Cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD (Han, 2012):
The hippocampus is an area of the brain that contains a high concentration of cannabinoid receptors and is involved in the formation of memories. Long-term depression (LTD) is a form of synaptic plasticity (cell signaling between neurons) that involves persistent weak synaptic stimulation that ultimately leads to decreased efficacy at a synaptic connection by decreasing a cell’s likelihood of firing. Conversely, Long-term Potentiation (LTP) is a form of synaptic plasticity that increases the likelihood of a cell to fire.
Both LTP and LTD are processes that contribute to memory formation and LTD specifically is altered by the activation of Cannabinoid Type 1 Receptors (CB1Rs) in the hippocampus. In this study researchers studied the connections between CA1 and CA3 regions of the hippocampus to determine what cell type was causing this difference.
To study these connections, researchers selectively blockaded CB1R’s in specific subtypes of neurons. In this case they blocked CB1R’s on glutaminergic neurons, GABAergic neurons, and non-neuronal cells called astrocytes. By selectively blocking each type in mice and subsequently observing their performance in a memory test researchers were able to determine the subtype of brain cell that caused this deficit in memory.
In summary: “We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB1R and is associated with astroglia-dependent hippocampal LTD in vivo.”
To watch a video of researchers explaining the studies findings check out this link:
Acetaminophen, also known as Tylenol, is one of the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief. But did you know that its compound’s pain fighting activity arises partially through its activity on the endocannabinoid system?
The acidic cannabinoids (THCA and CBDA) along with non-acidic CBD exhibit anti-inflammatory properties by inhibiting enzymes called cyclooxygenases (COX’s). These enzymes are responsible for the production of pro-inflammatory factors called prostaglandins. This same inhibition occurs when an NSAID is taken.
Isn’t it ironic that cannabis, a compound that is significantly less toxic and harsh on the liver is illegal yet it acts on the same pathways as a commercial pain reliever? Here’s how it works:
The Prostaglandin Synthesis Pathway:
Prostaglandins are synthesized from arachidonic acid. This compound is also the precursor for the synthesis of endogenous cannabinoids.
When acetaminophen is metabolized it results in a compound p-aminophenol that is conjugated to arachidonic acid to form N-Arachidonylphenolamine (also known as AM-404).
This compound is a CB1 receptor agonist and is partially responsible for the anti-inflammatory and analgesic effects of Tylenol.
Alzheimer’s Disease (AD) is a neurological disorder that is characterized by a loss of memory and learned behavior. Alzheimer’s normally occurs in adults 65 and older and has no cure. The pathology of the disease includes aggregates of the Aβ protein along with the hyperphosphorylation of tau protein, which ultimately leads to the formation of neurofibrillary tangles. These aggregates and tangles cause excitotoxicity and microglial activation, which prompts inflammatory responses, and ultimately lead to cell death.
Cannabis can inhibit the inflammation caused by the abnormal structures formed by Aβ and tau proteins and can also slow the progression of the disease. Investigators at The Scripps Research Institute in California in 2006 reported that THC inhibits the enzyme responsible for the aggregation of amyloid plaques [acetycholinesterase] — the primary marker for Alzheimer's disease — in a manner "considerably superior" to approved Alzheimer's drugs such as donepezil and tacrine. An excerpt from the paper states, "our results provide a mechanism whereby the THC molecule can directly impact Alzheimer's disease pathology. THC and its analogues may provide an improved therapeutic for Alzheimer's disease simultaneously treating both the symptoms and the progression of the disease." (Eubanks, 2006)
This figure from the Scripps Research Institute study shows THC’s effectiveness in reducing the formation of Aβ plaques by inhibiting the enzyme acetylcholinesterase (AChE).
Synthetic cannabinoids have also shown promise in the treatment of AD. Both in vitro and in vivo studies of WIN-55, 212-2 using Aβ treated cells showed a significant decrease in microglia-mediated neurotoxicity (Ramirez, 2005).
A study published in 2007 by V.A. Campbell thoroughly explains the potential of cannabinoids in AD, “The propensity of cannabinoids to reduce β-amyloid-evoked oxidative stress and neurodegeneration, whilst stimulating neurotrophin expression neurogenesis, are interesting properties that may be beneficial in the treatment of Alzheimer's disease. Δ9-tetrahydrocannabinol can also inhibit acetylcholinesterase activity and limit amyloidogenesis, which may improve cholinergic transmission and delay disease progression. Targeting cannabinoid receptors on microglia may reduce the neuroinflammation that is a feature of Alzheimer's disease, without causing psychoactive effects.” (Campbell, 2007)
Newer research has affirmed these positive findings using cannabinoids in mouse models. Researchers from The Roksamp Institute in Sarasota, FL found that the clearance of amyloid beta across the blood brain barrier was doubled in the presence of cannabinoid agonists or inhibitors of the enzymes that degrade cannabinoids (Bachmeier, 2013). This finding is significant because it describes the mechanism of how stimulation of the endocannabinoid system can reduce the burden of Aβ plaques in the brain.
Most recently research published in the journal Neuron from the Stanford School of Medicine has shown that early deficits in Alzheimers such as dementia can be triggered by a loss of the body’s own natural cannabinoids, anandamide and 2-arachidonoylglycerol (2-AG) (Orr, 2014). Based on this research one would think that ingesting exogenous cannabinoids would perform the same role however it would be inaccurate to assume that smoking cannabis could counteract the effects of beta-amyloid plaque on memory and learning “Endocannabinoids in the brain are very transient and act only when important inputs come in,” according to Dr. Daniel Madison, one of the authors of the study. "The primary active ingredient in cannabis, THC, has a much longer lasting effect".
With many significant scientific studies coming out on the therapeutic benefits of the compounds in cannabis there has been a growing interest in understanding how these compounds are produced in the plant. In 2011 these interests resulted in the formation of the company Medicinal Genomics, the first group to sequence the cannabis genome.
Kevin McKernan founder and CEO of Medicinal Genomics states that there are 84 compounds other than THC that could be used to treat a variety of ailments, however anti-drug laws make it difficult for scientists to breed and study the plant in most countries. That’s one of the reasons why he decided to publish the data for free on Amazon’s EC2, a public data cloud. McKernan hopes that their data will help scientists breed cannabis plants with lower THC content and higher amounts of the lesser known cannabinoids.
Check out the Medicinal Genomics website here: www.medicinalgenomics.com