Stoned Stupid

A 2020 study from Society For The Study of Addiction claims that moderate adolescant cannabis use is linked to cognitive impairment that cannot be attributed to familial factors (1).

Why might this be?

Let’s explore this and also how the outcome of cannabis on cognition may depend on mood.

Dynorphin and THC

A lot of research on this blog has focused on a neuropeptide that is under-represented in pop psychology: dynorphin. This neurotransmitter is a kappa opioid receptor agonist, like the hallucinogenic drug Salvia Divinorum (2). This neuropeptide may help in explaining the impairment to cognition observed with moderate cannabis use.

Cannabis (THC) is observed to stimulate dynorphin A release (3, 4). It appears that the ‘dysphoric’ component of THC is mediated by dynorphin as the removal of dynorphin from animals results in a disappearance of the dysphoric effects (3). This makes sense because dynorphin is thought to encode the dysphoric component of stress (5) and pain (6). Dynorphin is also involved in a whole slew of dysphoric mental health issues, such as PTSD (7), depression (8), anxiety (9, 10), and schizophrenia (11, 12, 13).

Dynorphin blocks glutamate NMDA receptors (like ketamine and PCP) (14) which are important for neuroplasticity (15). Dynorphin has been shown to shut down neuroplasticity in the hippocampus (16), a brain region associated to learning and memory. Dynorphin mediates impaired learning and memory that emerges from stress (17), alcohol consumption (18), aging and possibly Alzheimer’s disease (19, 20, 21). Dynorphin is implicated in schizophrenia, a disorder in which patients show impaired cognition and lower IQ (22). Dynorphin has also been found to be increased in individuals with Down syndrome (23).

THC has been found to impair plasticity in the hippocampus even after a single dose (24, 25), but a newer study found enhanced plasticity and neurogenesis and argued that THC cannot be categorized as enhancing or inhibiting plasticity and neurogenesis (26). Chronic use of cannabis is associated to decreased hippocampal volume (27). THC also appears to downregulate NMDA receptors through CB1 receptor activation (28), which suggests that the cognitive impairment is multi-faceted and not entirely dynorphin dependent. Taken together, this research suggests cannabis may impair cognition through increasing dynorphin and CB1 receptor activity to suppress NMDA receptors and thus neuroplasticity.

CBD

CBD is another component of cannabis that is studied often. It seems to have many opposite effects compared with THC (29). It may even prevent the loss of hippocampal grey matter observed with THC use (27).

Something interesting is that CBD has more than one mechanism that may decrease dynorphin activity. One of CBD’s mechanism is serotonin 5HT1a receptor agonism (30), which has been shown to decrease dynorphin activity that normally occurs in response to a dopaminergic (31). Another one of CBD’s mechanisms is agonism of the serotonin 5HT2a receptor (30), a binding target that has been popularly associated to the effects of psilocybin, LSD and other psychedelic drugs. LSD was found to diminish kappa opioid receptor mediated depressant effects (32). 5HT2a receptors have also been shown to enhance acetylcholine release in the hippocampus and prefrontal cortex (33) which is significant because one of acetylcholine’s targets, nAch alpha7, suppresses dynorphin release (34). 5HT2a receptor activity seems to enhance learning and memory (35, 36, 37, 38, 39) (although 38 is dose-dependent with psilocybin), while low density of 5HT2a receptors was linked to cognitive impairment (40). Both 5HT1a and 5HT2a have been linked to suppressing aversion (76, 77, 78, 30), which fits well since dynorphin is implicated in stress and pain aversion and these mechanisms seem to suppress dynorphin.

CBD has also been proposed to treat schizophrenia (41), anxiety (42), and depression(43), and also increase hedonic tone (44) which may work partly by decreasing dynorphin activity. Schizophrenia been observed to have reduced binding at 5HT2a receptors (45). It seems that applying CBD with THC reduces the psychotic effects of THC (29). I’ve proposed that 5HT2a receptor agonists may be able to treat schizophrenia in Dynorphin Theory.

Mood-Dependent Cognitive Ability?

Might the impact of cannabis on cognition be mood dependent? It is possible. There are cannabis users who claim to have increased cognitive ability and creativity under the influence of cannabis. Some research suggests that, contrary to patients with schizophrenia, bipolar individuals may experience enhanced cognitive function from cannabis use (46, 47).

Both schizophrenia and bipolar disorder have overlapping symptoms and connections, often viewed as closely related disorders. Despite this, there are actually lines of evidence suggesting there are opposite trends of associations between schizophrenia and bipolar disorder. For example, while schizophrenia is linked to decreased IQ (22), bipolar disorder has associated to high IQ and intelligence in multiple studies (48, 49, 50, 51, 52, 53), a contrary pattern that even showed up in a genome-wide association study (53). Schizophrenia was associated with decreased creativity (measured as divergent thinking), while bipolar mania and schizotypy were associated to increased creativity (54). A personality trait known as openness to experience was observed to be low in schizophrenia (55) but high in those with bipolar disorder (56). While schizophrenia appears to involve heightened dynorphin, individuals with bipolar disorder had almost 50% lower levels of dynorphin compared to normal (57) and dynorphin mimetic drugs are proposed to treat bipolar mania without their usual psychotic side effects (58). While CBD seems to help with schizophrenia, it does not seem to help with bipolar mania (59) and has even been associated to induction of mania in a case study (60).

If you are following along, you may have noticed that, yes, I am claiming that psychosis is more like salvia, while mania may be closer to psychedelia.

A clear distinction is that schizophrenia is generally associated to negative or neutral affect and reduced sensitivity to reward (even reduced mu opioid receptors), but intact aversion (61, 62, 63), while bipolar is associated to swings to states of very high positive affect, known as manic episodes. Historically, mania has been associated to creativity and genius in the popular culture. Perhaps the differing reaction to cannabis between these two conditions is due to the variable of mood.

Whether cannabis induces increased creativity, enhanced cognition, or the opposite may depend on mood. There is evidence from a meta-analysis that positive mood is linked to enhanced creativity compared to neutral or negative mood (64). On the other hand, aversive states have been linked to decreased cognitive abilities. A 14 IQ drop has been observed in conditions of stress and scarcity (65). PTSD has also associated with low intelligence (66, 67, 68) and traumatic experiences have been observed to suppress IQ performance (69), which makes sense because stress impairs plasticity (70, 71) and involves dynorphin activity.

These patterns in the research suggest that negative affect may reduce cognitive ability and positive affect may increase cognitive ability in some cases. Since THC can produce good or bad trips and influences both the reward opioid system (72) and the dysphoric opioid system (dynorphin), it may be that the outcome of cannabis on cognition is covariant with mood and potentially THC to CBD ratios. We might even discover that the induced or reduced neurogenesis and plasticity by THC is dependent on mood. Something to consider is that repeated use of cannabis is associated to depressive effects (75). Lastly, consider that the U.S. government funds research that shows Cannabis is harmful.

Important Clarification

A clarification is needed for study 57, which notes decreased dynorphin in structures of the amygdalas of both depressed and bipolar suicide victims. Dynorphin is thought to play a role in depression, but those with bipolar disorder, and especially those who are dysphoric-manic episodes commit suicides at higher rates than those with depression (73, 74). So it seems that when one has decreased dynorphin, they may become disinhibited and more willing to take the leap into suicide. Presumably dysphoric mania is a sweet spot of suffering and motivation that allows suicide.

. . .

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