Cannabis and memory

Consistent data in human and animal models aid in the understanding of underlying mechanisms and behavioural effects of cannabis on learning, memory and plasticity. However, many partial parties advocate against these findings.^[1]

Cannabinoid receptors

The structure of THC

Cannabis' constituent cannabinoids, primarily delta-9-tetrahydrocannabinol (Δ9-THC or THC), are believed to impair different aspects of cognitive functioning, including memory.^[2] An array of research into deciphering the modes of action for cannabis on the brain in memory has been conducted and collected. This research includes studies of cognition, brain imaging, and more recently cannabinoids and cannabinoid receptor research.^[3][4] With the discovery of the endogenous cannabinoid receptors, some recent scientific literature has focused on the effects of phytocannabinoids, synthetic cannabinoids (cannabimimetics) and endocannabinoids in understanding the mechanisms behind cannabis-related memory impairment.^[4][5] Cannabinoids in general act fairly consistently in the endocannabinoid system, allowing for flexibility in research because a variety of cannabinoids can be used for understanding the effects of cannabis.^[3]

There are currently two well-known cannabinoid receptors in humans and other animals: the CB1 and CB2 receptors.^[3] The CB1 receptor is known for its mediating effects primarily on memory and cognitive functioning. There are, as of yet, no CB2 receptors that are considered relevant to any cannabinoid-related cognitive effects.^[6][7] CB1 receptors are G-protein coupled receptors that are involved in retrograde signaling and are extensively distributed on presynaptic terminals in brain regions that are involved in cognition, particularly learning and memory.^[8][3] These brain regions include the hippocampus, the basal ganglia, the cerebellum and the neocortex.^[3][4][9] Moreover, these CB1 receptors are activated by cannabinoids, and modulate neurotransmitter release in the brain and body.^[3][10]

CB1 receptor knockout mice

CB1 receptor knockout mice or rats that lack CB1 receptors due to inoperative genes.^[11] Global CB1 receptor knockout mice are consistently reported to demonstrate enhanced long-term potentiation (LTP), and resistance to the effects of THC on the tetrad assay and the tasks that assess spatial memory.^[12][13] LTP is a long-lasting increase of synaptic efficacy, in response to high-frequency stimulation of neurons.^[14] Knockout mice also demonstrate impairments in the short-term and long-term extinction of aversive memories.^[2] In contrast, other research demonstrates that knockout mice show impairments in locating new hidden platforms in water maze tasks, which involve hippocampal function.^[12] This research suggests that the endocannabinoid system may be involved in the extinction of learned behaviour and may play an important role in forgetting and encoding mechanisms.^[15]

Neurotransmitters

Cannabinoids act on specific neurotransmitters in respect to certain memory regions of the brain.^[2][3] Glutamate, dopamine and acetylcholine are three neurotransmitter systems that are thought to play a role in possibly mediating the memory effects of cannabis.^[2][3][16] In particular, recent research focuses on glutamate for its responsibility in hippocampal LTP and long-term depression (LTD)—the long-lasting decrease of synaptic excitability.^[2][16] Additionally, dopamine is often investigated for its possible roles in working memory within the prefrontal cortex.^[17] Older research investigates acetylcholine in respect to cannabis memory impairments, but lacks credibility in comparison to other neurotransmitters, due to research controversies.^[2][16]

Glutamate

CB1 agonists (i.e. WIN55,212-2) are observed to decrease evoked excitatory postsynaptic potentials within the hippocampus, suggesting that cannabinoids play a role in decreasing glutamate levels by possibly using presynaptic mechanisms.^[16][17] Evidence suggests that these presynaptic mechanisms are mediated via inhibitory G-proteins.^[16] Other research suggests that a novel cannabinoid receptor is involved in mediating the inhibition of hippocampal glutamatergic transmission.^[18]

NMDA receptors are believed to be involved in cellular hippocampal LTP and LTD processes, in respect to memory consolidation and forgetting factors.^[2][16] For these process to occur on the cellular level, a high enough excitatory postsynaptic potential must occur to depolarize the CA1 hippocampal postsynaptic membranes and remove the magnesium blockade on NMDA receptors.^[19][20] Glutamate plays the role in activating NMDA receptors, allowing hippocampal calcium to flow through NMDA receptor channels—calcium NMDA receptor transmission is critical in inducing both LTP and LTD.^[16][19] Optical imaging evidence that monitors synaptic activity on in vitro hippocampal neurons, demonstrates that CB1 agonists (including THC) reduce glutamate release.^[21] Since glutamate release is required for NMDA receptor activation, and removing the magnesium blockade, a reduction of glutamate release causes a reduction of excitatory postsynaptic potential, suggesting an impairment of LTP and LTD is mediated via hippocampal NMDA receptors.^[16][19][20] This finding not only suggests that memory impairment affects long-term synaptic plasticity, but is also supported via experimental data.^[16] In fact, research shows that CB1 agonists in the hippocampus do not impair LTP and LTD, when the NMDA magnesium blockade is instrumentally removed on hippocampal CA1 neurons.^[22] Ultimately, with the consistency of scientific inference and experimental data, cannabinoid effects on memory are compellingly supported via the modulation of glutamate release.^[2][16][17]

Dopamine

Cannabinoids activate mesoprefrontocortical dopaminergic neurons, an activation that releases dopamine primarily in the prefrontal cortex.^[17] In fact, stimulation of the prefrontal cortex dopamine receptor D1 is associated with working memory impairments.^[2] This relationship suggests that the memory disrupting effects of cannabinoids might be due to D1 activation in the prefrontal cortex.^[2][17] In contrast, poor neurotransmitter interplay in the prefrontal cortex may be mediated by cannabinoid inhibition of GABA release.^[17][23] GABAergic interneurons may suppress a specific dopaminergic mechanism involved in prefrontal cortex neuronal excitability, possibly altering the normal signal processing in the prefrontal cortex.^[2][17] This evidence suggests that cognitive processes related to the prefrontal cortex, such as working memory, may be relevant to understanding the mechanisms associated with cannabinoid induced dopaminergic activity.^[2][17]

Acetylcholine

A study has demonstrated that cannabinoids selectively modulate the activation of cholinergic neurons that are in the septal-hippocampal pathway.^[24] It has been experimentally shown that WIN55,212-2, a potent-selective cannabinoid receptor agonist, inhibits acetylcholine release in the septal-hippocampal pathway.^[16][24] This inhibition of acetylcholine release from these neurons may contribute to other possible mechanisms for the underlying memory disruptive effects of cannabinoids.^[2] Contrary to this evidence, a more recent study has demonstrated that inhibiting these hippocampal cholinergic neurons with receptor antagonists does not disrupt memory in THC-intoxicated rats who are performing in the radial arm maze, challenging the idea that acetylcholine is involved in the memory mediating effects of cannabinoids.^[16][25]

Brain regions

Research studies that have focused on certain brain regions have formulated insights into the mechanisms of the local memory disruptive effects of cannabis.^[2] Different memory tasks seem to recruit different neural substrates with high densities of CB1 receptors that underlie cannabis-induced memory impairments.^[26]

Hippocampus

Animation: Hippocampus (red)

The hippocampus is considered one of the more important brain regions involved in information processing, encoding and memory consolidation.^[27] Research suggests that the hippocampus plays a predominant, and even necessary role in the memory disruptive effects of cannabinoids on the central nervous system.^[3][26] Cannabinoids have been suggested to disrupt long-term plasticity in hippocampal regions via reducing presynaptic neurotransmitter release.^[28] In respect to neural mechanisms involved in plasticity, CB1 receptor activation has been found to inhibit both LTP and long-term depression (LTD).^[2] LTD is the opposite of LTP, and is the long-lasting decrease of synaptic efficacy in response to weak synaptic stimulation in the hippocampus.^[2] Furthermore, hippocampal LTD may play an important role in the memory trace forgetting processes of cannabinoids.^[2] Even though CB1 receptors have been demonstrated to inhibit glutamatergic transmission through in vitro hippocampal cells, alternative evidence for the GABAergic pathways in the hippocampus also demonstrates the memory disruptive effects of cannabinoids.^[26][29]

CB1 receptors in the hippocampus are expressed at very high densities, especially on the terminals of a sub-set of GABAergic basket cell interneurons that contain the neuropeptide cholecystokinin. These cell terminals surround large pyramidal neuron somata in the hippocampal CA1-CA3 regions and correlate with the known memory impairing effects of cannabinoids.^[30] In fact, recent research suggests these CB1-expressing interneurons synchronize temporal population activity in principal cell assemblies, and may explain THC-induced amnesia—THC floods the network, thus inhibiting hippocampal GABA release, and possibly disrupting hippocampal temporal coordination.^[31][32] However, other research suggests that it is still not clear which specific hippocampal neurons mediate the memory impairing effects of cannabinoids.^[26]

Amygdala

The amygdala is known to play a role in emotional learning and emotional memory formation.^[33] In amygdala-prefrontal cortical circuits, the basolateral amygdala (BLA) relays functional output to the medial prefrontal cortex (mPFC) for salient information integration and memory formation processes.^[34][35] Research has shown that cannabinoids can modulate the neuronal magnitude of emotional learning in the mPFC via functional output from the BLA, when associative learning is pronounced in the mPFC, BLA input is no longer required beyond the initial memory formation. This evidence suggests that cannabinoid signaling plays a role in the salience of emotional stimuli, as well as the emotional learning and memory formation processes involved.^[34]

Prefrontal cortex

Cannabinoids are also known to have disruptive effects of working memory in the prefrontal cortex.^[36] In research that infuses THC into the prefrontal cortex of rats, memory impairments were observed in the standard 8-armed radial arm maze task that incorporated a one-hour delay, but not without the delay.^[37][38] Furthermore, THC injected intravenously into rat prefrontal cortex causes significant increases in extracellular dopamine and glutamate levels, as well as a reduction in GABA.^[23] This finding suggests that some cannabinoid-induced memory deficits may be due to a disruption of normal neurotransmitter interplay in the prefrontal cortex.^[23]

Short-term memory

Short-term memory is the system that allows people to remember things over a brief period of time and that can be used to describe performance on a particular type of task that involves the simple retention of small amounts of information and that is tested either immediately or after a short delay.^[39] From the short-term memory store, information is available for use by working memory or can be transferred to long-term memory.^[39] Short-term memory has a limited capacity that is often described as 7 ± 2 chunks of information such as words or numbers.^[40]

Word recall

In word recall tests, subjects are shown a list of words for a short period of time and are then asked to recall these words after a short delay.^[39] This recall may be done by using the method of free recall, where participants recall items in any order, or recognition recall, where participants are prompted by cues.^[39] Cannabis has been found to produce impairments in word recall tests by means of interrupting the consolidation of words presented early in the lists.^[2]

Encoding impairments

Memory encoding is the process that allows people to convert selected items into constructs via consolidation.^[2] These constructs can be stored for short-term or long-term usage by the brain and can be cued by different contexts that were available during encoding.^[39][41] Memory consolidation is a gradual process by which components of an initial experience and its interconnections become stabilized in memory.^[41] Cannabis has been shown to produce impairments in both free recall and recognition recall of word lists.^[2] The primacy effect—recall of words presented at the beginning of a list is better than recall of words presented in the middle—was significantly decreased by cannabis while the recency effect—recall of words presented at the end of a list is better than recall of words presented in the middle—was unaffected, a finding that seems to indicate that the cannabis is impairing the recall of information that should have been consolidated into long-term memory.^[42] No effects were found in retrieval of word lists in conditions with no intoxication; therefore, the recall impairment that was observed while participants were under the influence of cannabis was attributed to encoding deficits rather than retrieval impairments.^[2] Evidence that the hippocampus plays a large role in consolidation is demonstrated in one study where cannabis produces the same effects on rats as when the hippocampus is removed.^[43][44]

Prose recall

Similar to word recall, prose recall tests are tests where the participants are shown a story or paragraph instead of a word list and the participants are then tested on this prose, after a short delay.^[2] Cannabis has been shown to significantly decrease prose recall after immediate and delayed testing compared to a placebo group.^[2] In a two-day study, participants who had received cannabis on the first day showed decreased prose recall on the same day as well as decreased recall on the next day, even if they received a placebo on day two.^[2] This study not only demonstrates the effects of cannabis on recall but also suggests longer-lasting effects.^[2]

Intrusion effects

Cannabis is believed to increase intrusion errors in memory resulting in false positives during recognition recall in prose memory tests.^[2] Ranganathan and D’Souza hypothesize that "The increase in intrusion errors may reflect increased mental activity and subsequent irrelevant associations induced by cannabinoids, spilling over into the retrieval processes ..."^[2] This increased activation can be supported by increased blood flow in memory related cerebral regions of the brain activated by cannabis use.^[45]

Visual recall

Visual perception is one of the first stages of memory and is believed to be the most rapidly decaying memory system because it can easily be masked by other things following stimulus presentation.^[46] Although cannabis affects both verbal and visual memory, practice, such as rehearsal, has been shown to improve verbal memory with visual memory still impaired.^[2] This effect has been attributed to differences in learning style: Field dependent learners had more difficulty with visual recall than field independent learners, a finding that indicates that learning strategy may influence one's response to cannabis.^[2]

Long-term memory

Long-term memory (LTM) is the system or systems that are assumed to underpin the capacity to store information over long periods of time.^[47] There have been no direct links to the effects of cannabis on LTM; however, more direct links have been found at earlier stages in the processes that underlie LTM: attention, short-term memory, working memory, and episodic memory.^[43] This association results in impairment, caused by cannabinoids, in all stages of memory including encoding, consolidation, and retrieval.^[2][4] The majority of these research findings have shown impairments in attention and encoding (Note: encoding impairments).^[4][43] Although studies of the effects of cannabis on memory are limited, it is widely accepted that encoding is essential for proper consolidation and retrieval in memories; thus, information that is poorly encoded is seen as less likely to be effectively consolidated and stored in long-term memory.^[4][43]

Due to the complexity of memory, it is difficult to draw any strong conclusions with regard to the effects of cannabis on LTM. It does not seem that cannabis has direct effects on retrieval, but does indirectly affect LTM through disruption in attention, encoding, consolidation, and context-dependent memory.^[43]

Context-dependent memory

Context-dependent memory is the idea that information is typically easier to recall in the same environment as it was encoded.^[48] Depending on the size of dose, cannabis may significantly affect the users internal environment.^[2] Thus, if an individual is under the influence of cannabis during the encoding or retrieval stage and is not under the influence in the retrieval or encoding stage, then they are much less likely to match internal states and, thus, are less likely to successfully retrieve the information in LTM.^[48] This phenomenon is also called the encoding specificity principle.

Episodic memory

Episodic memory is the ability to consciously remember a past event, even after a distraction filled delay, without continuous and active maintenance of information between the study time and test time. Episodic memory relies upon the frontal cortex and hippocampus, which are both heavily saturated with cannabinoid receptors that are activated by THC. Using recognition tests that evaluate episodic memory, researchers, Ilian, Smith, and Gevins, tested participant recognition of words studied 5–10 minutes earlier. Those participants that were under the influence of cannabis, were more likely to identify false distractor words as being studied previously.^[43] An earlier study by Curran, showed that those under the influence of THC were found to have impaired performance on explicit memory tasks, compared to control subjects.^[49] It was found that impairment of episodic memory and learning varied depending on the size of an oral THC dose.^[50]

Working memory

Baddeley's model of working memory

Working memory is the memory system that allows people to temporarily maintain and manipulate information.^[51] More specifically, Alan Baddeley's working memory model incorporates four components that work together to allow the mind to both maintain and manipulate information for a short period of time: the central executive, the phonological loop, the episodic buffer, and the visuospatial sketchpad.^[51]

Spatial working memory

According to Baddeley's model of working memory, spatial working memory is the memory system that can maintain and manipulate spatial and visual information for a short period of time.^[51] This system is important for showing the differential effects of cannabis on working memory because the neural centres that are used during spatial working memory tasks seem to show increased activation when people who have been exposed to cannabis perform spatial working memory tasks.^[52][53] A meta-analysis of neural imaging that was conducted when participants were performing spatial working memory tasks, more specifically, the n-back task, revealed the primary neural areas that are associated with spatial working memory: prefrontal, premotor, and posterior parietal cortex.^[54][55]

Neurophysiological effects

Effects on neural activation

Studies seem to show that participants who are affected by marijuana have more increased neural activation when performing spatial working memory tasks: the brain seems to have to compensate for working memory deficits.^[52][53][55]

In those who are currently exposed

A study was conducted where functional magnetic resonance imaging (fMRI) was used to show the brain activity in a group of cannabis smokers, who had smoked cannabis within the last 36 hours, versus a group nonsmokers when performing a spatial working memory task. The fMRI showed increased activation in areas that are regularly associated with spatial working memory and activation in areas that are not regularly associated with spatial woking memory; therefore, this study seems to suggest that regular cannabis users have to compensate for deficits in working memory by recruiting other brain regions.^[52]

In those who were exposed

One study that was conducted, where a group of adolescents, who had previously used cannabis, but had abstained from using cannabis for 28 days and a group of adolescents who had not used cannabis, seemed to demonstrate that there are different brain responses in those who have been exposed to cannabis and those who have not been exposed to it. To explain, although the two groups had similar results on the spatial working memory task, the group who had used cannabis had greater activation in the basal ganglia and the bilateral parietal regions. The authors speculated that this difference in activation occurred because the cannabis users were still skill learning (associated with the basal ganglia) during the task and were compensating for activity in areas that are regularly associated with spatial working memory, by increasing activation in the bilateral parietal regions.^[54]

In those who were prenatally exposed

Evidence suggests that young adults who experienced prenatal exposure to cannabis exhibit different neural functioning than young adults who did not experience prenatal exposure to cannabis when completing a task that requires visuospatial working memory processing. More specifically, a study was conducted where a group of prenatally exposed and a group of nonexposed young adults, between the ages of 18–22, performed a visuospatial working memory task, while receiving an fMRI that recorded the functional neural activity in the young adults. Although there were no significant differences in the performance on the visuospatial working memory task between the group that was prenatally exposed and the group that was nonexposed, there were significant differences in the neural activation between the two groups: " . . . as the amount of prenatal cannabis exposure increased, there was significantly more neural activity in the left inferior and middle frontal gyri, left parahippocampal gyrus, left middle occipital gyrus and left cerebellum". Therefore, this study seems to show that prenatal exposure to cannabis alters the functional roles of neural structures when performing visuospatial working memory tasks.^[53]

Effects on neural signals

Cannabis has been implicated in the decreases of the amplitude of slow waves in the brain and the theta band activity that are regularly associated with brain activity during working memory tasks. To elaborate, a study was conducted where two groups of five performed a working memory task, while their brain activity was monitored using an EEG, and then one group was given cannabis to smoke and one group was given a placebo; after the smoking, both groups performed the same working memory task. The group that smoked the cannabis showed reduced amplitudes in slow waves, more specifically, the P300, and reduced theta band activity during the working memory task, compared to the group that smoked the placebo.^[43]

Possible prevention

One study has shown that the effects of THC on working memory could be diminished by the enantiomers of HA966, which is a glycine site partial agonist. To explain, a study was conducted on rats, where their performance on spatial working memory tasks was impaired by administration of THC, but it was not impaired when the THC was accompanied by HA966. This study suggests that the behavioural effects of THC on spatial working memory could be diminished moderated by the administration of HA966.^[36]

See also

• Cannabis
• Effects of cannabis
• Long-term effects of cannabis
• Psychoactive drug

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