Cannabis:
On the Brain and Body
Cannabis is one of the most chemically diverse plants ever analyzed, producing at least 550 different compounds most of which affect your brain and body.
*The statements below have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.*
Cannabis: On the Brain and Body
It is important to note that the exact biological activity of the chemicals in cannabis has been studied to varied degrees pre-clinically and clinically. This research has been greatly inhibited due to government restrictions. Therefore, despite how much research has been done already there is still so much to be discovered about the chemistry and biochemical effects exerted by the Cannabis plant.
Phytocannabinoids are a class of compounds that occur naturally in Cannabis sativa. Those that have been studied this far bind to cannabinoid receptors in the brain and body(1,2). Over 120 phytocannabinoids have been identified in Cannabis.
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Examples Include: Delta-9-THC, CBD, CBN
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In addition to binding cannabinoid receptors, these compounds also bind and modulate a variety of receptor types like serotonin and opioid receptors in both direct and indirect ways. (1)
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In addition to cannabinoids, Cannabis S. also produces an estimated 430 additional chemical compounds (6). A majority of these compounds have the potential to elicit a response in the body in some way. May it be nutritional, anti-inflammatory, antioxidant, cardioprotective, etc. This dynamic chemical profile exemplifies the uses for cannabis expand far beyond its cannabinoid profile and psychoactive activity.
Terpenes are some of the most commonly recognized additional compounds of cannabis to which 120
have been isolated such as linalool, alpha-myrcene, and alpha-pinene. They are a large part of what creates Cannabis' aroma (10), though additional compounds play a contributing role.
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Terpenes and cannabinoids are still just the tip of the iceberg. There have been at least 20 flavonoids identified in cannabis. Flavanoids are also available in a variety of fruits and vegetables like blueberries and kale. Flavonoids have been found to have a variety of beneficial effects on the body such as antioxidant and anti-inflammatory capabilities.
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An interesting group of flavonoids is called anthocyanins. They are responsible for the purple, and reddish color in strawberries, tomatoes, etc. as well as the renowned purple hue in certain cannabis cultivars like Purple Haze (9).
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Cannabis seeds are also host to a variety of beneficial compounds most notably for nutritional benefit.
There are a variety of omega-fatty acids in high quantities like oleic acid also found in olive oil and linolenic acid an essential (meaning ingestion is necessary for the proper development of all mammals) omega-3 also found in nuts.
Cannabis seeds are also high in vitamins, minerals, and protein. These include Vitamin A, E, and B6, Potassium, Magnesium, and Phosphorus, as well as 32 grams of protein per 100gs of seed(8).
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Cannabis also contains alkaloids. Alkaloids are fundamentally any compound that contains both carbon and nitrogen atoms. Plants, microorganisms, and animals all produce alkaloids. These compounds are the basis for approximately 60% of plant drugs. Cannabisativine, cannabimine A,anhydrocannabisativine (7) .
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Terpenes | Structure | Boiling Point | Reported Benefits |
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beta-myrcene
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beta-caryophyllene
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Limonene
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alpha-Pinene
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beta-Pinene
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Linalool
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Humulene
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alpha-terpineol
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(6)(10)(13)(14)(15)
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Anagesic
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Antioxidant
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Neuroprotective
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Anti-inflammatory (7)(13)
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166ºC and 168ºC (roughly 330ºF) (11)
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198°C (or 388.4°F) (11)
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156°C (or about 312°F) (11)
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119°C (about 246°F) (11)
Common Cannabis Terpenes
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177°C (just over 350°F) (11)
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166°C (or about 331°F) (12)
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Anti-inflammatory
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Anagesic
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Gut mobility (7)(13)
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Antiallergy
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Anticancer (7)
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Anxiolytic
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Anti-inflammatory
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Antimicrobial
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Neuroprotective;
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Sedative
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Induces apoptosis in cancer cells (7)(13)
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Antimicrobial
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Insect Repellant
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Anti-inflammatory
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Analgesic
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Anticonvulsant
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Antimicrobial
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Gastroprotective (7)
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Anti-inflammatory
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Antibacterial
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Antifungal
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Antioxidant
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Anticonvulsant
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Antidiabetic
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Antiviral (7)(13)
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Antimicrobial
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Bronchodilator
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Anti-inflammatory
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Memory enhancer
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Gastroprotective
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Acetylcholinesterase inhibitor (7)(13)(15)
217°C (or 422.6°F)
(13)
276°C or (529°F) (13)
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Anti-tumor
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Anti-coagulative
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Antioxidant (15)
Frequently Asked Questions (FAQ):
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Q: How does cannabis affect memory?
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A: In (2012) it was found that individuals with high THC levels (as measured by hair samples) displayed characteristics of poor or compromised episodic and verbal memory, whereas those who had CBD showed enhanced recognition memory.(4)
This makes sense if we recall the partial agonist activity of THC on presynaptic inhibitory CB1 receptors which present heavily in the hippocampus the part of the brain that dictates memory. CBD on the other hand decreases the activity of THC on the CB1 receptor as a negative allosteric modulator.
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Q: How long Does Cannabis stay in the body?
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A: Cannabinoids like THC are highly lipophilic which means they become stored in your fat with greater propensity the longer and more frequently you ingest it, and therefore excretion takes much longer. (5) Additionally, those with higher body fat are more likely to store THC in their body for longer. Cannabis can stay in your body anywhere from 1 day to over a month in urine samples depending on usage, up to 90 days in hair samples, up to 24 hours in saliva, and up to 12 hours in blood. (12)
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Q: How Does Tolerance Develop?
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Tolerance develops as a result of changes in the effects and mechanism (pharmacodynamics) of action triggered by chronic cannabis use. A notable receptor in which this occurs is the cannabinoid receptor type 1 (CB1) the expression of which decreases (downregulated), and receptor shape changes, leading compounds like THC to be less likely to interact with the receptor. (5) This is what is described as tolerance.
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Additionally, since THC is only a partial agonist, the intensity of its effects is greatly dependent on receptor density, structure, shape, and amount of G-proteins (the receptors signaling molecules). (5) All of these factors are altered from prior cannabinoid use.
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Q: What increases cannabis absorption?
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A: Cannabinoids like D9-THC are highly lipophilic (5) they are best absorbed after the ingestion of higher-fat meals.(15)
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Q: Is Cannabis Dangerous?
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A: There have been no known deaths directly correlated to acute toxicity following cannabis ingestion. Due to the low propensity of CB1 receptors in the brain stem, THC has a high safety profile. There have been a plethora of reported therapeutic effects attributed to cannabis ingestion (1)(2)(3)(6).
This being said too much of anything can begin to tip its effects from positive to negative over time. Extended and consistent use of cannabis can alter endogenous (natural) neurotransmitter signaling, which can dysregulate the plethora of systems the endocannabinoid is responsible for maintaining such as memory (5). Also, habituating a behavior can create a dependence on it even if a physical dependence isn't established.
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Q: How do researchers identify what compounds are in a plant?
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A: Thin-layer chromatography (TLC), Gas chromatography coupled with mass spectrometry (GC-MS),Liquid chromatography coupled with mass spectrometry (LC-MS), Supercritical fluid chromatography coupled with mass spectrometry (SFC-MS), Nuclear magnetic resonance (NMR) spectroscopy (10).
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Cannabinoid Receptors
Cannabinoid Receptor 1 (CB1 ):
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- Found primarily in the Central Nervous System (the brain) (1)
- CB1 receptors have been found to regulate memory, appetite, and fear response. (3)
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-Brain regions where the receptor is found include the hippocampus, cerebellum, and basal ganglia. (3)
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-The hippocampus controls learning memory.
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- The cerebellum modulates coordination and motor control.
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-The Basal Ganglia dictates behaviors and decision-making.
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-This receptor is also expressed in extremely low amounts in the brain stem. This contributes greatly to Cannabis' high safety profile.
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-The CB1 receptor is found presynaptically which means it regulates the activity of other receptors.
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-Activation of the CB1 receptor leads to inhibitory effects, inhibiting electron transport which decreases mitochondrial respiration, lowering cyclic AMP (cAMP). Also, inhibition of presynaptic Ca2+ (calcium) influx which leads to depolarization-induced suppression.(3)
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- The CB1 receptor is also expressed in the gut, where it is believed to promote eating by inhibiting the release of cholecystokinin (CKK).
CKK is known to induce satiation after eating.(1,2,3,5)
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-CB1 receptors in the periphery have been shown to increase cardiac dysfunction and inflammation. (3)
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Cannabinoid Receptor 2 (CB2) :
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-Found primarily in the Peripheral Nervous System (the body)(1)
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-Regions with the highest density of CB2 receptors include the gastrointestinal tract, spleen, lymphocytes, and bone marrow
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- Evidence shows activation of this receptor decreases inflammatory cell activation.(1,2,5)
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--The CB1 receptor is found presynaptically which means it regulates the activity of other receptors.
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-CB2 receptors have been shown to exert cardioprotective effects on the heart, decreasing inflammation and enhancing function. (3)
Endogenous Cannabinoids:
Endocannabinoids occur naturally in the body and regulate the activity of the Endocannabinoid system.
The Endocannabinoid system plays a major role in maintaining homeostasis, emotional regulation, stress response, reward signaling, gut mobility, modulating intestinal inflammation, and neuroplasticity. (3.4)
AEA (Anandamide):
- Partial agonist of the CB1 receptor with high affinity(3)
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-Almost inactive at the CB2 receptor(3)
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​2-AG (2-Arachidonoylglycerol)
-Full agonist at the CB1 receptor with moderate to low affinity (3)
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-Full agonist of the CB2 receptor(3)
Common Phytocannabinoids
Though there have been over 120 cannabinoids discovered, each of them exists in different concentrations. Those that are the most abundant have had the most research performed on them. The cannabinoids that have been researched like THC, still have much to be unveiled as to what they do to the brain/body and how.
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Delta-9-THC (delta-9-tetrahydrocannabinol) :
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Partial agonist of CB1 and CB2 receptor
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Proposed 5HT3A receptor antagonist
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Allosteric modulator for mu and delta opioid receptors(1,7)
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Via CB1 activity, THC has been found to increase glutamate (excitatory transmitter) levels in the brain by inhibiting uptake by transporters.
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This increase in glutamate has been associated with an increase in dopamine levels. (5)
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Delta-8-THC (delta-8-tetrahydrocannabinol):
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An isomer of D9 (just a different location of a double bond)
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Partial agonist at CB1 & CB2 receptor (lower affinity for receptor than delta-9-THC) (1,7)
CBD (Cannabidiol):
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Weak antagonist of CB1 & CB2 receptors (in vitro)
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Negative allosteric modulator of D9-THC, 2-AG,& and inhibits anandamide uptake (3,5)
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CBD has been found to block temporary psychotic symptoms due to acute D9-THC consumption in the striatum and prefrontal cortex. (5)
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5-HT1A agonist(1)
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5-HT2A agonist(1)
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The noncompetitive antagonist of 5HT3A receptors
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Serotonin receptors responsible for anti-inflammatory response and immunosuppressive effects (1,3)
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CBN (Cannabinol):
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Over time Delta 9-THC becomes degraded from light and heat when this occurs CBN is produced as a byproduct
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Weak psychoactive weak CB1 agonist
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Higher affinity toward CB2 receptor (though conflicting reports on whether it is an agonist or inverse agonist)(1,7)
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CBG (Cannabigerol):
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When THC and CBD are made in the plant they originate or are derived from a common compound, that compound is CBG
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Low affinity for CB1 and 2 receptors
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But can inhibit anandamide (AEA) uptake
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Potentially activate alpha 2 adrenergic receptor
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Antagonist 5-HT1A receptor (1,7)
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Delta-9-THCV (delta-9-tetrahydrocannabivarin):
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2 fewer carbons in the side chain than D9-THC
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Low doses in vitro is an antagonist at the CB1 receptor
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High doses in vivo show agonism at the CB1 receptor (antinociception model)
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CB2 receptor partial agonist both in vivo and in vitro (1)
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CBDV (Cannabidivarin):
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2 fewer carbons in the side chain than CBD(1)
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Weak affinity for CB1 and CB2 receptors (1)
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Vocabulary:
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Antagonist-Deactives cells which decrease the release of neurotransmitters for that specific cell type
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Agonist- activates cells, increases the release of neurotransmitters for the specific cell type
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Affinity- How strongly a molecule binds to a specific receptor
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Partial Agonist- can activate or inactivate a cell based on the presence of other neurotransmitters for that specific cell
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Depolarization-Activates a cell
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Isomer- Something with the same chemical structure but the atoms are arranged in a different way to create distinct structures.
Hyperpolarization-Deactivates a cell
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5HT3A receptor- serotonin receptor in the stomach responsible for regulating mobility and nausea
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Opioid receptors- regulate pain in the body, there are 3 subtypes (mu, kappa, delta)
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Allosteric Regulator/Modulator- If a positive modulator increases the effect of affinity for neurotransmitters to a receptor. Negative allosteric modulators decrease the affinity of neurotransmitters to a receptor
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In Vitro- Studies performed on cells in a petri dish
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In Vivo- Studies performed on a living model (i.e.- rodents, humans, etc.)
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References:
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1.Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi:10.1007/978-3-319-45541-9_4
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2.Mouhamed Y, Vishnyakov A, Qorri B, et al. Therapeutic potential of medicinal marijuana: an educational primer for health care professionals. Drug Healthc Patient Saf. 2018;10:45-66. Published 2018 Jun 11. doi:10.2147/DHPS.S158592
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3.Maccarrone M, Bab I, Bíró T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277-296. doi:10.1016/j.tips.2015.02.008
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4.Sagar KA, Gruber SA. Marijuana matters: reviewing the impact of marijuana on cognition, brain structure and function, & exploring policy implications and barriers to research. Int Rev Psychiatry. 2018;30(3):251-267. doi:10.1080/09540261.2018.1460334
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5. Colizzi M, Bhattacharyya S. Neurocognitive effects of cannabis: Lessons learned from human experimental studies. Prog Brain Res. 2018;242:179-216. doi:10.1016/bs.pbr.2018.08.010
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6. Lowe H, Steele B, Bryant J, Toyang N, Ngwa W. Non-Cannabinoid Metabolites of Cannabis sativa L. with Therapeutic Potential. Plants (Basel). 2021;10(2):400. Published 2021 Feb 20. doi:10.3390/plants10020400
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7. Gul W, Gul SW, Radwan MM, et al. Determination of 11 cannabinoids in biomass and extracts of different varieties of cannabis using high-performance liquid chromatography. Journal of AOAC INTERNATIONAL. 2015;98(6):1523-1528. doi:10.5740/jaoacint.15-095
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8. Cooke J. Does Cannabis Have Nutritional Benefits? [(accessed on 16 August 2023)]; Available online: https://thesunlightexperiment.com/blog/cannabis-nutritional-benefits
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9.Waheed Janabi AH, Kamboh AA, Saeed M, et al. Flavonoid-rich foods (FRF): A promising nutraceutical approach against lifespan-shortening diseases. Iran J Basic Med Sci. 2020;23(2):140-153. doi:10.22038/IJBMS.2019.35125.8353
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10.Liu Y, Liu H-Y, Li S-H, et al. Cannabis sativa bioactive compounds and their extraction, separation, purification, and Identification Technologies: An updated review. TrAC Trends in Analytical Chemistry. 2022;149:116554. doi:10.1016/j.trac.2022.116554
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11. Christianson C. Terpene boiling points and temperature. True Labs for Cannabis. January 19, 2022. Accessed August 26, 2023. https://www.truelabscannabis.com/blog/terpene-boiling-points#:~:text=Some%20terpenes%20will%20begin%20to,product%2C%20but%20also%20its%20effects.
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12. How long does marijuana (weed) stay in your system? American Addiction Centers. September 13, 2022. Accessed August 26, 2023. https://americanaddictioncenters.org/marijuana-rehab/how-long-system-body.
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13. Raz N, Eyal AM, Davidson EM. Optimal Treatment with Cannabis Extracts Formulations Is Gained via Knowledge of Their Terpene Content and via Enrichment with Specifically Selected Monoterpenes and Monoterpenoids. Molecules. 2022;27(20):6920. Published 2022 Oct 15. doi:10.3390/molecules27206920
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14. PubChem. National Center for Biotechnology Information. PubChem Compound Database. Accessed August 26, 2023. https://pubchem.ncbi.nlm.nih.gov/.
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15.Salehi B, Upadhyay S, Erdogan Orhan I, et al. Therapeutic Potential of α- and β-Pinene: A Miracle Gift of Nature. Biomolecules. 2019;9(11):738. Published 2019 Nov 14. doi:10.3390/biom9110738
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16. Crockett J, Critchley D, Tayo B, Berwaerts J, Morrison G. A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia. 2020;61(2):267-277. doi:10.1111/epi.16419