How CBD Affects The Brain

Cannabis contains more than a hundred phytocannabinoid compounds. These include the non-intoxicating cannabinoid named cannabidiol which is better known as CBD6. Estimates show that the CBD market in the US will grow to $2.1 billion in consumer sales by 2020. This explosion in popularity and demand for CBD is from its growing reputation as a beneficial compound for multiple conditions. One of those conditions begs the question of how CBD affects the brain.

CBD is in clinical trials for several diseases and disorders. Parkinson’s disease, Crohn’s disease, social anxiety disorder, and schizophrenia2,6 are among these. It is also a promising candidate for therapeutic use in epilepsy, Alzheimer’s disease, and multiple sclerosis.

CBD has anti-inflammatory, anti-oxidative, and protective properties that suggest it could be as useful for day to day ailments as aspirin or supplements. The most exciting thing about CBD is that it has a favorable safety and tolerability profile in humans with few side effects and the ability to take it at a wide range of doses.

The endocannabinoid system (ECS) has receptors throughout the whole body. Different types of cannabinoid receptors interact differently with cannabinoids and terpenes. The way CBD influences the ECS or produces an effect on the body is determined by how it interacts directly or indirectly with the different cannabinoid receptors. CBD can have influences through the whole body, but what does CBD do in the brain?

How Does CBD Affect The Brain?

The brain is like the command center of the nervous system, especially the central nervous system (CNS). Neurological conditions and diseases include a wide range of pathologies such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and seizure disorders like Lennox-Gastaut and Dravet syndromes.

Your brain is also host to psychiatric and mood disorders like schizophrenia, anxiety, depression, addiction, post-concussion syndrome, and post-traumatic stress disorder. CBD and other cannabis-derived compounds are being heavily investigated for the brain’s mental and physical ailments.  They have diverse effects that can be used to manipulate the endocannabinoid system.

The CB-1 (cannabinoid 2 receptor) is the most abundant cannabinoid receptor in the brain and through the CNS. THC is known for its ability to activate, or agonize CB-1 receptors, thereby creating effects like intoxication, sedation, memory problems, and the infamous food craving known as “the munchies.” CBD can also interact with CB-1 and deactivate, or antagonize, the receptor, counteracting the effects of THC depending on the ratio of CBD to THC in a cannabis product.

CBD has a low affinity for binding with CB-1 and CB-2 (cannabinoid 2 receptor) receptors but has more affinity for GPR557. GPR55 is a receptor that is thought to be a cannabinoid receptor and is expressed in the caudate nucleus and putamen in the brain. CBD is an agonist (activator) of GPR55, but for GPR3, GPR6, and GPR12, CBD plays a different role where it binds to the receptors like an agonist but produces a response that opposes the response that would normally be generated by an agonist, this is termed “inverse agonist.”

Receptor 5-HT1A

Another receptor located in the brain is the serotonin receptor 5-HT1A9. CBD also had an affinity for 5-HT1A, which is attributed to the anti-anxiety and antidepressant CBD benefits. CBD has also been reported to influence addiction behavior and potentially help combat opioid addiction. This may be attributed to the role of CBD as an allosteric modulator of the μ- and δ-opioid receptors as well. Another receptor agonized by CBD is peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG). PPAR-γ is thought to play a role in the pathology of numerous diseases, including obesity, diabetes, atherosclerosis, and cancer. Finally, CBD can influence intracellular calcium release. This plays a significant role in communicating signals through the body and influencing physiological reactions.

CBD can have direct and indirect effects on isoforms of peroxisome proliferator-activated receptors (PPARs α, β, and γ). Activation of PPAR, along with CB1 and CB2, mediates analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, antitumor, gastrointestinal, and cardiovascular effects, both in and outside the ECS5. PPAR-γ (gamma) agonists like CBD have been used in the treatment of hyperlipidemia and hyperglycemia because PPAR-γ decreases the inflammatory response of many cardiovascular cells, ultimately reducing atherosclerosis. CBD can increase the production of PPAR-γ by influencing transcriptional activity that creates PPAR-γ.

Positive Effects of CBD Oil On The Brain

  1. Reduces Blood Flow
  2. Lowers Degree of Excitation of Brain Cells
  3. Significant Antipsychotic and Anxiolytic Properties
  4. CBD is Neuroprotective
  5. Influences Neuropsychiatric Disorders

Beneficial modulation of the endocannabinoid system to treat diseases can occur by agonism (activation) or antagonism (blocking) of cannabinoid receptors themselves, or by interaction with the various enzymes in the ECS pathway such as N-acylphosphatidylethanolamine-selective phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase isozymes α and β, and monoacylglycerol lipase4.

CBD has multiple targets, but one important aspect of its biochemical and physiological properties may be to help regulate excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) transmission8. These two activities influence the activity of excitatory and inhibitory signaling pathways in the body’s nervous system. CBD enables glutamate and GABA neurotransmission across the brain through agonism at the transient receptor potential vanilloid 1 (TRPV1 receptor).

CBD may increase GABAergic transmission by antagonism at the G protein-coupled receptor GPR55 and in the basal ganglia of the brain8. It is thought that CBD also can act as an agonist at the brain’s prefrontal 5-HT1A receptors where glutamate and GABA transmission are suppressed by CBD.

CBD Reduces Blood Flow

Blood flow can influence cardiovascular diseases and conditions, including stroke, arrhythmia, and atherosclerosis10. In many heart conditions, increased blood flow from the relaxation of the veins (vasorelaxation) can help prevent cardiovascular events. There are still many studies needed on the role of CBD in cardiovascular health, but there is some evidence that CBD may have protective effects in the cardiovascular system.

CBD can influence white blood cell survival and death, white blood cell migration through the body, and platelet aggregation10. The study of the CBD analog Abn-CBD has revealed that Abn-CBD can decrease blood pressure (hypotension) through cannabinoid receptors. CBD is known to exert vascular effects such as producing vasodilation as well as hypotension5. These effects may help protect the body against cerebrovascular damage associated with stroke.

Vasorelaxtion

CBD may promote vasorelaxation in human arteries up to about 40%10. Many of the effects of CBD on blood flow and cardiovascular health take place outside of the brain and act on peripheral parts of the endocannabinoid system. Vasorelaxation from CBD in human mesenteric arteries is dependent on the state of the endothelium that covers veins and arteries and involves CB-1 receptor activation, TRPV channel activation, nitric oxide release, and potassium hyperpolarization. The significant cardioprotective effects of CBD may occur through a direct action on the heart or through a general anti-inflammatory and anti-oxidant mechanisms.

CBD treatment does not appear to have any effect on resting blood pressure or heart rate but does reduce the cardiovascular stress response through 5-HT1A inhibition, and contribute to vasorelaxation10. In addition to protecting against damage from stroke, CBD also may counteract the effects of high glucose environments in people with diabetes.

The ability of CBD to reduce stress sensation through 5-HT1A and the other anti-anxiety effects of CBD can reduce stress responses like increased heart rate and blood pressure10. The potential of CBD to reduce cardiovascular responses to stress could have significant effects on the development of heart conditions like atherosclerosis and hypertension, which are known to be accelerated by stress.

How CBD benefits the Cardiovascular System and Blood Flow

  • Modulates the immune system in ways that promote cardioprotective activity
  • May significantly decrease myocardial inflammation, oxidative stress, nitrative stress and fibrosis in diabetes
  • Influences blood cell function by altering phospholipase A2 expression and lipooxygenase in platelets
  • Inhibits adenosine, epinephrine, and collagen stimulated platelet aggregation
  • Decreases 5-HT release from blood platelets
  • Through CB-2, CBD induces apoptosis (cell death) of fresh human monocytes (white blood cells) and human leukemia cells
  • Can prevent serum-deprived cell death of lymphoblastoid cells through antioxidant mechanisms
  • Inhibited formyl-Met-Leu-Phe-OH (fMLP)-stimulated neutrophil migration
  • May inhibit monocyte adhesion, infiltration, and white blood cell margination in cerebral blood vessels
  • Significantly inhibits myeloperoxidase (which is expressed in neutrophils, monocytes, and some macrophage cells)
  • May cause a dose-dependent suppression of lymphocyte proliferation in collagen-induced arthritis

CBD Lowers Degree of Excitation of Brain Cells

Neurodevelopmental disorders, such as autism spectrum disorder (ASD) affect up to 1 in 59 individuals8. Of those who have ASD, about 70% of those affected also have co-occurring conditions such as epilepsy, and mood and anxiety disorders. In addition, the average lifespan of some individuals with ASD can be reduced by up to 20 years. Unfortunately, the pharmaceutical industry has struggled to offer people with ASD effective pharmaceutical options. Many are interested in the potential of alternative health options like CBD for that reason.

ASD symptoms have been linked to abnormalities in the GABA pathways of the prefrontal cortex and basal ganglia areas of the brain8. In these areas, excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels modulate brain activity in ways that create symptoms like epilepsy and mood and anxiety disorders. CBD is known to act on GABA pathways to alter those kinds of symptoms, but people with ASD may react differently due to the abnormalities in their brains.

To research the effect of CBD on brain cell excitation, brain MRIs have been taken after administering a single oral dose of 600mg CBD or placebo8. In that study, researchers saw differences in CBD effects on autistic brains and typical brains. Across regions, CBD increased GABA+ in typical brains, but decreased GABA+ in ASD; the group difference in change in GABA + in the prefrontal cortex was most significant.

CBD can ‘shift’ levels of the metabolites Glx and GABA+, which contribute to the regulation of excitatory and inhibitory neurotransmission in both the typical and the autistic brain. The possibility that CBD could increase brain homeostasis in people with ASD and ease their symptoms needs much more research, but the potential is very exciting.

CBD Has Significant Antipsychotic and Anxiolytic Properties

CBD in animal and human studies has demonstrated anxiolytic (anti-anxiety) and antipsychotic effects that affect psychological disorders by influencing brain function1,2. Human trials support previous observations from animal studies that report that CBD appears to be a safe compound for human use over a wide dose range. CBD is of interest in psychological and mood disorders because of its effectiveness and lack of side effects compared to available drug options. Antipsychotic and anti-anxiety pharmaceuticals often fail to control symptoms well and have disruptive side effects that CBD lacks.

Anti Anxiety

CBD induces acute anxiolytic effects when injected into the dorsal periaqueductal gray (dPAG) and bed nucleus of the stria terminallis (BNST) of the brain1. It also modifies anxiety-like behaviors in the medial prefrontal cortex (mPFC) of the brain, which prevents the expression of contextual fear conditioning mechanisms. In the hippocampus, the acute effect of CBD is still unknown. Repeated administration of the CBD prevents the anxiety generating effects of chronic stress by facilitating hippocampal neurogenesis. The acute anti-stress effects of CBD also have been linked to the BNST. It is thought that the antidepressant action of CBD could be mediated by the hippocampus and mPFC.

CBD produces anxiolytic effects with a dose-dependent bell-shaped curve, meaning that the effects are best seen at particular dose levels1. In one study, doses of 100mg, 300mg, and 900mg were evaluated against a placebo and against a 1mg dose of benzodiazepine clonazepam. Study participants reported the most anxiety relief in a public speaking trial with the 300mg CBD dose, which fell in the middle of the bell-shaped curve.

The researchers elaborated that using CBD oil for anxiety was able to reduce subjective measures of it without inducing sedation in treatment-naive social anxiety disorder patients1. The anxiolytic (anti-anxiety) effect was associated with reduced activity in the hippocampus, parahippocampal, and left temporal gyrus and increased activity in the posterior cingulated. These modulatory effects of CBD in limbic and paralimbic areas are compatible with the effects of anxiolytic compounds on healthy subjects and in patients with anxiety disorders.

CBD In Animal Brains

In an animal model of CBD antipsychotic effects, it was compared to the pharmaceutical haloperidol1. CBD was able to decrease stereotypy induced by dopaminergic agonists in a similar manner but did not produce side effects of haloperidol like catalepsy and impaired motor function. It also demonstrated effects similar to clozapine by increasing prolactin levels. These effects were only observed at CBD doses that were very high (greater than 120 mg/kg).

The antipsychotic effects of CBD were also investigated in first-episode schizophrenia patients1. CBD significantly decreased psychotic symptoms after two weeks when compared to baseline. The differences from placebo failed to reach statistical significance, as researchers need to do more work and larger studies. CBD could have an atypical antipsychotic profile that may provide benefits without the disruptive side effects of traditional pharmaceuticals.

CBD has also shown the ability to top increase stress-coping behaviors and may have significant antidepressant effects1. This has been suggested by researchers based on the observation that CBD induces an increased number of Ki67, BrdU, and doublecortin-positive cells in the hippocampus.

Finally, CBD has positive effects on synaptic remodeling. In rats with induced-brain damage, CBD normalized the expression of synaptophysin, an important protein related to proper synaptic function.

Overall, these interactions between specific brain regions and CBD makes it a promising option. Using CBD for pets may be considered for relieving symptoms of psychosis, anxiety, and depression, among other psychiatric and mood disorders.

CBD is Neuroprotective

The ability of CBD to increase levels of the compound adenosine in the brain is associated with neuroprotective effects and its ability to decrease inflammation after brain trauma5. CBD acts on multiple mechanisms to increase adenosine levels by inhibiting reuptake, a process similar to recycling the compound within the body.

Neuroprotective CBD Mechanisms

  • Inhibition of calcium transport across cell membranes
  • Impediment of anandamide uptake and enzymatic hydrolysis
  • Obstruction of inducible NO synthase protein expression and nuclear factor (NF)-κB activation
  • Regulation of glutamate and pro-inflammatory mediators
  • Neutralization of reactive oxygen species (ROS)
  • Reduced lipid peroxidation

Many of these mechanisms of CBD in neuroprotection have led researchers to believe that CBD could be used in the treatment of Alzheimer’s disease5. In a rat model of AD, CBD reduced the effects of β-amyloid-induced neurotoxicity.

CBD Influences Neuropsychiatric Disorders

Outside of the ECS, CBD’s influence on serotonin receptors has been attributed to many benefits like the stimulation of hippocampal neurogenesis5. CBD has shown (in rodent models) an ability to mediate stress, inducing anxiety and depression symptoms, by activating 5-HT1A receptors in a similar way as the drug buspirone that is FDA approved for relieving anxiety and depression in humans.

CBD has demonstrated positive effects on psychosis, anxiety, PTSD, depression, and other neuropsychiatric conditions. Benefits have also been attributed to CBD’s effects on oxidative stress, immune mediators, and neurotrophic factors. In rodent models, CBD effectively blocked the formation of fearful memories. Some evidence shows that CBD can help people forget memories that trigger anxiety and PTSD symptoms.

Antidepressants

Antidepressants possess numerous neuroprotective properties, such as preventing the formation of amyloid plaques, the elevation of BDNF levels, reduction of microglia activation, and decreased levels of pro-inflammatory mediators5. CBD has similarly demonstrated decreases in the production of inflammatory cytokines, the activation of microglial cells, and brain leucocytes infiltration. This gives further evidence to support the role of CBD in combating neuropsychiatric disorders.

In human imaging studies of CBD reduced the activity of the left amygdala-hippocampal complex, hypothalamus, and posterior cingulate cortex were observed along with increases to the activity of the left parahippocampal gyrus5. These imaging studies amazingly captured the anti-anxiety effects of CBD as they took place in the brain.

Negative Effects of CBD Oil on the Brain

The long term effects of regular CBD use are not completely understood. This lack of understanding causes concern about the possible negative effects of CBD oil on the brain. Side effects, like dry mouth, diarrhea, reduced appetite, drowsiness, and fatigue, have been observed on occasion. CBD itself has been lauded for its tolerability, safety, and ability to provide symptom relief without getting high though2.

Many CBD researchers would consider supporting CBD becoming “generally recognized as safe” by the FDA.  However, individual product quality is of great concern. CBD is not currently well regulated, and the FDA cannot guarantee the safety or efficacy of CBD products. It can be hard to tell which brands look legitimate and which have truly good quality.

There is some degree of trial and error in finding a CBD product and dosage that works well for you. Educating yourself and researching the different types of CBD products can help guide decisions. There is no single formulation or dosage that suits most people. Some negative CBD side effects (like experiencing stomach aches) may result from this trial and error process.

Resources

  1. Crippa JA, Guimarães FS, Campos AC, Zuardi AW. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front Immunol. 2018;9:2009. Published 2018 Sep 21. doi:10.3389/fimmu.2018.02009. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/30298064
  2. Iffland, K., & Grotenhermen, F. (2017). An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis and cannabinoid research, 2(1), 139-154. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569602/
  3. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology. 372 (5): 354–61. doi:10.1007/s00210-006-0033-x. Retrieved from: https://www.theroc.us/researchlibrary/Cannabidiol%20is%20an%20allosteric%20modulator%20at%20mu-%20and%20delta-opioid%20receptors.pdf
  4. Kolb, B., Saber, H., Fadel, H., & Rajah, G. (2019). The endocannabinoid system and stroke: A focused review. Brain circulation5(1), 1–7. doi:10.4103/bc.bc_29_18. Retrieved from: http://www.braincirculation.org/article.asp?issn=2394-8108;year=2019;volume=5;issue=1;spage=1;epage=7;aulast=Kolb
  5. Maroon, J., & Bost, J. (2018). Review of the neurological benefits of phytocannabinoids. Surgical neurology international, 9, 91. doi:10.4103/sni.sni_45_18. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/
  6. Millar, S. A., Stone, N. L., Yates, A. S., & O’Sullivan, S. E. (2018). A systematic review of the pharmacokinetics of cannabidiol in humans. Frontiers in pharmacology, 9, 1365. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275223/
  7. Pertwee R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol, and delta9-tetrahydrocannabivarin. British journal of pharmacology, 153(2), 199–215. doi:10.1038/sj.bjp.0707442. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/
  8. Pretzsch, C. M., Freyberg, J., Voinescu, B., Lythgoe, D., Horder, J., Mendez, M. A., … & Edden, R. A. (2019). Effects of cannabidiol on brain excitation and inhibition systems, a randomized placebo-controlled single-dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology, 1. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784992/
  9. Russo EB, Burnett A, Hall B, Parker KK. (August 2005). Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochemical Research. 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/16258853
  10. Stanley, C. P., Hind, W. H., & O’Sullivan, S. E. (2013). Is the cardiovascular system a therapeutic target for cannabidiol?. British journal of clinical pharmacology, 75(2), 313–322. doi:10.1111/j.1365-2125.2012.04351.xmg. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579247/