Motivation and emotion/Book/2021/Synthetic cannabinoids and emotion

Overview
Synthetic cannabinoids are psychoactive chemicals that interact with cannabinoid receptors in the brain and central nervous system (CNS), altering neurotransmitter activity (Alexandre et al., 2020). This chapter aims to understand the role of synthetic cannabinoids on neuronal functioning to explain the emotional and physical impact of consumption. Current research has determined that synthetic cannabinoids produce more adverse effects than natural cannabinoids due to the higher binding affinity and full-agonist activity toward the Cannabinoid-1 (CB1) and Cannabinoid-2 receptors (CB2) (Sutcliffe & Ralphs, 2018; Wells et al., 2011). The impact of consumption of synthetic cannabis will be discussed, including acute versus chronic intoxication, and outlining the psychical, behavioural, cognitive, and psychosocial symptoms.

Focus questions:
 * What are synthetic cannabinoids?
 * What is the history of synthetic cannabinoids?
 * How are synthetic cannabinoids produced?
 * How do synthetic cannabinoids impact users in the short term?
 * How do synthetic cannabinoids impact users in the long term?
 * How do synthetic cannabinoids impact emotions and emotional processing?
 * What is the impact of quitting and withdrawal on emotions?

History and Prevalence of Synthetic Cannabinoids



 * The first synthetic cannabinoid was developed by the organic chemist John Huffman of Clemson University in 2008. The active ingredient in synthetic cannabis is JWH-o18, a naphthoylindole, belonging to the aminoalkylindole family, which are cannabinergic compounds that pose as cannabinoid receptor agonists. Despite JWH-o18 having a different chemical structure to Tetrahydrocannabinol (THC), the effects are similar (Byard & Payne-James, 2015).
 * Production of synthetic cannabinoids begins on a large scale in China. A bulk powder is produced via simple chemical reactions using legal substances (Sutcliffe & Ralphs, 2018). The bulk powder is then shipped to Europe and mixed or sprayed onto dried plant material that does not contain tobacco or cannabis. The material is dried and packaged as an air freshener, incense, or a smoking mix, and is distributed to other countries including America and England to sell (Sutcliffe & Ralphs, 2018).
 * Synthetic cannabis is legally sold in many countries and is available to purchase online or in head shops (Cottencin et al., 2014).
 * Synthetic cannabinoids are known as K2 or Spice but have many other names (Sutcliffe & Ralphs, 2018). Similarly, synthetic cannabis has many different chemical formulations - the contents are unknown (Wells et al., 2011), this causes unpredictable reactions after intoxication due to the varying potential toxicity (Millis et al., 2018).
 * Synthetic cannabinoid products first appeared on the internet for sale in 2006. Popularity began in 2008 when a German reporter announced that Spice had a similar high to natural marijuana but did not appear in drug tests (Sutcliffe & Ralphs, 2018). The unpredictability of synthetic cannabinoids combined with the inability to be detected in urine drug tests pose a large public health concern (Millis et al., 2018).

Synthetic Cannabinoids and Short Term Impacts
Acute intoxication of synthetic cannabinoids can cause users to experience both positive and negative effects due to the varying binding affinity to the CB1 and CB2 receptors (Wells et al., 2011).

Lana first tried synthetic marijuana at the age of 17. She brought it under the name “Spice”, her dealer told her it was natural weed. Lana met with a friend and smoked a joint, having a good time, she felt happy and relaxed. The next day Lana experienced a low mood accompanied by headaches and feeling disconnected from reality (Soussan et al., 2014).

Description of Synthetic Cannabinoids:



 * Synthetic cannabinoids such as JWH-018 mimic the effect of THC (the main psychoactive component of cannabis) (Sutcliffe & Ralphs, 2018), Lana's acute intoxication caused her to experience positive and happy feelings. This euphoric effect caused by synthetic cannabis is common as the chemical structure of JWH-018 produces similar effects to natural marijuana (THC) (Wells et al., 2011). Despite Lana's positive experience, acute intoxication of synthetic cannabis can also cause users to experience fear, paranoia, nausea and dizziness, respiratory difficulties, and tachycardia (Akram et al., 2019).

Neurology

 * JWH-018 is the most common synthetic cannabinoid compound found in Spice and K2. Synthetic cannabis is abused due to the full-agonist activity to the CB1 and CB2 receptors (Wells et al., 2011). Synthetic cannabinoids have a higher affinity for the CB1 and CB2 receptors than natural cannabinoids. THC is a partial agonist, whilst synthetic cannabinoids are full agonists (Zaleta et al., 2016), producing an effect four to five times stronger than natural marijuana (Wells et al., 2011).
 * As synthetic cannabinoids vary in ingredients, they vary in affinity toward either the CB1 or CB2 receptor, producing unpredictable outcomes. A higher affinity toward the CB1 receptor produces more psychotropic effects, including alterations in mood, perceptions, and cognition due to the presence of the receptor in neuronal cells (Alexandre et al., 2020). Whilst having a higher affinity toward the CB1 receptor causes pain relief but reduced psychotropic effects (Alexandre et al., 2020).

CB1 Receptor

 * The CB1 receptor produces euphoric feelings and psychoactive effects, including alterations in mood, perceptions and cognition (Wells et al., 2011; Alexandre et al., 2020). The receptors exist in neuronal cells within the brain, densely packed in the prefrontal cortex and the hippocampus, within the central nervous system, connective tissue, glands, organs, and gonads (Fantegrossi et al., 2018; Alexandre et al., 2020; Samaan et al., 2016). The location of these receptors explains why users experience nausea relief and a sense of euphoria (Samaan et al., 2016). The binding of the CB1 receptors inhibits the release of hormones including acetylcholine, noradrenaline, GABA and glutamate, altering brain functions including memory, cognition, motor cognition, and autonomic functioning (Alexandre et al., 2020).

CB2 Receptor

 * The CB2 receptor is responsible for mood regulation, behavior regulation, and pain control, as the receptors are located in the immune system, nervous system, and gastrointestinal system (Fantegrossi et al., 2018; Wells et al., 2011). The CB2 receptor regulates the immune system and central nervous system as they are densely located in immune cells (Alexandre et al., 2020). The synthetic cannabinoids interact with the CB2 receptor, causing 2-Arachidonoylglycerol, an agonist to activate the CB2 receptors located in the brainstem to produce effects in the nervous system (Samaan et al., 2016). The cannabinoid interaction with the nervous system produces the pain relief that users experience after intoxication. The increased activity in the central nervous system can also cause agitation, explaining why users experience confusion or delusions (Samaan et al., 2016).

Hangover

 * Lana’s symptoms of exhaustion and feeling sluggish are characterized by the ‘hangover’ period of using synthetic cannabis. This period causes users to feel dull, tired, monotonous, and dehydrated. (Akram et al., 2019). Users often develop a dependence to smoking synthetic cannabis to avoid this feeling.
 * Users experience a zombie-like, emotionally numb state characterized by feelings of apathy and disconnect from reality. The constant feeling of depersonalization causes life to feel mundane, resulting in users losing interest in the things they normally would enjoy (Soussan et al., 2014).
 * Research is limited in determining the cause of the hangover period but findings are consistent in multiple clinical case studies.

“It’s like losing the magic of life, the thing that makes me feel animated, soulful and having a personality.”

"The next day I feel lobotomized, and nothing is fun or boring.”

Comments from individuals who experienced the hangover period (Soussan et al., 2014)



What receptor is responsible for Lana feeling happy?

1. The CB1 receptor

2. The CB2 receptor

1. Correct 2. Incorrect

The CB1 receptor produces the happy feelings and psychoactive effects from the synthetic marijuana (Wells et al., 2011).

Memory Problems and Synthetic Cannabinoids
Long-term use of synthetic cannabinoids results in short-term and long-term disruptions in memory retention (Cohen et al., 2017).

After smoking for four months, Lana has trouble remembering things, this interferes with her daily life as she cannot remember important events or recall the things she would do. Lana often feels confused and is not able to distinguish what is real and what is not, she is delusional and disorganized (Soussan et al., 2014)




 * Chronic use of synthetic cannabinoids causes volume reductions and disruptions in the hippocampus, disrupting short-term and long-term memory retention (Wells, 2011; Cohen et al., 2017). Synthetic cannabinoids are agonists to the CB1 receptors located in the hippocampus, causing impairments in synaptic plasticity, and therefore, memory processes (Cohen et al., 2017). This explains Lana's inability to recall her memories.
 * The hippocampus is responsible for encoding and acquiring new information. The new information is manipulated by the working memory system within the prefrontal cortex. Synthetic cannabinoids have deleterious effects, directly reducing hippocampal encoding ability, therefore, reducing input relay to the prefrontal cortex. This causes disruptions within the working memory system (Cohen et al., 2017).
 * As the working memory system is responsible for complex cognitive tasks such as learning, comprehension, and stores and processes information, this can explain why Lana is having problems recalling her short-term memories and is delusional as her cognitive ability is negatively impacted.
 * Synthetic cannabinoid abuse also affects the insula, anterior cingulate cortex, precuneus, inferior frontal gyrus, frontal orbital gyrus, and middle frontal gyrus. The functional and structural changes in these brain regions are responsible for the emotional disturbances in users, inducing feelings of confusion, loss, and feeling fragmented (Soussan et al., 2014).

“I tried watching Family Guy during intoxication, but the whole time I forgot what the episode was about.” (Soussan et al., 2014).

Users experience difficulties concentrating after consumption of synthetic cannabis, which can induce feelings of frustration (Soussan et al., 2014).



Why is Lana experiencing memory loss?

1. The synthetic cannabinoids interact with the amygdala causing disruptions in memory retention

2. The synthetic cannabinoids interact with the hippocampus causing disruptions in memory retention

1. Incorrect 2. Correct

The hippocampus is responsible for storing and processing new information, therefore, the interaction of synthetic cannabis disrupts normal functioning, resulting in memory problems (Cohen et al., 2017).

Synthetic Cannabinoids and Depression
Chronic use of synthetic cannabinoids increases the risk of developing depression (Cohen et al., 2017).

Lana has been smoking for six months. She has experienced several depressive episodes since she began abusing synthetic cannabis but is enduring her worst episode yet. She feels emotionally numb, apathetic, and disconnected from reality (Cohen et al., 2017). She feels depersonalized, and her life feels mundane. She no longer has an interest in anything that she used to enjoy. She feels fatigued daily and also experiences headaches and nausea (Cohen et al., 2017).

Emotionally numb
‘The drug-totally distorted my personality, it turned me inside out… it made me blunt, and switched off my brain’ (Akram et al., 2019)

Mood changes
‘When I smoked I was wallowing in self-pity, I felt sorry for myself, I was alone, I didn’t care about anybody else, I hated everyone (Akram et al., 2019)


 * Consumption and abuse of synthetic cannabinoids cause CB1 receptor agonists to induce a decrease in prefrontal serotonin levels. The decrease in serotonin alters cognitive functioning and specifically learning abilities (Cohen et al., 2017). The decrease in serotonin is responsible for Lana's depressive mood and feelings of apathy.
 * The study by Akram et al. (2019) found significantly higher correlations of depression in synthetic cannabinoid users compared with natural cannabinoid users.
 * Synthetic marijuana products have been found to contain large amounts of vitamin E, causing vitamin K to antagonize. Large amounts of vitamin K cause feelings of fatigue, headache, nausea, diarrhoea, and muscle weakness (Wells, 2011). The excess in vitamin E is responsible for producing Lana's low mood, fatigue, headaches, and nausea.

Synthetic Cannabinoids Cause Cardiac Problems and Psychosis
Chronic and long-term synthetic cannabinoid abuse is correlated with cardiac problems including tachycardia, and psychotic problems leading to the development of psychosis (Fantegrossi et al., 2018; Soussan et al., 2014).

Lana is admitted to the hospital after experiencing a rapid heart rate after smoking. Her roommate called an ambulance after finding her with chest pains and in a disoriented state screaming, ‘where am I?'. Her heart rate was abnormally high which caused her to experience fear.

Psychosis

 * Lana's disoriented state is not an uncommon symptom for chronic users of synthetic cannabis. Her inability to distinguish her location and her screaming indicates she is experiencing a psychotic episode. Welter et al. (2017) found that 71.4% of inpatient psychiatric patients who abused synthetic cannabis were diagnosed with a psychotic disorder. 61.5% of psychiatric patients diagnosed with a psychotic disorder did not use synthetic cannabis. A higher percentage of psychotic disorders is correlated with synthetic cannabis usage, establishing a relationship between synthetic cannabis and psychotic disorders.
 * Chronic exposure to synthetic cannabis results in psychosis due to the interactions with the Dopamine-1 and Dopamine-2 receptors as they are associated with cognitive dysfunction and psychotic symptoms (Fantegrossi et al., 2018). Synthetic cannabinoids increase the interaction of the 2A dopamine receptor within the prefrontal cortex as this receptor responds to antipsychotic drugs. The 2A receptor regulates impulse control and mood and is located in the central nervous system (Fantegrossi et al., 2018). Psychosis manifests as chronic exposure to synthetic cannabis prevents alterations in the serotonin 2A receptor expression (Fantegrossi et al., 2018). This exposure increases susceptibility for users to experience altered perceptions and hallucinations. The altercations are the underlying cause of psychosis and drug addiction, explaining why Lana experienced psychosis and has an addiction as she has been smoking for eight months. (Fantegrossi et al., 2018).
 * Fantegrossi et al. (2018) reviewed six studies of synthetic cannabinoid users and found a direct correlation to psychosis and psychotic symptoms.

Tachycardia
“There was a bolt of lightning in the body and my heart started racing like I was having a heart attack.” (Soussan et al., 2014).


 * Smoking synthetic cannabis can induce tachycardia, causing the heart to beat abnormally fast. Users report experiencing heart pains, respiratory difficulties, muscle tension, and general body pain (Soussan et al., 2014). These symptoms can induce feelings of fear and discomfort.
 * When the CB1 receptor is blocked, atheroma formation is directly reduced. Atheroma formation is the build-up of fatty deposits and scar tissue on the heart, restricting circulation and increasing chances of heart-related altercations (Zaleta et al., 2016). Since synthetic cannabinoids are agonists to the CB1 receptor, this increases the possibility of atheroma formation and, therefore, explains Lana's symptoms of chest pains and tachycardia (Zaleta et al., 2016).



Lana is admitted to the hospital. They do a routine check on her, Lana states that she has been smoking spice for the past eight months and had it earlier in the day. A routine drug test is done. What is Lana’s result?

1. Cannabis is detected in Lana's system

2. Cannabis is not detected in Lana's system

1. Incorrect 2. Correct

Lana’s drug test does not pick up cannabis in her system (Millis et al., 2018).

Synthetic Cannabinoids - Dependence and Withdrawal
Long term abuse of synthetic cannabinoids causes a strong dependence, producing withdrawal symptoms that negatively impact quality of life and mental health (Soussan et al., 2014).



Lana realizes that her addiction is ruining her life. Lana has poor memory and motor skills; she requires help on her daily tasks. She quits with professional help but experiences withdrawal symptoms including headaches, anxiety, stomach aches, sweating, and vomiting (Soussan et al., 2014). This causes Lana to feel sad, due to her loss of control and loss of her normal life, she is in a state of distress as she is unable to soothe her cravings.


 * Long-term chronic use of synthetic cannabinoids causes dependency and withdrawal from not smoking (Soussan et al., 2014). Quitting warrants feeling of restlessness, aggression, agitation, and uncontrollable mood swings and shifts in emotional states (Soussan et al., 2014). Basic human functions including hunger and sleep are disturbed from the withdrawal. Mental health problems and difficulties in daily functioning can manifest as withdrawal causes insomnia and loss of appetite (Soussan et al., 2014). Quitting synthetic cannabis often warrants the desire to consume other drugs to distract themselves from the urge to consume synthetic cannabis, causing individuals to develop a dependency on other substances (Soussan et al., 2014).
 * Lana is dependent on synthetic marijuana and is experiencing withdrawal symptoms characterized by her memory impairments, concentration difficulties, agitation, and feelings of disconnection, causing her to be emotionally numb. She experiences mood swings and uncontrolled agitation (Akram et al., 2019). The study by Akram et al (2019) revealed that individuals who quit synthetic marijuana have suicidal and depressive thoughts. Other symptoms include diarrhoea, insomnia, and sweating (Akram et al., 2019).

'''“The side effect for me was unfortunately and solely a strong addiction. A dependency appeared as soon as I tried to relax or sleep.” (Soussan et al., 2014).'''

“Used it daily and my temper went up and down and I also became sad and depressed for nothing.” (Soussan et al., 2014).

Most Common Symptoms of Synthetic Cannabinoids
As the chemical formulations of synthetic cannabinoid mixes vary, binding affinity to the CB1 and CB2 receptors vary, producing unpredictable symptoms (Alexandre et al., 2020). Users can experience a combination of the following symptoms depending on their dose and previous usage (Alexandre et al., 2020).

Conclusion
Synthetic cannabinoids are a human-made drug that replicates the feeling of natural cannabis (Byard & Payne-James, 2015). Consumption of synthetic cannabinoids results in adverse psychical, behavioral, cognitive, and psychosocial symptoms determined by the binding affinity to the CB1 and CB2 receptors (Samaan et al., 2016). Research literature concludes that intoxication warrants euphoric feelings due to the CB1 receptor. Short-term and long-term memory problems occur, causing individuals to experience confusion due to disruptions in the hippocampus (Cohen et al., 2017). Synthetic cannabis causes users to experience depression and delusions due to decreased serotonin levels (Cohen et al., 2017). Psychosis manifests in chronic synthetic cannabis users due to the interactions with dopamine receptors (Fantegrossi et al., 2018). Users often experience tachycardia to the cannabinoid interaction with the CB1 receptor, promoting atheroma formations (Zaleta et al., 2016). Synthetic cannabis is addictive and withdrawal is characterized by depression, suicidal thoughts, and urges to consume other drugs (Soussan et al., 2014). Synthetic cannabis causes unpredictable emotional, physical, cognitive, and psycho-social symptoms, thus the conclusion is it should be avoided and not consumed (Millis et al., 2018).