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Is it a good idea to mix Cannabidiol (CBD) with caffeine?

Cannabis and Coffee are two of the most widely used psychoactive substances in the world. Whereas cannabis is often consumed to relax the body, enhance perception, and stimulate creativity, coffee-like tea and other caffeinated beverages – is typically used to help and energize people focus, especially in the face of exhaustion.

So, does it make sense to consume coffee and cannabis together? How do they interact? Is it fitting that decriminalized THC-rich cannabis was first sold over-the-counter in Amsterdam’s coffee shops?

More recently, several unregulated cannabis start-ups have begun producing and selling coffee infused with doses of hemp-derived Cannabidiol (CBD). Are cannabidiol (CBD) and caffeine really a good combo, or is this only a clever marketing trick?

OPPOSITE EFFECTS

Caffeine is typically considered as a mild cognitive enhancer.  It increases one’s ability to focus and can improve short term memory. Physiologically, caffeine increases fat metabolism and wards off drowsiness. These effects are mostly opposite those of THC, which can also help one focus, but briefly impairs short term memory while decreasing fat metabolism.

Caffeine is a stimulant that activates the sympathetic nervous system, which is intrinsic to the basic human stress-response. But THC mitigates many of the effects of stress. Illogically, THC can even recover memory in animals weakened by chronic stress. When cannabis and coffee are combined, which effects earn-out?

Since plant-cannabinoids like Cannabidiol (CBD) and THC weakly hinder the metabolism of caffeine by preventing an enzyme named CYP1A2, people might expect that caffeine would defeat the cannabinoids.

As it turns out, their interplay is not so simple. Caffeine actually amplifies memory impairment caused by THC. And this effect may be specific to short-term memory. To understand how this happens, it’s necessary to look at the neurological properties of these special compounds.

LOW & HIGH DOSES OF CAFFEINE

Caffeine has two major biochemical effects. At low doses it blocks adenosine receptors (A1, A2A, and A3). These receptors are typically associated with sleepiness. Adenosine regulates the dilation and regulates the sleep-wake cycle and constriction of blood vessels. The stimulating influences of tea and coffee are due to the hindrance of adenosine receptors. And the headaches that some people experience during caffeine withdrawal are likely due to constriction of blood vessels in the brain.

At higher doses, caffeine inhibits a type of enzyme called a phosphodiesterase (PDE). PDEs break down important chemical messengers that are generated by both cannabinoid and adenosine receptors. These messengers are called cyclic AMP (cAMP) and the related cGMP. They are some of the most common signaling molecules in cells.

ADENOSINE: CB1 GATEKEEPER

CB1 cannabinoid receptors and A1 adenosine receptors both populate the hippocampus – a region of the brain responsible for many aspects of memory. Short-term memory, in particular, is processed by brief neurological changes in the hippocampus. When hippocampal A1 is highly stimulated, the effectiveness of cannabinoids at CB1 is decreased. Endocannabinoids, THC or an experimental synthetic cannabinoid will still be capable to activate CB1 receptor, but even high doses will provide a smaller effect.

In a 2011 study led by Portuguese scientists at the University of Lisbon, THC’s effect was one third as strong when given along with an A1 adenosine receptor agonist. (An agonist activates a receptor; an antagonist blocks the receptor.) Conversely, blocking the A1 receptor would increase the effect of cannabinoids, but only in situations where A1 is already active. The specific mechanism by who A1 reduces CB1’s ability is still ambiguous.

This research suggests that elevating adenosine levels might protect people from THC-induced memory impairment without diminishing THC’s important effects outside of the hippocampus, which include neuroprotection, reduction of nausea, and painkilling, as well as psychoactivity. Adenosine levels are highest before sleep. So nighttime use of cannabis may have a lesser effect on memory than daytime use, though this has not been tested experimentally.

for example, where cannabis is utilized to ease trauma, caffeine drinkers may end up benefiting by combining the herb or its components with a cup of Joe. But this might not be the case for a stressed employee who drinks coffee to get through the day. A few introductory studies have shown that taking coffee occasionally or regularly had the same effect: Both increase THE ability to temporarily weaken memory.

THE NEUROLOGY OF MEMORY

So how does THC actually affect short-term memory?

Memory is not encoded in the firing of a single neuron – it develops through changes in the brain’s network. If certain connections between neurons are highly utilized, it would make sense for the brain to strengthen those pathways. In another way, if 2 neurons rarely communicate, it would be better not to disburse much energy maintaining the connection. Elimination of neural connections  and the dynamic strengthening is a key aspect of brain plasticity.

Endocannabinoids play a significant role in synaptic plasticity (and overall neuroplasticity) by regulating what scientists refer to as “long-term potentiation” (LTP) and “long-term depression” (LTD). Both of these processes have a direct bearing on memory and many other brain functions.

LTP involves potentiating or strengthening neural connections between cells; this can occur by increasing the amount of neurotransmitters released by the presynaptic (signal-sending) neuron or by heightening the sensitivity of the postsynaptic (signal-receiving) neuron. LTD entails the reverse process, which ultimately decreases the effect of neuronal action. LTD in the hippocampus helps the clearance of old memories.

Endogenous cannabinoids and plant cannabinoids inhibit neurotransmitter release by activating the CB1 receptor. This can result in bidirectional physiological effects depending on which neurotransmitters are inhibited. CB1 exists on both excitatory (glutamatergic) and inhibitory (GABAergic) neurons. When CB1 impedes the release of GABA, an inhibitory neurotransmitter, CB1 increases (“disinhibits”) brain activity. And by slowing glutamatergic neurons, cannabinoids (via CB1) generally promote LTD and the removal of old memories in the hippocampus.

FINE-TUNING THE BRAIN

Adenosine is constantly released in small concentrations onto the same part of the hippocampus where cannabinoid, adenosine, and glutamate receptors reside. Adenosine, by activating the A1 receptor, reduces the efficacy of THC and other cannabinoids at CB1. And this partially overcomes cannabinoid-mediated LTD, whereby improving short-term memory.

But caffeine blocks A1 receptors. This amplifies the impact of cannabinoid activity and, in turn, will lead to greater LTD and temporary impairments in working memory.

CB1 and A1 receptors also exist on GABAergic neurons in the hippocampus. A1 plays a similar gatekeeping role for CB1 in these neurons (it impedes CB1’s suppression of the inhibitory neurotransmitter GABA). GABAergic neurons act as the major brake slowing glutamate release in the hippocampus.

By engaging the CB1 receptor, cannabinoids can promote either LTD or LTP under different circumstances. LTD appears to be more common. Adenosine acting at A1 receptors will enhance memory by reducing LTD. These complex interactions and feedback loops provide neurons with subtle means to fine-tune the brain.

Cannabidiol (CBD) & ADENOSINE

Cannabidiol (CBD) does not immediately activate CB1, but exerts effects through multiple other pathways. For example, high doses of Cannabidiol (CBD) elevate adenosine levels in the brain by preventing the reuptake of adenosine. This may account for CBD’s ability to ameliorate the short-term memory impairments attributed to THC in some studies. It could be one of many mechanisms that contribute to the “ensemble effect,” whereby the variety of compounds in cannabis can mitigate each other’s side effects and promote each other’s efficacy.

Adenosine is not just a neurotransmitter; it is also known to have intrinsic anti-inflammatory effects. Its reuptake is the principal method the body cancels adenosine signaling. Cannabidiol is protective in some models of heart attack, multiple sclerosis, lung injury, and retinal problems because Cannabidiol (CBD) indirectly activates (via adenosine reuptake inhibition) A2A and A1 receptors.

The sedative side effect of high doses of Cannabidiol (CBD) might also be related to amplified adenosine. In clinical trials of a sublingual Cannabidiol (CBD) isolate called Epidiolex, sedation is one of the most common side effects. Although the molecular cause of this is not known with certainty, a high dose of Cannabidiol (CBD) may augment adenosine signaling and contribute to tiredness.

When mixed with caffeine, CBD’s effects on adenosine would probably be dwarfed by caffeine’s antagonistic activity at adenosine receptors. The extent to which this might diminish CBD’s medicinal properties is unknown. Given cannabidiol’s many modes of action, it is unlikely that this would be seriously problematic. But as of now, there aren’t clear advantages to combining or marketing Cannabidiol (CBD) and caffeine together.

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