Part 2: Cannabis & The ECS
Cannabis Overview
Cannabis exerts its psychoactive/physiological effects through interacting with the endocannabinoid system (ECS) in the human body. To date, more than 500 chemical compounds have been identified in the cannabis plants (cannabis plant = cannabis sativa, cannabis indica, cannabis ruderalis, and hybrid strains). Of which more than 120 are classified as phytocannabinoids, including Delta-9-Tetrahydrocannabinol (THC), Cannabidiol (CBD), Cannabinol (CBN), Cannabigerol (CBG), Tetrahydrocannabivarin (THCV), Cannabichromene (CBC), and etc. [1, 2].
THC and CBD are the two most abundant and well-studied phytocannabinoids in the cannabis plants. Thus, this post will primarily focus on the effects of THC, the main psychoactive compound in cannabis, on the ECS.
(P.s. Phytocannabinoids are also referred to as cannabinoids in cannabis research.)
The Pharmacokinetics of Cannabis [3]
(Pharmacokinetics: the processes of absorption, distribution, metabolism, and excretion of any compound entering into the human body.)
Smoked Cannabis
Onset of Effects: seconds to minutes
Peak Effect: 15 minutes to 30 minutes
When heated, the cannabis plant releases chemical compounds — phytocannabinoids (THC, CBD, CBG, etc.), terpenes, and flavonoids — into the human respiratory system. When phytocannabinoids reaches the lungs, they are then absorbed by the alveoli in the lungs to enter into the bloodstream/systematic circulation [3].
After entering into the circulatory system, the phytocannabinoids are then rapidly distributed throughout the brain and body (ranging from seconds to minutes), where they bind to the endocannabinoid receptors (eCBs) to exert their psychoactive and physiological effects.
From the bloodstream, THC enters into the liver and undergoes first-pass metabolism.
Ingested Cannabis
Onset of Effects: 30 minutes to 2 hours
Peak Effect: 1.5 hours to 3 hours
When ingested, the phytocannabinoids enter into the bloodstream through the gastrointestinal (GI) tract (GI Tract = mouth → esophagus → stomach → small intestine → large intestine → anus), mainly through the intestinal lining in the small intestine, but can also be through the stomach lining to some extent.
In the case of ingestion, THC enters the liver through portal circulation. Since ingested cannabis needs to go through the digestive system, the onset of effects tends to be slower compared to inhaled cannabis where phytocannabinoids are directly absorbed into systematic circulation through the alveoli in the lungs.
(Systematic Circulation: the general circulation of blood throughout the body.)
v.s.
(Portal Circulation: specialized circulation of blood that involves passing through a second organ before returning to the heart. In this case, the second organ is the liver, and this portal circulation is called the hepatic portal system.)
(Hepatic Portal System: a specific portal circulation where the portal vein carries blood containing drugs/nutrients/other substances absorbed from the GI tract to the liver. In the liver, the blood goes through metabolic processes such as detoxification and nutrient processing/storage before returning to the heart through the hepatic portal veins. The blood then joins the systematic circulation from the heart. In addition to the GI tract, the hepatic portal vein also carries blood from the spleen and pancreas to the liver.)
(P.s. Since the phytocannabinoids in cannabis require heat to go through decarboxylation, a process of removing a carboxyl group (COOH) from the phytocannabinoids in order to convert them from their inactive/acidic forms (THCA, CBDA, etc.) to psychoactive forms (THC, CBD, etc.), consuming raw cannabis without heating methods has limited psychoactive effects. However, limited decarboxylation can occur during digestion due to the heat and acidic conditions in the stomach.)
First-pass Metabolism (Liver) & Excretion
When THC reaches the liver through either hepatic circulation (ingested cannabis) or systematic circulation (smoked cannabis), it is intensely metabolized by the cytochrome P450 enzymes (aka the CYP450 system) in the liver before going or going back into systematic circulation.
Step 1: Hydroxylation
First, THC is hydroxylated by CYP2C9 and CYP2C19 in the liver [3, 4] into 11-OH-THC (11-hydroxy-delta-9-tetrahydrocannabinol), which is also psychoactive. In fact, a mice study found that 11-OH-THC exerts stronger psychoactive effects than THC, potentially due to its higher binding affinity to CB1R [5].
(First-pass Effect/Metabolism: a reduction in the concentration of a drug at a specific physiological site (e.g. liver) before the drug reaches its site of action or systematic circulation.)
Step 2: Oxidation
Subsequently, 11-OH-THC is oxidized by CYP3A4/5 [4] into THC-COOH (11-nor-9-carboxy-delta-9-tetrahydrocannabinol), which is non-psychoactive [3].
As a result of extensive first-pass metabolism in the liver, the bioavailability of smoked THC is 10% to 35%, and that of ingested THC is only 4% to 12% of the total consumed cannabis. When smoked, THC concentration is also higher in the brain than in the blood, potentially inducing a stronger psychoactive effect [3].
On the other hand, compared to smoking, eating cannabis produces more 11-OH-THC, the potentially stronger psychoactive agent than THC, as ingested THC is transported directly to the liver through hepatic circulation, and thus, more THC is metabolized to 11-OH-THC. As opposed to smoked cannabis, where a portion of THC would have already been absorbed as it travels through systematic circulation before reaching the liver.
In summary, smoked cannabis leads to higher levels of THC bioavailability and concentration in the brain. Ingested cannabis leads to a lower level of THC bioavailability but a higher level of 11-OH-THC while causing no damage to the lungs.
(Bioavailability: the extent a substance or drug becomes available to its intended biological destination(s).)
Circulation & Storage
After first-pass metabolism in the liver, the remaining THC and its metabolites — the psychoactive 11-OH-THC and non-psychoactive THC-COOH — enter into systematic circulation and are distributed throughout the body, including the heart and brain, where they bind to CBRs to exert their effects.
After its binding activities, THC can detach from the CB1Rs and redistribute into the bloodstream. Since THC is highly lipophilic (having an affinity for fat molecules), it is taken up and stored by adipose (fat) tissues, and then slowly released back into the bloodstream, contributing to THC’s long elimination half-life and long detection period in drug tests.
Excretion
Both 11-OH-THC and THC-COOH can undergo further metabolism in the liver — glucuronidation, a process of adding a glucuronic acid to the molecule. Glucuronidation can happen both during first-pass metabolism and after THC has traveled through systematic circulation and reached back to the liver.
11-OH-THC glucuronide is the primary glucuronide conjugate in human feces while THC-COOH glucuronide is the primary glucuronide conjugate in human urine. The majority of cannabis is excreted in poop (>65%), and 80% to 90% of cannabis is excreted within 5 days [3].
To summarize:
THC → (hydroxylation) → 11-OH-THC → (oxidation) → THC-COOH
Both 11-OH-THC and THC-COOH can undergo glucuronidation:
11-OH-THC + glucuronic acid → the most abundant glucuronide conjugate in feces
THC-COOH + glucuronic acid → the most abundant glucuronide conjugate in urine
Binding Affinity & Activities
Binding Affinity
THC
On a systematic level, THC is found to be a partial agonist of both CB1R and CB2R [6]. It is also found to be a full agonist of hippocampal GABAergic CB1Rs [7]. Thus, THC is capable of producing the maximum effect of CB1R. THC is generally considered a stronger CB1R agonist or shows higher binding affinity than the endocannabinoids (eCBs) [8].
CBD
CBD has been shown to be a partial agonist of both CB1R and CB2R [9], as well as an antagonist of CB1R and CB2R [6]. Thus, CBD is capable of deactivating the CBRs. Indeed, CBD is also shown to be a non-competitive negative allosteric modulator of CB1R, and thus, potentially reducing the efficacy of THC (and AEA/2-AG) when administered together [8].
Both THC and CBD can also interact with other components of the ECS. Specifically, CBD is found to inhibit FAAH, the degrading enzyme of AEA, and interact with other non-traditional cannabinoid receptors such as TRPV1 and serotonin 1A receptor (5-HT1A) [8].
Binding Activity
The effect of smoking or ingesting cannabis is synonymous with the systematic administration of exogenous cannabinoid agonists. While there is no experimental evidence suggesting synergic/coordinated physiological activation of the ECS by phytocannabinoids such as THC, this can be inferred by one’s ability to maintain relatively normal operation under cannabis intoxication.
In other words, engaging in a specific cognitive process will still activate its designated brain areas, and the more activated a brain region, the more blood flow gets directed to that specific brain region. Since THC and its metabolites travel through systematic circulation, the more one engages in a specific cognitive process (e.g. contemplation), the more THC and metabolites-infused blood flow gets directed into its related brain region, and the more cannabis affects the specific cognitive process. On a neurological level, this should translate into stronger activation of neuronal activities in the direction (excitation or inhibition) of the individual’s thought processes.
Specifically, if an individual engages and succeeds in processes such as emotional reappraisal or fear extinction, where the behavioral outcome depends on the reconstruction of dendritic structures through mechanisms such as LTP/LTD, this effect may be enhanced under cannabis intoxication as THC is a stronger CB1R agonist than the eCBs, and thereby eliciting more pronounced changes in synaptic transmission than the eCBs.
On a whole brain level, cannabis induces an overall meditative state, as evident with increased alpha rhythm — a state associated with meditation and creativity — in cortical regions during resting state in heavy cannabis users [10]. There is also evidence for decreased delta, unchanged alpha, and increased theta, beta, and gamma rhythms in cannabis users compared to nonusers, suggesting increased cortical activation (more neural activities) during resting state [11]. This again shows strong individual differences in how the brain state changes after persistent cannabis use, and these differences are likely due to the unique thought processes of each individual. Cannabis users also showed increased intra-hemispheric (within the hemisphere) and inter-hemispheric (between the two hemispheres) brain coherence/synchronization/connectivity [11].
(Resting State: when one is not engaging in any cognitive or physical activity.)
Brain Waves of Cortical Activation:
Delta (0.5 - 4 Hz): slow-wave sleep; unconsciousness
Theta (4 - 8 Hz): light sleep; inward focus and attention; deep relaxation or meditation (before falling asleep); intuition; creativity
Alpha (8 - 12 Hz): alert but relaxed; passive outward attention (absorbing information); awake meditation; intuition; creativity; calmness and mindfulness; daydreaming
Beta (13 - 30 Hz): active thinking, concentration, and alertness; relaxed external focus (e.g. reading); associated with stress and anxiety
Gamma (31 - 50 Hz): intense concentration such as processing of complex information, learning, and problem-solving; associated with moments of insight or peak mental performance
This cannabis-induced “forced” meditative state is likely reached through cannabis inducing an overall decrease in neuronal excitability (through selective/non-selective binding to glutamatergic CB1Rs) alongside an overall decrease in neuronal inhibition (through selective/non-selective binding to GABAergic CB1Rs). Since CB1R is primarily located on GABAergic axon terminals in most brain regions, the final cannabis state should be characterized as increased neural activities in a depressed/decreased neuronal excitability state (i.e. increased thought processes in a meditative state).
Therefore, cannabis should exhibit mainly selective binding (depending on the individual’s specific — habitual or cannabis intoxication-induced — cognitive processes), alongside a relatively significant degree of non-selective binding.
The Spiritual Effects of Cannabis
The spiritual effects of cannabis have been well-documented throughout history [12]. Although there has been some formal investigations on the spiritual benefits of cannabis [13, 12], there lacks a formal description of these spiritual effects from a physiological standpoint. Therefore, this is the first attempt to parse out the spiritual effects of cannabis using neurological explanations.
Reevaluation
While CB1R is present everywhere in the body, it is most abundantly expressed in Brodmann area 46 (BA46) in the dlPFC, especially layer 4, which primarily receives sensory inputs from the thalamus. In layer 4 of BA46, CB1R is primarily located on inhibitory PV+ interneurons.
(Thalamus: the brain’s sensory input relay station. It receives almost all sensory inputs — visual, auditory, somatosensory, and gustatory (taste) — but not olfactory (smell) information, as it bypasses the thalamus and is directly relayed to the olfactory cortex.)
Thus, BA46 becomes more excited under cannabis intoxication. BA46 or the dlPFC in general is known to be the executive regulator of working memory (WM) processes — they monitor external sensory inputs and decide which sets of neural signals to enhance, depending on the individual’s internal objective/goal.
From the highest perspective, the most relevant WM contents should be the ones that point to the nature of reality, or to the spiritual/internal growth of self, such as one’s behavioral patterns. Indeed, BA46 is known to be particularly activated when one is faced with personal moral dilemmas [14] — an indispensable factor in spiritual learning and personal growth.
Examples of personal moral dilemmas:
Whether to extend a hand to someone who is capable of helping themselves but is expecting to receive help.
Whether to embody and express anger or to keep one’s internal peace when being disrespected.
Whether to play nice or to express oneself authentically but risk hurting other people’s feelings.
In addition to CB1R activation in the dlPFC, which is associated with solving moral dilemmas, noticing the most relevant external sensory events, and making decisions that require the consideration of multiple sources of information (which underlies the introspective process that leads to personal growth or deeper understanding of the world), CB1R activation in the hippocampus (HPC) also plays a role in the reevaluation effect of cannabis as it mediates the forming of incidental associations. In other words, CB1R activation in the HPC is required for connecting the dots between seemingly unrelated events (or understanding signs and synchronicities if put in spiritual terms) for better decision-making in the future.
(Mediate: directly regulates)
v.s.
(Modulate: indirectly regulates)
Therefore, when under cannabis intoxication, one becomes more inclined to question their understanding of the world, and subsequently, the significance of their current life obligations.
Intuition
Aside from being able to decipher signs better when under cannabis intoxication (due to a more excited dlPFC and HPC), CB1R is also particularly rich in areas that receive and process somatosensory and visceral sensory information. Namely, the dorsal horn of the spinal cord and the solitary nucleus (NST) of the medulla oblongata, respectively.
Thus, when under the influence of cannabis, or as these regions become more excited with THC-mediated CB1R activation, one becomes more aware of their internal sensations, which is a key component to intuition. This includes becoming more aware of one’s gut instinct (the vagus nerve, which relays to the NST) and sensations from the heart, skin, and virtually any area within the body. Provided that one chooses to tune into, and thereby amplify its sensations by enhancing its neural representations.
To tune into a specific sensation: close your eyes and focus your internal attention on the specific sensation you wish to amplify.
Additionally, CB1R activation within the basolateral amygdala (BLA) resulted in the detection of normally sub-threshold BLA-activating (emotionally salient) positive and negative sensory stimuli by enhancing the neural representations of such stimuli in the medial prefrontal cortex (mPFC). In other words, THC-induced CB1R activation in the BLA makes one more sensitive to external sensory information by making one more aware (mPFC) of them.
Intuition requires the combination of sensing one’s bodily sensations — both from vital internal organs such as the heart and gut, and from organs that interact with the external world such as the skin, eyes, and ears — and accurately understanding the meaning they entail (incidental associations and associative learning in general). The vagus nerve, which is especially involved in relaying sensory information from the gut to the brain (NST), also processes viscerosensory information alongside visual, auditory, and olfactory patterns [15].
Thus, cannabis intoxication enables an individual to access their innate intuitive system, by providing an agent (THC) that enhances the neural representations of vital internal sensations (through CB1R activation). Once these internal sensations are recognized, one can then learn to better decode their messages, and thereby enhance their intuition.
Indeed, increased functional connectivity within the empathy neural network is observed in cannabis users compared to nonusers [16].
Emotional Healing
The dlPFC is critically involved in the emotional reappraisal of personal traumatic memories such as one’s own wrongdoings, and such reappraisal is essential for spiritual advancement: when one learns compassion for self, one also learns compassion for others. In general, emotional reappraisal involves redefining negative events into positive teachings while lessening their negative emotional impact, which lies in the core of spiritual learning and personal growth.
Additionally, BLA CB1R activation allows one to be more aware of their emotional triggers, as it elicited behavioral responses to normally sub-threshold emotional stimuli (for both aversive [17] and rewarding [18] stimuli) — although subliminal, the event still exists and is still emotionally arousing, as evident with BLA activation.
Thus, BLA CB1R activation by exogenous agents such as THC potentially points to a path into one’s subconscious mind/wounds, if one so chooses to introspect and reflect on the emotionally arousing incident.
Emotional healing occurs when one no longer reacts the same way to the same emotionally salient stimulus, or when the same event no longer triggers an emotional reaction/BLA activation.
Self-actualization
Cannabis aids in self-actualization by enhancing imagination, or the episodic simulation of the future. This is achieved by CB1R activation in the HPC, which leads to an increased number of activated hippocampal pyramidal neurons (storage units for episodic contents). This increases the access to, and thereby combinatorial possibilities of, activated episodic contents, leading to enhanced imagination.
Along with the simulation of more potential future possibilities for oneself/life, THC can also induce stronger emotions/feelings for these future possibilities as it excites the dlPFC, a region known for the top-down generation of affective (emotional) states.
Furthermore, since exogenous CB1R agonists such as THC can increase the valence (emotional value) of normally sub-threshold reward through stimulating the ventral HPC (vHPC), and thereby increasing dopamine (DA) release in the nucleus accumbens (NAc) shell (enhanced motivation and reward) [18], combined with the ECS’s ability to activate the motivated motor system (the nigrostriatal pathway), cannabis can evoke one to take action on previously unaware desires.
In summary, cannabis can expand one’s vision for oneself, generate stronger emotional states in response to those future scenarios (a key component to visualization and manifestation), and finally, push one to take action and break out of old patterns to explore life.
The Therapeutic Potential of Cannabis
Central nervous system (CNS) diseases and psychiatric disorders can be seen as a physical manifestation of internal or spiritual illnesses. CNS diseases share common neural dysfunctions such as neuroinflammation, oxidative stress, and neurodegeneration, which can be exacerbated by, or alleviated with, daily habits, lifestyle factors, and mindsets (e.g. one’s perception of stress affects one’s physiological reaction to stressful event). Meanwhile, psychiatric illnesses stem from maladaptive mental/thought processes, which can cause maladaptive brain structural changes over time.
Cannabis as an exogenous agent that can directly interact with the ECS and induce spiritual healing effects, has the potential to heal one’s body through healing one’s mind first. Thereby improving one’s actions in life. Additionally, most, if not all CNS diseases and psychiatric illnesses show ECS irregularities, and cannabis is known for relieving negative symptoms associated with CNS diseases such as neuropathic pain, nausea, and epilepsy. Thus, providing further evidence for the therapeutic potential of cannabis.
Side Effects & Risks of Cannabis Use
Although cannabis exhibits spiritual and physiological therapeutic benefits, its side effects and risks can also be detrimental to one’s quality of life. Thus, cannabis should be used with caution, and one should be well-educated before initiating cannabis use.
Side Effects
CB1R Downregulation
CB1R Downregulation is one robust side effect of persistent cannabis use: long-term and heavy (near daily) cannabis users show a consistent 10% to 20% decrease in CB1R densities across brain regions [19, 20, 21, 22].
In short, all CB1R-mediated functions will be disrupted when CB1R is downregulated:
(dl)PFC
CB1R is primarily located on PV+ GABAergic inhibitory interneurons in the dlPFC → CB1R downregulation in the dlPFC leads to increased PV (fast-spiking and high-frequency inhibitory) and increased GABA (inhibitory) transmission.
Diminished executive control for WM processes:
Less efficient in determining the relevance of working memory contents, and thus, in shifting attention towards the most relevant WM content (attentional control).
Less effective in distraction elimination (due to diminished ability to increase focus on the most relevant WM content).
Reduced attentional awareness (right dlPFC).
Diminished emotional regulation: (inhibitory) cathodal stimulation over the right dlPFC decreased emotional reappraisal.
Diminished cognitive control abilities such as processing and integrating multiple sources of information, task- and task-set-switching, and inhibitory control.
Disrupted time-processing: cathodal dlPFC stimulation resulted in judging time being shorter than it actually is — more time will have passed than what you have subjectively experienced.
Overall, CB1R downregulation in the PFC, including the dlPFC, will result in a subjective feeling of slowness in processes requiring executive functions (see more functions of the dlPFC in Part 1: The Endocannabinoid System).
HPC
CB1R is primarily located on CCK+ GABAergic interneurons in the HPC → CB1R downregulation in the HPC leads to increased GABA (inhibitory) and increased CCK (asynchronous inhibitory) transmission.
Hippocampal CB1R is required for the consolidation of episodic memory into long-term memory (through inducing LTP/LTD at relevant synapses) [23, 24].
Hippocampal CB1R modulates neurogenesis during adolescence [25].
Thus, the memory impairment side effect of persistent cannabis use lies in one’s diminished ability to consolidate memory contents into long-term memory.
BLA
CB1R is primarily located on CCK+ GABAergic interneurons in the BLA → CB1R Downregulation in the BLA leads to increased GABA (inhibitory) and increased CCK (anxiety-inducing) transmission.
Increased Anxiety (as observed in CB1R-KO monkeys [26]):
Disrupted night sleep
Agitated psychomotor behaviors (thoughts and physical movements) in new environments
Decreased social desires
Increased plasma cortisol (stress hormone) levels
Diminished Emotional Regulation (as observed in CB1R-KO mice [27]):
Increased depressive and aggressive behaviors when chronically exposed to unpredictable mild stressors, which is a condition that is similar to the human living experience.
DA Systems
CB1R is primarily located on GABAergic interneurons innervating midbrain DAergic neurons → CB1R downregulation leads to increased inhibitory transmission and decreased DA release.
CB1R availability is shown to return to baseline level after 2 - 30 days of abstinence [19, 20]. The degree of CB1R downregulation is not correlated with the amount of current cannabis use [20], but rather with the duration or years of cannabis use [21]. This is likely due to the ECS making adjustments according to persistent lifestyle factors and habits.
Lower AEA
As the ECS acts as the spiritual system of the human body, and AEA as the neurotransmitter that specifically governs the changes in synaptic transmission due to spiritual enlightenment (and thus, the induction of internal bliss), AEA levels should decrease as one engages in activities that diminishes one’s spiritual/personal growth, such as addictive behaviors.
Indeed, AEA levels are found to be lower in heavy/frequent cannabis users compared to infrequent cannabis users [30], while acute (single-time) cannabis use is not found to affect baseline eCB levels including AEA [31]. Thus, AEA decrease is likely due to the compulsive use of cannabis rather than cannabis itself. Additionally, higher AEA level is associated with fewer psychotic-like symptoms in cannabis users [30].
In addition, 2-AG levels are found to be higher in frequent compared to infrequent cannabis users [30], suggesting an increased proportion of ECS-signaling is mediated by 2-AG instead of AEA in frequent cannabis users.
Lower FAAH
In theory, lower FAAH should increase AEA. However, lower FAAH observed in cannabis users is likely due to a decreased level of AEA, and thus, a decreased need for its metabolism enzyme FAAH.
In general, FAAH level is 14% - 20% lower in cannabis users compared to nonusers across brain regions, and lower FAAH is associated with higher cannabinoid concentration in blood and urine, with more cannabis use in the past year, and with higher levels of impulsiveness (personality trait) [32, 33].
Risks
While the side effects of persistent cannabis use are relatively constant and predictable, the risks of cannabis use are dependent on the individual and are not guaranteed. Therefore, the next section provides the recommended way of cannabis usage to minimize the risks of cannabis use.
Cannabis Use Disorder (Cannabis Addiction)
[ A Neurological Perspective ]
Cannabis-induced Euphoria
Cannabis can induce the feeling of euphoria by exciting the vHPC, which sends excitatory projections to the NAc shell, and DA release in the NAc shell is strongly linked to the feeling of euphoria and motivation [34].
Since the vHPC mainly stores emotional contextual memories, excitation of PNs in this hippocampal region should lead to the subjective feeling of remembering past emotional memories and/or using that past emotional memory contents to generate future possibilities. And when that triggers DA release in the NAc shell, it should signal that the activated past memory, or future simulation using these activated memory contents, or both, have brought the individual a surge of motivation or a sense of reward/euphoria. And this is aligned with my personal experience.
(Emotional Contextual Memories: memories with contextual details that are also emotionally significant. For example, the contextual details (place, location, weather, and etc) on one’s graduation day.)
More generally speaking, the ECS plays a superordinate regulatory role over the DA system. CB1R is highly expressed on GABAergic interneurons that innervate midbrain DAergic neurons, and thus, CB1R activation by THC can reduce inhibitory GABA transmission onto these DAergic neurons, excite DAergic neurons, increase DA release, and induce a sense of euphoria.
Cannabis Addiction
Addiction of any kind can be attributed to a dopamine reward system imbalance/dysregulation. According to contemporary neuroscience, the dopamine reward system works like a seesaw scale (as with everything else) — a tip towards one end (pleasure) will result in a tip in equal and opposite amount to the other end (emotional/motivational pain). The optimal state for the brain, for the dopamine system, and for everything else in life, is to stay balanced/in homeostasis.
Addiction occurs when one repeatedly satisfies their cravings for a certain drug, leading to a dysregulation of the brain's reward system. Initially, drug use shifts the pleasure/pain balance towards pleasure, but over time, it will lead to a diminished ability to experience pleasure and an increased sensitivity to emotional and motivational pain [35].
Thus, to minimize the risk of cannabis addiction, one should avoid cannabis use when it is driven by cravings/the pursuit of pleasure. If one has already reached the point of using cannabis to avoid emotional/motivational pain, one should cease use immediately to restore homeostasis of the motivation and reward system, and find joy in other activities — expand the options for experiencing motivation and reward.
[ A Spiritual Perspective ]
From a spiritual perspective, addiction boils down to a lack of self-control/discipline, which can be seen as a fatherly wound as one is disconnected from the divine/empowered masculine energy.
Addiction of any kind significantly damages one’s self-confidence and personal power, as one continuously observes oneself not being able to control their actions according to their own will. Similarly, addiction — specifically the satisfying of cravings — lowers one’s self-worth as one knowingly and repeatedly engages in decisions and actions that harm one’s physical body and spiritual self.
In reality, everybody has their own set of pleasurable activities, and it is only when the balance between hard work/effort/creation and pleasure/consumption is disrupted that one might develop an addiction. Thus, to overcome an addiction, one must willingly choose to engage in effort and hard work and find joy in creative activities instead of instant gratifications.
Lastly, an addiction is meant to be overcome — if you have developed an addiction, it means that it is now your task to overcome such an addiction to gain back your personal power, and of course, to obtain your own set of spiritual growth.
(A helpful tip: an addiction is less about the drug itself, but more so about your action. It is about your ability to control yourself and thereby your life (personal power). Try to tap into the energy of GOD (imagine Zeus minus the f-ing around part LOL) and channel his personal power when overcoming addiction (his because self-control/discipline is a divine masculine trait.)
(!! You got this !! It is your job, and you wouldn’t be assigned this job if it is not meant for you to do it.)
Cannabis-induced Psychosis
Cannabis-induced psychosis occurs with the combination of one or more of these mechanisms:
The extensive forming of incidental associations due to the over-excitation of hippocampal CB1R. This should translate into the subjective experience of focusing too much on signs/synchronicities that one feels overwhelmed to move forward.
When one goes into a freeze response due to excessive incidental associations, one fails to engage in reality-testing — taking actions on the incidental association they induce or the signs/synchronicities they receive. As a result, one might find it difficult to distinguish between imagination and reality. Keep in mind that any wild imagination can become the reality if one chooses to bring it to life, as seen with inventions and innovations.
CB1R downregulation in the dlPFC can lead to diminished ability to integrate and process multiple sources of information, and thereby impair decision-making.
CB1R downregulation in the BLA and dlPFC can lead to diminished ability for emotional regulation, and thus, more intense adverse emotional responses (e.g. stress, anxiety, agitation, and etc.) to life stressors, further contributing to the emotional aspect of psychotic symptoms.
Cannabis users show increased hyper-priming, where the presentation of one sensory input/stimulus leads to faster and broader activation of the neural representations of its related contents (memory or cognitive concepts). This could potentially contribute to the sensory hallucinations (visions, sounds, smells, tastes, touch, and etc.) associated with cannabis-induced psychosis [36].
On the other hand, psychosis and spiritual awakening are often two sides of the same coin, as reality by nature is trippy af. Also, psychosis reflects more of a state (psychotic episodes) rather than a trait, and one should learn to self-regulate oneself out of this state when it happens.
Ways to Self-regulate:
Engage in Reality-testing: consolidate your intention/anchor into one decision, and stick with it until the end.
Stay Grounded: remind yourself that it is just a state, and shift your attention and focus back to your immediate next step/task.
Recommended Way of Usage
These recommendations are also applicable to medical cannabis use:
Use strictly with the intention of spiritual awakening/growth or physical healing (be mindful of your motive behind cannabis use).
Avoid using cannabis from a place of chasing reward, as that would trigger the dopamine reward circuitry, and thus, neurologically consolidate cannabis cravings and increase the risk of cannabis addiction.
Avoid using cannabis as a coping mechanism for escaping personal problems or unpleasant emotions, as that would only delay their resolution and escalate negative consequences.
Avoid consecutive use to prevent CB1R downregulation.
Avoid using cannabis more than two days in a row (on consecutive days).
Avoid excessive consumption of cannabis in a single session to prevent CB1R desensitization (overstimulation of CB1R leads to the production of pregnenolone, a negative allosteric modulator of CB1R [37]).
(Negative Allosteric Modulator (NAM): a molecule that changes the shape of the receptor to decrease its binding affinity and/or efficacy.)
Cease use immediately as soon as psychotic symptoms appear. One should engage in reality-testing by taking action on their desired future simulations immediately post-cessation to minimize emotional upheaval.
Cannabis use as a round trip (i.e. a treatment phase with an end date) or strictly as a spiritual ritual.
[ Treatment Phase ]
Cannabis use for spiritual awakening/physical healing should cease once:
One has awakened to the spiritual nature of reality and/or has connected with their own internal intuitive system. Once one of these two condition is established, one should aim to gain spiritual insight/growth through natural and sustainable practices such as regular/daily physical exercise, meditation, breathe work, and/or introspection.
OR
One has solidified their vision for the future or when the immediate next step becomes clear. Any use beyond this point would be a hindrance to self-actualization, as cannabis use is a significant expenditure of one's time, energy, and material resources.
Whichever comes first.
[ Spiritual Ritual ]
Set aside a specific time when there is no other commitment involved — as cannabis intoxication will occupy one’s mind, body, and spirit/energy, making one less efficient in engaging with other tasks.
Set a strong intention for the specific spiritual conflict you wish to resolve before smoking/ingesting cannabis and focus primarily on that during the session.
Avoid using cannabis during adolescence.
CB1R expression is highest during adolescence [38], and the ECS is a very sensitive system to exogenous agents [39] as it is critically involved in regulating most, if not all, physiological and neurological processes.
CB1R deactivation is shown to decrease neurogenesis in adolescence [25]. Thus, persistent cannabis use during adolescence, which leads to continuous CB1R downregulation, may reduce neurogenesis and harm brain structures and cognitive functions, although this difference is shown to disappear as mice age (i.e. levels of neurogenesis in CB1R-KO mice slowly catch up to mice with normal CB1R expression) [25]. This suggests that CB1R is not the only regulator of neurogenesis. However, if an adolescent consistently lives with a downregulated brain (CB1R, neurogenesis, etc.), it will damage their daily performance, self-image, and overall quality of life.
On the other hand, cannabis is shown to benefit older adults by strengthening the functional connectivity of their brains during resting state [40]. This is likely because older adults tend to have a lower ECS tone due to normal brain aging. Thus, cannabis can boost their ECS tone and improve their cognitive functions. As opposed to teenagers, adolescents, and young adults, whose brain conditions including the ECS tone are at their prime.
When deciding the optimal usage for self, one should keep in mind that cannabis is a herb that has analgesic (pain-relieving without blocking consciousness) properties — it is thus clinically characterized as a depressant/downer. Persistent use over time will result in depressive symptoms such as decreased energy/vitality level and decreased mood, reducing the overall quality of life.
Also, according to the practice of Traditional Chinese Medicine (TCM), any medicinal herb is considered neutral with its own physiological properties (therapeutic benefits and side effects), and it should then be utilized accordingly. However, no medicinal herb should be administered with the intention of lifelong use. It is always utilized within its prescribed treatment period for a specific condition, and cannabis should be approached in the same manner.
Ways to Improve The ECS Tone
The ECS system is highly dynamic. CB1R expression, as well as levels of AEA and 2-AG all fluctuate along the light-dark cycle/circadian rhythm [41, 42].
That being said, one can intentionally boost the ECS tone:
Singing: 30 minutes of singing increased the plasma level of AEA by 42% [43].
Exercise: 30 - 60 minutes of physical activities increased AEA [44].
Optimize Brain Health In General: sleep well, stay hydrated, and eat brain food to maintain optimal brain functioning.
Side Notes on Cannabis & The Human Body
[ Reintoxication ] [45]
Lipolysis increased the release of THC stored in the adipose (fat) tissue back into the bloodstream.
(Lipolysis: the metabolic process of breaking down fat for heat and energy.)
Adrenocorticotropic hormone (ACTH) increased the release of stored THC back into the bloodstream.
(Adrenocorticotropic Hormone (ACTH): a stress hormone produced by the pituitary gland in response to stressful stumuli. The ACTH then triggers the release of cortisol from the adrenal gland.)
[ Subjective Intoxication Effect ]
Different variants of CN1R, the CB1R-encoding gene, are associated with differences in the subjective effects of cannabis intoxication [46], potentially due to differences in CB1R densities [47].
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