with implantation failure, spontaneous miscarriage, fetal growth restriction, and premature birth in humans. Future research efforts will be needed to unravel the full complexity of the ECS involvement in the process of reproduction.

Skeletal system

In addition to immunomodulatory pathways, CB2-R receptors are involved in maintaining proper bone mass.[31] CB2-R receptors are abundant in osteocytes, osteoclasts, and osteoblasts. CB2-R agonists enhance endocortical osteoblast reproduction and activation, while inhibiting osteoclastogenesis.

Endocannabinoid degradation

Endocannabinoids have a short life span. AEA and 2-AG are quickly degraded through transport protein reuptake and hydrolyzation by either FAAH or monoacylglycerol lipase (MGL), respectively.[32] Degradation may be an important regulatory control point, since inactivation of FAAH results in 15-fold elevated AEA levels in genetic FAAH knock-out mouse brains. Furthermore, these enzymes, FAAH and MGL, have become therapeutic targets for pharmacologic interventions of the ECS. FAAH inhibition has shown the advantages of a lack of abuse potential or physical dependence compared with MGL.[10, 14, 29] See the figure below.

The principal catabolic pathways for both AEA and The principal catabolic pathways for both AEA and 2-AG by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), respectively, both producing arachadonic acid.

Other less important enzymatic pathways exist, demonstrating redundancy in EC degradation. Interestingly, the catabolite arachidonic acid (AA) is a precursor for the cyclooxygenase (COX)–2 enzyme, leading to a number of bioactive eicosanoids (eg, prostaglandins, prostacyclin, thromboxane, leukotrienes). The significance of the EC–COX-2 eicosanoid pathway is under investigation.[33]


Pharmacologic Therapy

Cannabinoid receptor agonists

A cannabidiol oral solution (Epidiolex) was approved by the US Food and Drug Administration (FDA) in 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of childhood-onset epilepsy.[34] In 2020, the FDA extended the approved indications to seizures associated with tuberous sclerosis complex (TSC), a rare genetic disorder that causes non-cancerous (benign) tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.[35]

THC and cannabidiol are active components of Cannabis sativa that bind to CB1-R and CB2-R receptors. Their bioavailability is unknown. A buccal spray that contains THC and cannabidiol (Sativex) is approved for use for neuropathic pain associated with multiple sclerosis and is licensed in 25 countries, including Canada and most of Europe.[24, 36, 37, 38]   A phase 3 trial  in the US to assess its safety and efficacy was delayed due to the COVID-19 pandemic. The placebo-controlled trial is expected to enroll about 446 adults with multiple sclerosis and spasticity and is expected to be completed at the end of 2022.[39]  

Dronabinol (Marinol and Syndros), a synthetic THC, is a CB1-R and CB2-R receptor agonist that has been approved by the FDA for use as an antiemetic for chemotherapy patients and an appetite stimulant for persons with acquired immunodeficiency syndrome (AIDS). Its bioavailability is 10%.[40]  Significant adverse effects have been reported, particularly central nervous system toxicity.[41]

Nabilone (Cesamet) is a synthetic analogue of THC; it is a CB1-R and CB2-R receptor agonist that has been FDA approved as an antiemetic in chemotherapy patients in whom all other therapy has failed. Unapproved use is in patients with upper motor neuron syndrome who have spasticity-related pain not controlled by conventional treatment.[24, 42]

CB1-R receptor antagonists

CB1-R receptors activate the dopaminergic reward system. Commonly abused drugs, such as nicotine, opiates, THC, and alcohol, share a common pathway, the dopaminergic surge in the nucleus accumbens. Independent studies involving humans and mice reported an increase in smoking cessation rates, decreased alcohol intake, and a reduction in cocaine-seeking behavior with CB1-R antagonism.

Rimonabant (Acomplia or Zimulti) is a selective CB1-R receptor antagonist, SR141716, with an affinity to centrally acting CB1-R receptors. Rimonabant was sold in Europe for the treatment of obesity. It was not approved in the United States and later withdrawn because of psychiatric effects, especially depression.[43, 44, 45]

Nevertheless, the ECS is an ubiquitous regulator of cellular function in both health and diseases. Potential therapeutic targets for cannabinoid pharmacologic intervention (ECS agonist and antagonist) are as follows[46] :

  • Pain
  • Antinausea
  • Cough
  • Glaucoma
  • Cachexia
  • Neurologic diseases: Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, alcohol-induced neuroinflammation/neurodegeneration, traumatic brain injury, stroke, seizures
  • Autoimmune diseases: Autoimmune uveitis, systemic sclerosis, inflammatory bowel disease
  • Infection: HIV-1 brain infection
  • Psychiatric disorders: Anxiety-related disorders, impulsivity, bipolar disorder, personality disorders, attention-deficit/hyperactivity disorder, substance abuse and addictive disorders, anorexia nervosa
  • Cardiovascular: Atherosclerosis
  • Gastrointestinal: Gut motility disorders, inflammatory bowel syndrome, chronic liver diseases, alcoholic liver disease
  • Diabetic nephropathy
  • Osteoporosis
  • Cancer: Breast, prostate, skin, pancreatic, colon, and lymphatic, among others