One way THC causes memory impairment is by reducing acetylcholine release. Can certain cannabis terpenes rescue memory by increasing acetylcholine?

Cannabis can cause impairments in several different types of memory. This is one of the most significant unwanted side effects for medicinal and recreational users alike. Many people are seeking strategies to sidestep this effect of THC.

The entourage effect is the idea that other components of cannabis can modify the effects of THC. Thus, by breeding plants with different ratios of cannabinoids and terpenes, each strain can give a different high. Although many entourage effects are speculated, few have significant evidence for them from scientific studies.

One of the speculated effects of terpenes is to rescue impairments in memory produced by THC. In particular, pinene is often mentioned due to its ability to inhibit an enzyme called acetylcholinesterase. A well-known 2011 review article on the entourage effect is frequently cited to support this:

“Perhaps most compelling, however, is [α-pinene’s] activity as an acetylcholinesterase inhibitor aiding memory…this feature could counteract short-term memory deficits induced by THC intoxication.”

Well today I will be putting this theory to the test. Read on to see what evidence there is and what we are still missing.

Basic Pharmacology of Acetylcholine

Acetylcholine is a signaling molecule used throughout the body for different purposes:

  • It is released from motor neurons and causes muscles to contract.
  • It is released by the parasympathetic nervous system and is responsible for the “rest and digest” signal (opposite of the more famous “fight or flight” signal from the sympathetic nervous system).
  • It is a neurotransmitter released in the brain by cholinergic neurons, which regulate alertness, attention, learning, and memory.

Two types of receptors are activated by acetylcholine: nicotinic (which are ion channels) and muscarinic (which are G protein-coupled receptors). Although both are involved in memory, I will save the details of receptor subtypes for another article.

Acetylcholine is metabolized by an enzyme called acetylcholinesterase (AChE). AChE inhibitors increase levels of acetylcholine in the brain by blocking its breakdown.

The Role of Acetylcholine in Memory

Acetylcholine has an important role in memory. There is a huge body of research around this, but here are just a few highlights:

  • Selectively destroying cholinergic neurons in animals impairs memory
  • Memory deficits in early Alzheimer’s disease correlate with the degree of cholinergic neuron damage
  • AChE inhibitors are used to improve cognitive symptoms in various types of dementia
  • Scopolamine, a drug sometimes used to rob people, blocks muscarinic receptors and can cause complete amnesia

Cholinergic pathways in the brain. Sep=Medial Septum. Hip=Hippocampus

There are various cholinergic pathways in the brain. The septohippocampal pathway is one of the cholinergic pathways involved in learning and memory. This pathway contains cholinergic neurons that project from the medial septum to the hippocampus. Acetylcholine released from these neurons regulates memory functions of the hippocampus.

The hippocampus has the job of both encoding new memories and retrieving old memories. However, it cannot do both properly at the same time. It is believed that the hippocampus rapidly oscillates between encoding and retrieving information (these oscillations can be detected by hippocampal EEG and are called theta waves).

EEG theta wave. Note: this is a cortical theta wave, not a hippocampal theta wave, but it gives you the basic idea. [Wikimedia]

Naturally, there are times when it is advantageous for your brain to focus more on either encoding new memories or more on recalling old memories. When you encounter a novel situation, your hippocampus should prioritize encoding new memories over recalling old memories.

It appears that acetylcholine regulates this prioritization of encoding or recalling memories. Acetylcholine levels in the hippocampus are high when exposed to novelty, and this high acetylcholine changes the theta oscillations to favor encoding over memory recall. On the other hand, when certain acetylcholine receptors are blocked, the oscillations favor memory retrieval and encoding is impaired.

Acetylcholine and THC Memory Impairment

As described above, decreased acetylcholine levels in the hippocampus are associated with worse memory. We know that THC worsens hippocampus-dependent episodic and working memory. It should be no surprise then that THC reduces acetylcholine levels in the hippocampus.

[One interesting side note: at very low doses, THC actually had the opposite effect and increased hippocampal ACh.]

Although acetylcholine has a role in memory impairments due to THC, it is not the only player. In rodents, working memory was impaired within 20 minutes of THC administration, yet acetylcholine levels did not drop until up to 80 minutes after dosing. I will discuss some of the other mechanisms in upcoming articles.

So what happens when acetylcholine levels are boosted by using an AChE inhibitor? At least 3 different studies have shown that the working memories of rats treated with an AChE inhibitor were protected against impairment from THC or other CB1 receptor agonists!

Inhibition of acetylcholinesterase with physostigmine improves THC impairments in working memory in rats

The data above come from a 2002 study.  These results show that inhibiting AChE is a valid strategy to overcome THC-induced deficits in memory. However, there is no guarantee that these results in animals will extrapolate to humans.

Can Terpenes Affect Acetylcholine Levels and Memory?

We now know that inhibiting AChE is a promising strategy to overcome memory impairments from THC. So let’s turn to the next questions: 1) can terpenes inhibit AChE, and 2) can terpenes improve memory?

In Vitro Studies

Several terpenes found in cannabis do inhibit AChE. The problem is that their potency is incredibly low (meaning that you need a really high level of the terpene to achieve significant inhibition).

Some examples of AChE-inhibiting cannabis terpenes include 1,8-cineole, a.k.a. eucalyptol, (IC50=670 μM), α-pinene (IC50 range= 400-630 μM), Δ3-carene (IC50=263 μM), and limonene (IC50=4305 μM). Other cannabis terpenes such as camphor and linalool had no significant AChE inhibitory activity.

There are still several missing pieces of information. Not every major terpene in cannabis has been tested for AChE inhibitory activity and the mixture of different terpenes could have greater activity than individual terpenes. Plus terpene metabolites formed by your body may have activity, but these have not been tested.

Animal Studies

  • A 50 μL dose of Spanish sage essential oil (which contains high levels of α-pinene and 1,8-cineole) was able to reduce hippocampal AChE activity by about 25% in rats.

This study provides some in vivo confirmation that terpenes can inhibit AChE in this brain region.

Anecdotal Evidence

There is various anecdotal evidence of terpenes impacting memory. Calamus root is reported both in historical literature as well as more recent online reports to mitigate cognitive effects of cannabis:

“Calamus adds an extra degree of mental clarity to the cannabis experience”

Calamus contains β-asarone, a terpene that is a more potent AChE inhibitor (IC50= 3.33 μM) than the cannabis terpenes that have been studied so far.

Calamus plant [Wikimedia]

Clinical Studies

  • A 2011 study (and several earlier studies) examined the effects of Spanish sage essential oil (which contains α-pinene and 1,8-cineole) on human memory and did see some improvement.
  • A 2012 study of rosemary essential oil showed that improved memory was significantly correlated with 1,8-cineole plasma concentrations.

These studies provide some general evidence that terpenes can boost memory. However, I could find no published studies on memory in people who ingested THC. So we still do not know how terpenes affect memory impairments caused specifically by cannabis.

Conclusion on Terpenes and THC Memory Impairment

There is still insufficient evidence to say whether cannabis terpenes can improve THC-related memory impairments, but it is certainly possible. Here is what we know for sure so far:

  • AChE inhibitors overcome THC memory deficits in rodents
  • Certain terpenes from cannabis can inhibit AChE, although with low potency
  • Essential oils with some of the same terpenes found in cannabis can improve memory in sober people

Will anybody do a controlled clinical study to see whether terpenes can block THC memory deficits? I hope one of the enterprising cannabis startup companies focusing on terpene entourage effects will be answering this question soon!

In the meantime, you can buy Calamus Root from Amazon and try for yourself. I think this has the best chance of improving memory impairment from THC given its much higher potency. If you try this, please let us know the results in the comments!

[Featured image: Pixabay]

Last modified: September 11, 2017

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