Article at a Glance
- There does appear to be a link between cannabis use, especially before age 25, and mental illness, or psychosis.
- Polymorphisms in the dopamine related genes such as AKT1 and COMT play a role in the likelihood of developing marijuana induced psychosis.
- The higher the THC in a marijuana product, the more dangerous it becomes. Best to avoid synthetic THC and mega doses of THC in favor of products that contain more CBD.
- What is Cannabis?
- How do Cannabinoid Receptors Work?
- Does the fact that we have Cannabinoid receptors mean we were designed to use Cannabis?
- Tetrahydrocannabinol (THC)
- Studies on Cannabis Induced Psychosis
- Wrapping up
What is Cannabis?Firstly what exactly is cannabis? Well, broadly speaking there are three species of cannabis plant, Cannabis sativa, Cannabis indica and Cannabis ruderalis. In social circles, sativas are known as “uppers” and indica strains are described as more “mellow.” Indica strains are popular for people using cannabis for sleep. The cannabis plant is originally thought to have originated from central Asia, but is now grown worldwide for medical, industrial, and recreational use. In fact it’s a common misconception that hemp and cannabis are separate species, but hemp can be made from the stalk of any cannabis species.
How do Cannabinoid Receptors Work?The psychoactive effect of cannabis is driven by a family of molecules known as cannabinoids (nearly 500 have been described), with tetrahydrocannabinol (THC) being perhaps the most active. CBD, the popular “healthy” ingredient in cannabis is also a cannabinoid, but as we will learn in a moment, it blocks the activity of the cannabinoid receptor, rather than enhancing it as THC does. As a family, cannabinoids act on the cannabinoid receptors (CB1 – CNR1 and CB2 – CNR2) found on cells which control the release of neurotransmitters in the brain. So these receptors already exist in the body and are used to regulate a whole host of processes relating to anxiety, pain, inflammation, gastrointestinal activity and motor control. The receptors, and the factors which act on them in the body, are termed the endocannabinoid system. Upon activation, the receptors are thought to stimulate a complex intracellular signaling pathway, that ultimately results in a reduction in the release of glutamate and GABA. Of the two receptors, CB1 is thought to have the largest effect in the brain as it is expressed more highly. Based on those systems you can see how the cannabinoids expressed in cannabis can lead to a lot of the positive and negative effects associated with the drug, depending on how exactly they interact with the receptor, more detail below when we look at two key cannabinoids with quite different effects.
Does the fact that we have Cannabinoid receptors mean we were designed to use Cannabis?A common misconception around the naming of the cannabinoid receptors (and the system) is that it means we were designed to use cannabis. The truth is actually rather more prosaic and has to do with how the receptors were discovered. It was long known that cannabis has a profound effect on the brain, but it wasn’t until 1988 when researchers were first able to determine this effect was being modulated at the molecular level. The researchers used a synthetic cannabinoid and were able to identify and isolate a receptor in the brain which responded to cannabinoids, and hence the name was born. It was later discovered, in 1992, that our body produces its own molecules which target these receptors, and so these became known as endocannabinoids, or to break that name down, cannabinoids from within. Had the receptors been discovered without using cannabinoids they would likely have been named something else entirely. So, no, just because we have cannabinoid receptors does not mean we were “designed” to use cannabis.
Tetrahydrocannabinol (THC)THC is the main psychoactive component of cannabis, and it acts as a “partial agonist” of the CB1 and CB2 receptors, which means it binds and has an effect, but not as strong an effect as “full agonists” such as 2-arachidonoylglycerol. THC activates the cannabinoid receptors, much more so when it is delivered in synthetic forms. Synthetic forms of cannabis, such as spice, have been designed with a much more potent effect accounting for the often severe effects experienced by users. Simply put the receptor is being hit by a high dose of a very potent agonist, for a prolonged period of time, whereas natural cannabinoids may be expressed at a lower dose and only for short time periods. THC from cannabis is much less potent than its synthetic counterparts. Outside of CB1 and CB2 THC has also been shown to bind to other receptors with varying effects, although these are typically less well studied. Effects of THC on the seven-item positive symptom and negative symptoms subscales of the Positive and Negative Syndrome Scale (PANSS a medical scale used to measure the severity of schizophrenia). THC at both a low dose (2.5 mg) (green) and moderate dose (5 mg) induce an increase in positive and negative symptoms, compared to placebo (yellow) 1.
Cannabidiol (CBD) – the Non-psychoactive CannabinoidCBD is also found in cannabis but does not have the same psychoactive effects as THC, with some studies suggest that it actually acts to modulate the harmful effects of THC. CBD also works through the CB1 and CB2, but rather than being a partial agonist, it is said to be a “partial antagonist”, meaning it turns off the pathways activated by THC. So, in effect it is opposing the action of THC. Things aren’t quite so simple though as there is some evidence that CBD may also upregulate some of the responses to THC by increasing the number of CB1 receptors present. So, bottom line is that CBD can make the impact of THC stronger when high THC products are used. Furthermore, CBD as with THC has also been shown to bind to a wide variety of other receptors, which are all thought to drive its antipsychotic effects, including the serotonin 1A receptor and delta opiod receptor. if THC is a pro psychotic, CBD has the exact opposite effect.
Studies on Cannabis Induced PsychosisSo onto the main focus of the article. Psychosis is something we’ve all probably heard of but the definition can actually be quite nebulous. For a working definition, two main features are:
- hallucinations where a person hears, sees and, in some cases, feels, smells or tastes things that aren’t there, a common example being hearing voices, and
- delusions where a person has strong beliefs that aren’t shared by others; a common delusion is someone believing there is a conspiracy to harm them.
MechanismsSo as you can see, psychosis is a catch-all diagnosis, which is why it’s difficult to investigate. Diagnosis is tricky, and making a consistent diagnosis that works for large groups of people is trickier still. The field of measuring such events is known as psychophysiology, or more simply attempting to observe psychological effects by measuring physiological metrics. Typically this refers to the use of electroencephalography (EEG) to map what is happening in the brain following various stimuli. One stimulus that is often used is termed the P50 response. The P50 response is an event which occurs in the brain approximately 50 ms after being presented with a simple stimulus, like a click or a beep. Patients with schizophrenia have been shown to have an abnormal suppression of the P50 response, and studies comparing chronic cannabis users to non-users showed a similar suppressed P50 response, even after abstaining from drug use for 24 hours, in a dose-dependent manner (the more you smoke the bigger the effect). Another measure is the P300 response, which is typically measured when an individual is presented with a stimulus and is asked to decide on a response. As above, deficits in P300 have been demonstrated in patients with schizophrenia 2 3 4. Further studies then showed that THC caused a similar deficit in response to occur in healthy individuals 5 6. However, studies in long-term cannabis users are more confusing with both positive and negative effects described 7 8. The opposite effect was observed when looking at mismatch negativity, a response that occurs in the brain after hearing a deviant auditory stimulus in a sequence of normal stimuli (so, for example, imagine someone saying S over and over then occasionally inserting a T). Deficits in MNN have been shown in people with schizophrenia and early psychosis 9, and also in long-term cannabis users 10. However, studies attempting to replicate this in the lab using THC did not see any effect.
EpidemiologyThe first study linking cannabis with psychosis was published in the 80’s and investigated the association between cannabis and psychosis in a population of 45,000 Swedish conscripts. The take-home message from the study was that conscripts who reported having used cannabis at least once in their lifetime had a 2.4-fold increased risk of developing schizophrenia over the course of 15 years and this relative risk rose to 6-fold in those who had used cannabis more than 50 times in their lifetime 11 12. However, several issues have been raised with the study over the years, the first is to do with directionality, as in are those who smoke cannabis more likely to develop schizophrenia, or are those who are more likely to develop schizophrenia more likely to smoke cannabis? This is an issue which dogs many of these studies and is a difficult one to address when a clear mechanism remains unknown 13. Other issues relate to the difficulty in controlling for other factors such as other drug use, and other factors which may arise from the fact that such studies are self-reporting.
|Consumption||Number (Percentage)||Cases of schizophrenia||Relative risk||Confidence Intervals|
|1-10||2,836 (6.2)||18||1.3||0.8 - 2.2|
|11-50||702 (1.5)||10||3.0||1.6 - 5.5|
|>50||752 (1.7)||21||6.0||4.0 - 8.9|