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THCA and THCV molecules


THCA and THCV molecules

THCA and THCV: molecules with great therapeutic potential

S Pagliazzi and A R Mohammad


The use of the Cannabis plant as a medicine is deep rooted in history, with evidence of its medicinal use dating back to the 2900 B.C. [1]. There are up to 92 known active compounds present in the plant, with variable activities and potencies. The percentage levels of the respective compounds are extremely variable, largely dependent on the genetics of the strain (which control the expression levels of each compound). It’s well known that the psychoactive property of the Cannabis plant is largely due to the presence of Tetrahydrocannabinol (THC), which is a major compound present in many strains of the Cannabis plant. It is largely due to this compounds that Cannabis is registered as a Schedule 1 drug in many countries around the world.

Interestingly the psychoactive properties of THC can create confusion about the other structurally similar compounds present in Cannabis. The two compounds that will be discussed are the biosynthetic precursor of THC, Tetrahydrocannabinolic acid (THCA) and the structural homologue Tetrahydrocannabivarin(THCV). Unlike THC these two compounds do not have psychoactive properties (that eventually led to the illegal status) and display considerable therapeutic potential in a variety of diseases and conditions. They are meant to be responsible for the well-regarded therapeutic effects of Cannabis in a variety of diseases, and henceforth require further probing from a scientific standpoint.

THCA is the acidic precursor to THC, and the decarboxylation of THCA occurs as a result of […]

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Cannabis effects and therapeutic cues: Part 2 Paranoia


Cannabis Effects and Therapeutic Cues – Part 2

A very common psychological effect from Cannabis use (both medicinal and recreational) is the development of an overwhelming sense of fear. Slightly irregular situations or provocations can trigger a sense of paranoia, where the danger is perceived to be higher than it is actually. Paranoia can also be provoked by dangerous and negative thoughts or memories, which develop while the individual is under the influence. However, the development of paranoia varies significantly amongst individuals, and can also be dependent on the emotional state of the person. On the other hand, individuals suffering from Post-Traumatic Stress Disorder (PTSD) often find comfort and a reduction in the recurrence of their fear memories while using cannabis, or a cannabis derived medication

[1]. Investigating the neurocircuitry and the different scenarios which might increase or decrease emotions of fear from Cannabis prove interesting and reveal many neuropsychiatric mechanisms. The neurobiology of the pathological nature of various anxiety disorders could be uncovered. Consequently it could also determine whether Cannabis derived medications are suitable for the treatment of anxiety disorders.
The emotion of fear is primarily prompted by a recognition of a threat. From an evolutionary perspective, this emotion carries a significant fitness advantage as it acts as an ‘alarm bell’ for anything that may cause harm (or perhaps kill!) to the animal [2]. To be able to sense these threats quickly, and respond rapidly forms the basis of this emotion.

The amygdalae (plural for amygdala) are two ovular nuclei located deep within the temporal lobe. The amygdalae are considered as the processing centre of fear, as well as controlling autonomic responses associated with fear, arousal and emotional stimulation [3]. Specifically the neurocircuitry of fear in the human brain initially stems from receiving sensory inputs such as noise, sight (e.g. a dangerous animal), smell, or touch. These inputs are mediated via the thalamus (the relay centre of the brain) directly to the amygdala (the “short route”) or to the amygdala via the neo-cortex structures of the brain (the “long route”) [4].

The balance of both these routes is critical for the balance of the emotion of fear. The “short route” of fear is the critical element of survival, as it facilitates quick and responsive reactions to potential situations of danger. On the other hand in the “long route”, the stimulus is processed by neocortical brain structures such as the prefrontal cortex, cerebrum and the hippocampus. This “long route” discriminates between perceptual and actual fears, and consequently plays a big role in regulating fear expression and suppression.

The interplay between the amygdala and the medial pre frontal cortex (mPFC) is particularly important for the processes of fear expression and suppression. Within the amygdala, fear stimuli are processed by the basal amygdala (BA) which in turn activates the central amygdala [5]-which drives the physiological effects typically seen with fear such as freezing, increased heart rate, and increased catecholamine levels e.g. adrenaline [6]. The two subdivisions of the mPFC have opposing roles in fear modulation. The prelimbic mPFC promotes amygdala activation and consequently fear expression, while the infralimbic mPFC inhibits amygdala activation to suppress fear output [5]. The complexity of this neuronal system and the convoluted emotion of fear are still being studied, as there are many other brain regions thought to be involved such as the hippocampus [7] and the anterior cingulate cortex [8].

Although not many studies have specifically looked at the neuronal basis of paranoia, one study has provided some cues into the role of the CB1 receptor on possibly enhancing the onset of fear behavior. This study showed that CB1 agonism enhanced the neuronal emotional learning of fear [9], which could be reason why there could be a higher tendency to feel the emotion of fear and become paranoid under the influence of cannabinoid medication.

CB1 receptor agonists are reported to induce biphasic effects, with lower doses being anxiolytic and higher doses being anxiogenic [10], and these effects could be studied in greater detail to demystify the complex neurocircuitry governing fear. It is also important to note that cannabinoids can also effect several cognitive functions (while under the influence), most importantly attention and working memory (is the ability to transiently hold and process information [11])[12]. By not being able to focus and provide considerable logical reasoning to the fear creating stimuli (and why it may not be as frightening as it seems), is exactly the reason for which the emotion of fear is heightened.

The main active principle in most available Cannabis plants, d9-tetrahydrocannabinol (THC), could be the main cause of its fear inducing effects (upon administration…). It is important to note that the Cannabis plant consists of more than 100 active compounds within its secondary metabolites [13]. The other common active principle found in this plant is Cannabidiol (CBD), which has well documented anxiolytic effects [14]. Studies have shown that CBD might modulate anxiety responses by the dampening prelimbic mPFC neuronal activity acting via the 5-HT1A receptors [15], consequently decreasing freezing responses which occur as a result. Therefore CBD may be a beneficial negative modulator on paranoia and anxiety, acting to reverse the anxiety and paranoia induced by THC.

Fear-surpression under the influence of CBD and THC
Figure 1: The influence of CBD and THC on the neuro-circuitry involved in the emotion of fear.


PTSD is an anxiety disorder which is triggered by a traumatic experience. PTSD causes changes in the brain’s structure as a result of serious trauma, and causes the sufferer to continuously be reminded of the traumatic experience. Patients with PTSD have shown a marked decrease in the functionality of mPFC, and increased activity in the amygdala [16]. This hyperactivity is triggered by stimuli closely related to a previous traumatic experience, causing the sufferer to re-visit a previous memory.

The development of PTSD is caused by the impaired process of fear extinction [17], which is an essential process performed by the brain to erase fear provoking memories. In contrast to increasing fear expression to stimuli (mentioned above), administration of CB1 agonists has also shown to facilitate this fear extinction process [17]. The dilemma, particularly a medical one, is whether Cannabis-based or derived medications should be considered as potential anxiolytic drugs-when they can also have mild anxiogenic effects.

Cannabis is widely used as a treatment option for PTSD in countries where it is legally accessible and anecdotes indicate that it can be effective. A double-blind study with Nabilone (synthetic THC) provided tremendous relief in the reduction of adverse effects caused by PTSD, and showed to be tremendously effective in extinguishing traumatic and fear provoking memories [18]. Therefore targeting the CB1 receptor might be a viable option for the treatment of PTSD, but further investigation into the dosage requirements is required.

Cannabis presents an interesting paradox in relation to fear, paranoia and anxiogenic disorders. This paradox has developed due the multifaceted effects of this plant to both induce and reduce fear, as well as its potential to treat anxiety disorders such as PTSD. However the complexity is caused by varying hypotheses, mainly caused by the categorisation of Cannabis as a single drug. Cannabis can exist in many different forms, made up of varying constituents-some of which have completely opposing pharmacological properties. Closer observation of how specific individual components of Cannabis modulate fear and disorder stemming from the neurocircuitry of it, presents an interesting field of study for drug discovery.

By Abdul Rehman Mohammad, Catherine Passariello, Riccardo Franci Montorzi, Tilman Benzino

“Cannabis effects and therapeutic cues” is a series of articles describing the common effects of Cannabis on the human body. By examining these effects with a biological basis we are aiming to present new therapeutic oppurtunities for a various array of diseases.

As described by the great Albert Einstein, “The formulation of the problem is often more essential than its solution, which may be merely a matter of mathematical or experimental skill.” If the effects of the Cannabis plant are seen as “problems”, exploring these problems may provide great cures for multiple disorders-many of which are deprived of effective treatments.


Cannabis effects and therapeutic cues: Part 1 The “Munchies”


Cannabis Effects and Therapeutic Cues – Part 1 The “Munchies”

The ‘Munchies’, a term well associated with the insatiable desire to eat when under the influence of Cannabis, is caused by a various array of physiological events which lead to the stimulation of hunger. This is accompanied by, and often preceded by, feelings of euphoria as a result of the activation of certain cannabinoid receptors. Studying the ‘Munchies’ effect has developed a greater deal of understanding in the role of the endocannabinoid system (ECS) and appetite stimulation. However much still remains a mystery in this area. Further investigation of the intricate interplay between various cellular signalling pathways could be the key to finding novel ways to treat various eating disorders such as anorexia, cachexia and obesity; as various studies have implicated the role of the ECS in the aforementioned diseases [1].

It is widely accepted that the smell of food causes the stimulation of appetite [2]. Agonism or stimulation of the CB1 receptor dampens the effect of the negative feedback system present in the olfactory cortex, and this double negative effect leads to an enhanced sense of smell [3]. Therefore people experiencing the ‘high’ have an augmented sensory response to odour, and tend to have a higher appreciation of food than usual. This olfactory pathway is presently being used to give appetite suppressing effects through an aromatherapy technique that involves the smelling of a strong fragrance (such as Vanilla or grapefruit) for more than five minutes, to magnify the negative feedback loop on the olfactory bulb.

Figure 1: The negative feedback loop of the olfactory cortex acting on the olfactory bulb, and how stimulation of the CB1 receptor inhibits this loop


Cannabis has been shown to have its effect on appetite mainly through the CB1receptor. The CB1 receptor has been implicated in the olfactory system that triggers smell, but is also involved in the neuronal signalling that triggers the sense of hunger and satiety[4]. Therefore it can be a key regulator in […]

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Cannabinol: degradation leads to opportunity?


Cannabinol: degradation leads to opportunity?

Abdul R Mohammad, Sergio Pagliazzi

Cannabinol (CBN) is the cannabinoid which is generally indicative of the age of the cannabis plant. This is because CBN is formed from the degradation of THC on exposure to heat and UV light, and this conversion occurs over time-subject to storage conditions. As well being a degradation product of THC, it has also shown to be a rapid metabolite of THC in the blood (McCallum et al., 1975).

Figure 4: The degradation of THC to CBN, which occurs in the presence of heat and UV light. The reaction is a partial hydrogenation of one of the aromatic rings of THC.


CBN acts as a weak agonist to CB1 and CB2, about four times less potent at CB1 compared to THC (Rhee et al., 1997). CBN exhibited a much higher inhibitory constant (Ki) than THC (about 6 times higher) on brain CB1 receptors, indicated in brain synaptosomal binding experiments (Rhee et al., 1997). Hence it has a much lower affinity to CB1 as compared to THC. This could provide the explanation behind CBNs minimal psychoactive effects. CBN is metabolised to 11-OH-CBN (via 11- hydroxylation), which is twice as potent as CBN on CB1 receptors but can only exhibit partial agonist activity at the CB2 receptor (Rhee et al., 1997). Even though it is more potent on brain CB1 receptors than CBN, it is still three times less potent than THC on these receptors (Rhee et al., 1997). It has shown to have less than 10% of the Psychoactive and cardio acceleratory effects of THC in humans (Howlett, 1987). In another study the effects of CBN were considered to be less intense (both physiologically and psychologically) in humans subjects compared with the effects of THC (Hiltunen and Jrbe, 1986).

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