Neuropsychological effects of THC (notes of a Pharmacologist)


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Expert Pharmacologist
Jul 6, 2021
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The dose-dependence of THC has become mainstream in both the narrow scientific circles of psychopharmacologists and the general consumer community. This variation in effects can be explained by the unimaginable multidirectional functions of the cannabinoid brain system. Many still believe that endocannabinoids act as retrograde neurotransmitters, being released from the postsynapse and acting on the presynapse. This is so insulting to the cannabinoid nature that it couldn't be further away. In fact, cannabinoids act in all directions, even on themselves-autocrinally.


THC is a polyreceptor ligand: a partial agonist of CB1 and CB2, a positive allosteric modulator of the glycine receptor, an antagonist of 5-HT
3, GPR18, and an agonist of several vanilloid receptors (further effects of THC will be explained through CB1 activation, although the effects of the other receptors cannot be denied or ignored!). I will draw your attention to the fact that the effects of cannabis products are strikingly different from synthetic cannabinoids, because the second main phytocannabinoid, cannabidiol, counteracts the activation of many cellular targets, thus softening the final result. However, the "protective" effect of cannabidiol is not infinite and an overdose, though difficult, is still possible, at least on a mental level.


Dose Dependence
Anxiety. THC has a clear biphasic effect on anxiety. At low doses it is anxiolytic due to inhibition of cortical glutamatergic terminals, at high doses it is anxiogenic due to inhibition of GABAergic terminals expressed mostly in the midbrain.

Short-term and working memory. The hippocampus is simply studded with CB1 and the corresponding endocannabinoid degradation enzyme systems, it makes perfect sense that the superplastic region wields anticonvulsant indulgence. Such a neurochemical basis explains why superplasticity disappears somewhere after the next tasty . The actual long-term neuroadaptation to THC leads to impaired working memory, attention, verbal learning, and mental flexibility. Despite these horrors, the effect of THC on memory is also biphasic, though very low doses of THC, almost microdosing, are needed to stimulate neurogenesis and memory. This is because THC can inhibit AChE until significant activation of CB1. Given the pattern of cannabis use, the doses needed to maintain memory are quickly and significantly overcome by absolutely everyone. But further doses disrupt cholinergic transmission in the cortex and limbic area and even have a cognitive picture similar to that of cholinoreceptor antagonists.

Self-stimulation threshold and motor activity. The addictive potential of THC is an extremely hot topic, the data is too conflicting.
Spoiler alert: THC is both addictive and addictive, but it takes longer than other addictive substances.
Animal models show us that even low doses of THC are addictive in CPP (conditioned place preference) and self-injection tests. What helps THC stay in the low-addictive compounds zone? It is the lack of pronounced negative reinforcement on withdrawal, because THC is highly lipophilic and its "molecular tail" hides all the negativity of withdrawal. In general, low doses of THC can raise the threshold of self-stimulation and lead to increased motor activity, while high doses are the opposite. Translating into human language: low doses can lower the hedonic threshold, i.e. make you more "motivated" (I should say right away that we are talking about so-called inner motivation) to do something in conjunction with facilitating the execution of motor programs.

General comment on the biphasic effect of THC:
  • The CB1 receptor has different sensitivity in different neuronal populations, i.e. the receptor is the same, but the neuronal reactivity is different.
  • Different neuronal populations produce different signaling pathways from the CB1 receptor, so the effect of THC at different doses is heterogeneous with respect to cellular response in different neuronal populations (GABA and glutamate).
  • Inhibitory terminals express 20-fold more CB1 receptors compared to activating ones in the hippocampus and cortex.
  • The CB1 receptor on glutamatergic neurons has an "on-demand" physical inhibition function, whereas on GABAergic ones it is tonic. This is the leading feature of CB1, interpreting the low-dose profile from THC - it is glutamatergic synapses that are more significantly affected by THC, and then only GABAergic synapses, despite the difference in receptor density.
Long-term effects of THC on motivation
The motivational effect of cannabis is quite difficult to isolate, because it is quite difficult to find subjects who used only cannabis and nothing else, even beer on Fridays. And this is very important, because alcohol itself influences the motivational sphere quite strongly (see the graph of the motivational index in the self-report of the subjects).


Laboratory measurements of motivation
Motivation itself, as we have already identified, is hard to define in research. Accordingly, THC affects various aspects of motivation. Current research confirms that the so-called "amotivational syndrome" can occur in the chronic user, but in a small fraction. I believe that this small portion suffers from a psychogenic form of depression, because they make up the cohort of people who already have problems in their lives even without cannabis.

Chronic users may have reduced levels of dopamine synthesis in the striatum, which can lead to decreased sensitivity to reinforcing stimuli and amotivation.

The Iowan Game Test revealed that chronic consumers exhibit an increased sensitivity to immediate rewards, which can weaken inhibitory motivational control and increase the future likelihood of risk-taking and reinforcement behavior.


A two-option experimental motivational measure (two-option test by Cherek et al) was created to study motivation. Participants could earn "working" and earn but less "not working. The graphs show that chronic consumers went into "not working" mode faster on days 1 and 2 of the test, and also earned more in "not working mode" compared to controls.


The most interesting thing about the study of motivation in chronic patients is the battery of cognitive tests with one nuance - potheads were stimulated by explaining to them how this experiment is important in legalism and that their score can lead to the fact that the police will never be able to grab their ass :) The result was amazing: after the motivational speech, they scored higher than the control.

Conclusions: chronic THC (cannabis) use does not lead to amotivational syndrome in the long term. The evidence from studies of motivation in chronic users is mixed. Observations of users with decreased motivation are of the nature of co-founding, where the real cause of amotivation is socio-economic conditions and level of education.

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