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Marijuana is the most commonly used illicit drug in the United States[1]; globally, it is the most widely cultivated, trafficked, and abused illicit drug,[2] and it has the longest recorded history of human use. As early as 5,000 years ago, early Chinese texts documented the medicinal benefits of Cannabis sativa extracts unrelated to its psychoactive properties, including alleviation of pain and cramps.[3,4] Cannabis was also familiar in the Old World (eg, ancient Greece, Rome, the Middle East, North Africa) and its use gradually spread to the New World (Western Hemisphere, including the Americas).[4]
The image shows the effects of delta-9-tetrahydrocannabinol (delta-9-THC or THC), a well-known psychoactive compound in cannabis,[2,5] on brain activity related to capsaicin-induced hyperalgesia. On functional magnetic resonance imaging (fMRI), capsaicin (red) demonstrates increased blood-oxygen-level-dependent (BOLD) activation in the anterior cingulate cortex (ACC) (top left) and thalami (bottom left), but the effect of the interaction between THC and capsaicin (blue) is significant only in the ACC. The graphs clarify the effects of THC and placebo (PLC) on capsaicin-induced BOLD responses (calculated as the difference [cap - con] in percentage BOLD signal change between capsaicin [cap] and control [con] sessions). Compared to PLC, THC decreased the hyperalgesia-related BOLD response in the ACC (top right); however, there was no significant difference related to hyperalgesia in activation within the thalami. The colored bars represent the range of z scores, and the clear and black bars, respectively, represent PLC and THC. Error bars represent the standard error of the mean (SEM).
Image courtesy of Lee MC, Ploner M, Wiech K, et al. Pain. 2013;154(1):124-34. [Open access.] PMID: 23273106, PMCID: PMC3549497.
"Marijuana," or cannabis, typically refers to the dried leaves, flowers, stems, and seeds of C sativa (shown); some of the chemical components of this hemp plant (cannabinoids) are psychoactive, including THC.[1,2,5]
"Hashish" denotes unpollinated female plants concentrated in a resin, whereas "hashish oil" or "cannabis oil" is a concentrate of cannabinoids extracted from the crude plant or the resin with solvents.[2]
Image of drying cannabis courtesy of Wikimedia Commons/Cannabis Training University.
In the early 20th century in the United States, the introduction of recreational marijuana by Mexican immigrants following the Mexican Revolution of 1910 eventually led to Americans associating the drug with social and economic ills. Prejudice and fear rose against Mexican immigrants and marijuana.[6] Thus, over the objections of the American Medical Association (AMA), the United States passed the Marijuana Tax of 1937 which included a complicated set of provisions that was meant to discourage, prohibit, and criminalize the personal and medical use of cannabis in the country.[3,6] Over the next 60 years, between various wars and political and cultural changes, marijuana-related drug sentencing laws alternately loosened and tightened.
Introduction of the 1970 Controlled Substances Act followed by President Nixon's declaration of a "war on drugs" in 1971 eventually led to increases in the size and presence of federal drug control agencies as well as harsh drug-sentencing laws.[7,8] Despite a unanimous recommendation by the National Commission on Marihuana and Drug Abuse—which Mr Nixon appointed to study and advise him on the classification of marijuana—to decriminalize the possession and distribution of marijuana for personal use and to reschedule it, Mr Nixon rejected its recommendations and categorized marijuana among the most dangerous drugs, schedule I drugs (no currently accepted medical use, high abuse potential).[7,8]
In November 1996, California passed Proposition 215 (the Compassionate Use Act of 1996) into law. Patients with a valid physician's prescription could now possess and cultivate marijuana in the state for medical use in the treatment of severe conditions, including cancer, acquired immunodeficiency syndrome (AIDS), chronic pain, and spasticity.[6,9]
Image courtesy of Wikimedia Commons.
The legalization of marijuana for medical use and/or its decriminalization for recreational use remains controversial and continues to rapidly evolve. As of April 17, 2016, 24 US states, Washington DC, and Guam have made cannabis legal for medical use.[10-13] As of April 2016, Colorado, Washington, Alaska, Oregon, and the District of Columbia have decriminalized the use of recreational marijuana, Nevada residents will vote on the issue in the November 2016 ballot, and at least six other states will consider the issue (Arizona, California, Maine, Massachusetts, Rhode Island, Vermont).[14,15] However, at the federal level, marijuana remains illegal for recreational use.[9,16] Thus, under federal law, the Controlled Substances Act of 1970 still classifies marijuana as a schedule I substance.[17] It is this schedule I classification that makes it difficult to study cannabis.[18,19]
However, in May 2015, HR 6 (2015-2016), or the 21st Century Cures Act, called for an additional $1.75 billion in funding for biomedical research under the National Institutes of Health,[20] and in July 2015, the House of Representatives submitted a bipartisan proposal to amend the Controlled Substances Act by creating a new subcategory that "reschedules marijuana, and its derivatives including cannabidiol, under a new 1-R schedule that would better facilitate credible research on its safety and efficacy as a medical treatment. Marijuana could then be rescheduled further after this research is completed…."[21] In effect, Schedule I-R would regulate cannabis research.
Adapted image courtesy of Congress.gov.
Globally, the medical use of cannabis is allowed in a small number of countries, with a few nations also considering decriminalizing it for recreational use.[22] The United Nations (UN) Single Convention on Narcotic Drugs of 1961, as amended by the 1972 Protocol, classifies cannabis as a schedule I and IV drug (low potential for abuse, low risk of dependence[17]).[23] It prohibits cannabis resin smoking and the nonmedical use of cannabis.[24] Consequently, in 2013, the UN warned the United States against the rising US trend of decriminalizing marijuana for recreational or medical use, stating that such policies were not in line with international law.[25] The UN reiterated their concerns in a March 10, 2016 letter to President Obama as well as called for a new approach to global drug policy reforms.[26]
Uruguay remains the only nation that has specifically regulated the production and sale of nonmedical use of marijuana, with the world's first state-owned and operated marijuana dispensaries expected in mid 2016.[22,25,27] However, Canada appears to be in favor of a nationwide legal marijuana system, and the Supreme Court in Mexico has ruled in favor of recreational marijuana use.[26]
Portugal decriminalized all drugs in 2001, even "hard drugs" such as heroin and cocaine, effectively categorizing their use as administrative violations punishable by fines and community service rather than criminal violations requiring prosecution.[28,29] This policy appears to have been successful in that no severe consequences have resulted; instead, drug-related deaths and infection rates of human immunodeficiency virus (HIV) have decreased, and no increase in drug use has been noted.[28,29]
Adapted image of C sativa courtesy of Wikimedia Commons.
As noted earlier, C sativa contains a number of cannabinoids, of which THC is the best known ingredient and cannabidiol (CBD) of particular interest.[2,5,30,31] Cannabinoids are responsible for the physiologic and psychoactive effects of cannabis and act mainly through cannabinoid receptors types 1 (CB1; central nervous system (CNS), peripheral nerve terminals) and 2 (CB2; peripheral organs/tissues).[30,32]
In the last 2-3 decades, the existence of endogenous cannabinoids (endocannabinoids or eCBs), which activate the same receptors as THC, has come to light. This relatively newly discovered endocannabinoid system (ECS) has important regulatory functions in the heart as well as the digestive, endocrine, immune, nervous, and reproductive systems (pleasure, memory, thinking, concentration, movement, coordination, sensory and time perception, appetite, pain).[30,32]
Image courtesy of Medscape/Dr George Griffing.
Despite the obstacles presented by existing US federal restrictions, medical marijuana research continues to advance. In general, investigations have focused on searching for cannabis-derived chemicals with the potential to target and treat specific conditions and/or symptoms—while minimizing or eliminating the psychoactive side effects.[30,31] For example, THC stimulates appetite and reduces nausea, and it may reduce pain, inflammation, and spasticity, whereas CBD is a nonpsychoactive cannabinoid that may reduce pain and inflammation, control epileptic seizures, and possibly treat psychosis and addictions.[31]
A 2015 systematic review and meta-analysis from 79 trials comprising 6492 participants published in the Journal of the American Medical Association (JAMA) found moderate-quality evidence to support cannabinoids for therapeutic use in chronic pain and spasticity, as well as noted low-quality evidence for improvements in nausea/vomiting in those undergoing chemotherapy, appetite stimulation in patients with HIV infection/AIDS, sleep disorders, and tic severity in Tourette syndrome.[33] In addition, there was an increased risk of short-term adverse events associated with cannabinoids (eg, psychiatric, nervous system, musculoskeletal, hematologic disorders).
However, the utility of these findings were limited by methodologic issues, such as inclusion of studies with (1) several different forms of cannabinoids, which have different pharmacodynamics (eg, nabiximols [1:1 THC:CBD ratio oromucosal spray], pure THC oromucosal spray, dronabinol and nabilone [synthetic pure oral THC], vaporized whole-plant cannabis of unspecified strengths, ajuvant acid capsules, unspecified oral THC), and (2) different types of conditions (eg, central, peripheral, and unspecified neuropathic pain; HIV-related sensory neuropathy; pain from multiple sclerosis or other neurologic conditions; musculoskeletal problems; chemotherapy-induced pain).[34] Moreover, the investigators judged 70% of the studies as having a high risk of bias, 5% at low risk of bias, and 25% at unclear risk of bias.[33]
The left image shows a commercial hybrid cannabis strain, the White Widow, coated with trichomes. In an unfertilized, female flowering cannabis plant, these hairlike or glandular outgrowths can produce floral dry weights containing 14%-25% THC, depending on how well the botanical materials are processed.[35] The right inset image is a closeup of THC-filled trichomes on a C sativa leaf.
Images courtesy of Flickr/Théo (left) and Wikipedia/Indirectantagonist (right).
As of April 20, 2016, a PubMed search for scientific journal articles published in the last 20 years (1996-2016) using the search term "cannabinoid" resulted in over 16,300 articles, of which 1,274 were published in 2015 and 537 in 2016. A search for open clinical trials (excluding those with unknown status) at clinicaltrials.gov using the term "cannabinoids" or "marijuana" revealed 459 and 560 studies, respectively; the same search for completed studies (excluding those with unknown status) revealed 270 and 293 trials, respectively.
Among the many areas of study are the effects of cannabis administration routes on pharmacokinetics and pharmacodynamics, as well as use of cannabis for treatment of conditions such as psychiatric disorders (eg, schizophrenia, psychosis), cancers, knee osteoarthritis, and neuropathic pain. Research into cannabis dependency and/or withdrawal remains an area of interest, with recent literature emphasizing health concerns associated with marijuana use as opposed to therapeutic benefits.
The image illustrates the effects of CB1 activation or inhibition on norepinephrine (NE) release in tissue. CB1 regulates the amount of NE released from sympathetic nerve terminals. The red zone depicts the effects of CB1 agonism (decreases NE release). Only cells within this boundary can be modulated by β-adrenergic receptors under CB1 activation; beyond the dotted boundary, α-adrenergic effects prevail. Under basal conditions, the β-adrenergic area is increased (black dotted line). Under CB1 inhibition, NE release is boosted and maximal β-adrenergic effects can be achieved (green dotted line). Beta receptor activation on immune cells decreases production of proinflammatory mediators (eg, tumor necrosis factor).
Adapted image courtesy of Lowin T, Straub RH. Arthritis Res Ther. 2015;17:226. [Open access.] PMID: 26343051, PMCID: PMC4561168.
The primary indications for medical marijuana are restricted to five general categories comprising treatment of (1) pain, (2) nausea and vomiting (usually related to cancer chemotherapy but also for other causes), (3) weight loss associated with debilitating disease, (4) neurologically induced spasticities, and (5) other conditions, such as inflammatory bowel disease (IBD).[30,31,36,37]
Three dosage strengths of marijuana for medical research in the United States are currently available, as follows[38]:
This is problematic, as dispensaries rarely carry cannabis with THC content below 10% and often carry strains whose THC content is as high as 30%.[39,40] Accordingly, the sanctioned research in the United States actually tells us little regarding both the safety and clinical efficacy of the medical marijuana that is actually being used.
Adapted image illustrating the molecular architecture of endocannabinoid signaling at an excitatory synapse in the brain courtesy of Hill MN, Patel S. Biol Mood Anxiety Disord. 2013;3(1):19. [Open access.] PMID: 24286185, PMCID: PMC3817535. 2-AG = 2-arachidonoylglycerol, AEA = anandamide, CB1 = cannabinoid type 1, FAAH = fatty-acid amide hydrolase, MAGL= monoacylglycerol lipase.
Two synthetic THC cannabinoids, dronabinol (Marinol) (schedule III) and nabilone (Cesamet) (schedule II), have US Food and Drug Administration (FDA) approval to treat nausea and vomiting related to chemotherapy.[30,41-44] Dronabinol is also FDA approved to manage loss of appetite in patients with AIDS.[43] However, high concentrations of THC increase the risk of its adverse effects[1]; the literature indicates that very few patients can tolerate pure THC, thereby limiting the potential uses of dronabinol and nabilone.
An investigational synthetic CBD cannabinoid (Epidiolex) has been granted fast track orphan drug designation (but is not yet FDA approved) for two severe childhood forms of epilepsy, Dravet and Lennox-Gastaut syndromes,[42,45] as well as received orphan drug designation for the treatment of tuberous sclerosis complex in April 2016.[46]
Nabiximols (Sativex), another investigational drug, consists of THC and CBD; it is administered as an oromucosal spray and is in trials for managing pain in advanced cancer and spasticity in multiple sclerosis[42,47]; although nabiximols is not FDA approved, it has received regulatory approval for its spasticity indication in 27 other countries.[47]
The image shows one proposed spinal circuitry for motor cortex stimulation (MCS)–induced analgesia. In rats with sciatic nerve chronic constriction injury and MCS, MCS activates the spinal cannabinoid and opioid interneurons. Endocannabinoids bind to CB2 receptors and inhibit cytokine secretion by glial cells, whereas endogenous opioids interact with mu-opioid receptors (MOR) and suppress neuronal transmission, thus reverting neuropathic pain.
Adapted image courtesy of Silva GD, Lopes PS, Fonoff ET, Pagano RL. J Neuroinflammation. 2015;12:10. [Open access.] PMID: 25600429, PMCID: PMC4311417.
In an effort to provide guidance to clinicians, Grant et al developed an algorithm[48] to aid decision making in jurisdictions where use of medical marijuana is allowed.[12] Their decision-tree approach suggests key considerations for clinicians in making a determination about recommending medical marijuana to a patient. For example, for a patient who presents with persistent neuropathic pain, some issues to consider are whether their signs and symptoms are consistent with the diagnosis; if they've been previously evaluated, received standard therapy, and/or had a good treatment response; whether they are receptive to using medical marijuana; and what degree of risk there may be for drug abuse, addiction, and/or diversion.[48] Such an approach may help physicians more easily weigh the risks and benefits of treatment with medical marijuana in their patients.
Another consideration is the use of a type of informed consent for medical cannabis treatment. The agreement would be between patients and pain practitioners, in which a written document would provide evidence-based data regarding cannabinoid therapeutics and their associated risks. Pain specialists would review the information with patients, whose signatures would be acknowledgement of having receiving it.[49] Important details to cover would include addressing the following[50]:
In addition, patients should be informed that medical authorization is not protection against job loss, and physicians have the right to discontinue cannabis treatment.[50]
The image shows vials of medical marijuana and a vaporizer system.
Image courtesy of Wikimedia Commons/Coaster420.
Oral ingestion of cannabis leads to low and variable oral bioavailability.[30] The peak THC plasma concentrations occur after 1-6 hours; the terminal half-life is 20-30 hours. Oral THC cannabinoids are initially metabolized in the liver to a potent psychoactive metabolite.[30] These facts can present problems with edible forms of cannabis (eg, marijuana brownies/cookies), particularly in the pediatric population, because the lengthy period required for orally ingested cannabis to take effect means it is extremely difficult to dose to effect—creating the potential for overconsumption, overdose, and unpredictable side effects.[50-52] Indeed, the inability to titrate cannabis edibles effectively has resulted in not only increased emergency department (ED) visits from THC intoxication[53] but also deaths.[54]
Inhaled cannabinoids (eg, smoke, vapor) undergo rapid hematologic absorption. Peak concentrations occur within 2-10 minutes, with a rapid decline within 30 minutes and a decrease in the psychoactive metabolite.[30] Smoking remains the most common route of administration,[55] despite the large quantity of evidence regarding its adverse pulmonary effects.[30,56-58] Although vaporization is not without risk, the side effects appear to be less than those from smoking cannabis; thus, it is probably the best route of administration at this time.[52]
Image courtesy of Wikimedia Commons/Erik Fenderson.
In 2014, the American Academy of Neurology (AAN) reported results from a systematic review of 34 studies over a 65-year period (1948-2013) on the efficacy of medical marijuana for symptomatic treatment of multiple sclerosis (MS), epilepsy, and movement disorders (Parkinson disease [PD], Huntington disease [HD], Tourette syndrome [TS], cervical dystonia [CD]).[57,59,60] Their findings regarding formulations of oral cannabis extract (OCE) (pills; pure CBD, mixed THC/CBD), synthetic THC (pills), mixed THC/CBD (nabiximols; oromucosal spray), and inhaled medical cannabis on these conditions included the following:
The AAN continues to recommend that clinicians carefully consider the risks and benefits of medical marijuana use, particularly over the long term.[57,59,60]
Image of the basal ganglial circuitry in PD and potential cannabinoid targets to improve motor disability in PD courtesy of More SV, Choi DK. Mol Neurodegener. 2015;10:17.[Open access.] PMID: 25888232, PMCID: PMC4404240. GABA, gamma-aminobutyric acid, GPe = external segment of the globus pallidus, GPi = internal segment of the globus pallidus, SNpc = substantia nigra pars compacta, SNpr = substantia nigra pars reticulate, STN= subthalamic nucleus, TRPV1 = transient receptor potential vanilloid 1.
Pain: There is increasing evidence regarding the efficacy of medical marijuana in managing chronic neuropathic pain and chronic nonmalignant neuropathic pain.[61-67] However, further investigation is needed, particularly regarding the long-term efficacy, safety, and best routes of administration. Nabiximols is undergoing phase III clinical trials in the management of pain in advanced cancer.[47]
The AAN found OCEs to be effective in relieving central pain and painful spasms but excluded neuropathic pain.[57,59,60] The Canadian Pain Society consensus statement on chronic neuropathic pain recommends cannabinoids as third-line therapy.[63]
One study that evaluated the effects of cannabidiol on paclitaxel-induced neuropathic pain found that cannadibiol not only had protective effects (mediated in part by the 5-HT(1a) receptor system) against paclitaxel-induced neurotoxicity but also lacked both conditioned rewarding effects as well as cognitive impairment.[68]
In an observational study comprising 279 Israeli cancer patients who received a permit for medical cannabis use, 46% of 113 patients alive and using cannabis at 1 month renewed their permit, with 70% each reporting improvement in pain and general well-being, 60% with improved appetite, and 50% with improvement in nausea.[69]
Findings from a retrospective study that analyzed data from 121 adults diagnosed with migraine headache at two medical marijuana specialty clinics in Colorado showed symptomatic improvement in 39.7% of patients, including 19.8% who reported prevention and reduced frequency of migraine headache and 11.6% with aborted migraine headache.[70] However, 11.6% reported negative effects, such as somnolence. Edible marijuana was associated with more negative effects compared with other forms of cannabis.[70]
The image shows the effects of THC on brain activity related to capsaicin-induced hyperalgesia in a study. As seen on fMRI, THC significantly reduced the functional connectivity (Fc) between the right amygdala and the primary sensorimotor cortex during capsaicin-induced ongoing pain (z >2.0; cluster-based correction). z-Scores indicating the degree to which THC reduced Fc are scaled in blue. Montreal Neurological Institute (MNI) coordinates are indicated at the bottom right of each slice.
Adapted image courtesy of Lee MC, Ploner M, Wiech K, et al. Pain. 2013;154(1):124-34. [Open access.] PMID: 23273106, PMCID: PMC3549497.
Cancer: Some laboratory evidence exists to suggest cannabinoids may have an anti-tumoral effect (eg, colon cancer,[71] breast cancer,[72,73] glioblastoma[74]). However, the data are not consistent, no human clinical trials exist, and further research is needed.[30,75-78]
Chemotherapy-related nausea/vomiting: The antiemetic effects of the synthetic THC cannabinoids dronabinol and nabilone are well established.[30] The National Comprehensive Cancer Network (NCCN) incorporates dronabinol and nabilone into its guidelines for supportive care.[79]
Gastrointestinal (GI) diseases (noncancer): There is anecdotal evidence to suggest that cannabinoids may modulate the ECS and thereby affect gastric emptying and colonic motility, and strong evidence exists of the intestinal anti-inflammatory effects of cannabis.[80-84] C indica strains have higher CBD content than C sativa strains,[85] and they appear to be effective at relieving pain and GI symptoms; unfortunately, use of C indica strains is associated with severe sedation and dysfunction.[86] Thus, although cannabinoids may have the potential to target treatment of gut disorders (eg, IBD [shown]), more human trials are needed to investigate these effects.
Glaucoma: In 2014, the American Academy of Ophthalmology (AAO) reiterated that it does not recommend the use of medical marijuana or other cannabis products to treat glaucoma, particularly when standard therapies are available and effective.[87,88] The AAO used findings from an analysis by the National Eye Institute (NEI) and the Institute of Medicine (IOM) as the basis for their position. Although evidence of a reduction in intraocular pressure following medical marijuana use exists, the effect is short lived.[87,88] Currently, there is no scientific evidence for its long-term efficacy in managing glaucoma.
Image of severe IBD colitis courtesy of Medscape.
Although the long-term consequences of cannabinoid use remain under investigation, several clinical features of recreational cannabis use are known, including its effects on brain structure with long-term use.
CNS: Regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex.[89] Diminution of gray matter is particularly problematic among young adults with attention-deficit hyperactivity disorder (ADHD),[90] a group that is prone to self-medicating.[91]
Cardiac system: Cardiovascular effects include an increased rate of acute myocardial infarction (two-fold) and cardiovascular mortality,[92,93] as well as an association with higher rates of acute ischemic stroke.[94]
Pregnancy: Cannabis use in pregnancy does not appear to be linked with higher rates of birth defects.[95] However, it is associated with disruptions in neonatal brain functional connectivity[96]; in utero cannabis exposure also causes profound T-cell dysfunction and a greatly reduced immune response to viral antigens.[97]
The electrocardiogram (ECG) shown was obtained from a young adult male with no previous medical history who presented to the emergency department with acute chest pain following cannabis smoking 1 hour before admission. He had a smoking history of a daily half pack of cigarettes for 10 years and a daily minimum of two cannabis cigars. The admission ECG shows anterior ST elevation (leads V2-V4) with reciprocal changes in the inferior leads. Within 20 minutes of admission, he suffered sudden cardiac arrest with ventricular fibrillation but was successfully resuscitated with electrical cardioversion.
ECG courtesy of Bilbault P, Duja CM, Bornemann JY, Kam C, Roul G, Kopferschmitt J. J Emerg Trauma Shock. 2010;3(3):307. [Open access.] PMID: 20931005, PMCID: PMC2938524.
Neurology/Psychology: Neuropsychiatric effects of cannabis use include its being uniquely predictive of (1) the development of bipolar disorder, panic disorder with agoraphobia, and social phobia, as well as (2) declines in mental, but not physical, health.[98] Continued cannabis use at 1 year in bipolar I patients appears to elevate mood and lower global functioning.[99] The data regarding cannabis use and increased anxiety appears to be mixed[100,101]; however, there is good evidence for associations between its use and increased risks of depression in adolescents, young adults, and late middle-aged/older adults, as well suicidality in late middle-aged/older adults.[101,102]
Evidence also exists for early-onset psychosis in adolescents who initiated cannabis use before age 18 years[103]; in addition, high-potency cannabis users have almost a three-fold risk of induction of psychosis compared to those who never use cannabis, and the risk increases to five-fold for daily users of this cannabis form.[104] The induction of psychosis by cannabinoids is potentially due to (1) THC disruption of gamma-band neural oscillations,[105] (2) increased dopamine release in the striatal and prefrontal areas of susceptible individuals,[106] or (3) mutations in the dopamine receptor gene (DRD2).[107] Note that chronic cannabis users with subclinical depression appear to have worse outcomes in first episode-psychosis,[108] including psychosocial functioning.[108,109]
The image shows a proposed mechanism of cannabinoid-induced N-methyl-d-aspartate (NMDA) receptor (NMDAR) hypofunction. In the CNS, the NMDAR allows calcium to permeate into the postsynaptic cleft and regulates essential processes (eg, synaptic plasticity, learning, memory formation, cognition). NMDAR dysfunction in associative cortical areas may lead to changes such as those typically seen in schizophrenia. CB1 and the NMDAR receptor type 1 (NR1) subunit associate in the postsynapse via the homodimeric HINT1 (histidine triad nucleotide-binding protein 1) protein. In step 1, the agonist binds to CB1 and (2) promotes co-internalization of CB1–HINT1 and NR1 subunits. These proteins separate in the cytosol and (3) CB1–HINT1 returns to the plasma membrane. In step 4, the resensitized CB1 associates with new NR1 subunits and (5) the cycle is reinitiated while the agonist remains in the receptor environment.
Image courtesy of Sanchez-Blazquez P, Rodriguez-Munoz M, Garzon J. Front Pharmacol. 2014;4:169. [Open access.] PMID: 24427139, PMCID: PMC3877778.
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