In recent years, there has been a growing medical interest in cannabis plants in order to further understand the whole composition and the effects that each substance can produce in our bodies.  So far, the most studied cannabinoids are THC and CBD, but they are just two of the thousands of compounds found in the plant.

Unfortunately, not all cannabinoids can be legally used worldwide due to certain cannabinoids’ ability to alter the state of consciousness of the users, causing stigma regarding its medical usage. The best known for producing this effect is THC. For this reason, cannabis strains with a high THC content are most common in recreational cannabis users. However, cannabis plants also include several chemical compounds which are able to produce different effects on the brain without altering the consciousness of the user. The huge number of these chemicals, known as cannabinoids, leads researchers to further study cannabis plants, to reveal the full potential and effects of each substance and to understand how to avoid the adverse effects that some may produce.

The main purpose of this article is to distinguish the differences between the psychoactive and psychotropic effects induced by cannabinoids, and how they produce them. This will allow us to assess what influence cannabinoids have on the brain and whether or not they alter a person’s perception of reality.

Cannabinoids’ Psychoactive and Psychotropic Effects

In the majority of scientific articles which analyse synthetic cannabinoids, phytocannabinoids and endocannabinoids, THC is normally classified as the main “psychoactive” compound to describe its effects on users’ mood, feeling and perception of reality. On the other hand, CBD has been classified as the most prominent “non-psychoactive” substance, which does not have any influences on the brain through perception altering effects. Most scientists researching the medicinal benefits of cannabinoids use the term “non-psychoactive” in order to identify the “not-intoxicating” effects of CBD. But it is also true that CBD is psychoactive even though it doesn’t produce mental intoxication.

We at Kalapa Clinic want to clarify, in the world of medical cannabis research, the difference between the terms “psychotropic” and “psychoactive”, relating to cannabinoids, in order to properly evaluate a clear distinction of the effects produced on the brain, according to the following definitions:

Psychoactive cannabinoid: this is every cannabinoid that has an influence on the central nervous system (CNS), possessing the ability to alter mood, anxiety, stress, cognitive processes and also neurological signalling processes, without affecting the sensorial perception, identified as “intoxication”. This can include every cannabinoid which somehow has influences on the CNS, without producing the ‘high’ from recreational cannabis.

Psychotropic cannabinoid: this is every cannabinoid influencing the CNS and specific areas of the brain, though “intoxicating effects”. Apart from the several medicinal benefits, the alteration on perception, emotion and behaviour, overall, on the sensorial perception is defined as “intoxication” and sometimes as a “psychotropic effect”. The best known cannabinoid responsible of these alterations is delta-9-tetrahydrocannabinol (THC).

These two terms seem quite similar, as we are talking about cannabinoids which act on the CNS in order to induce mood alterations. This is to say that not every cannabinoid acting on the CNS produces sensorial alterations, even if it acts on the brain and induces changes in mood.

For specificities and clarification, several cannabinoids are psychoactive compounds, including THC, but THC can be differentiated as a psychotropic cannabinoid given its ability to alter our senses. So far, THC, THCV and CBN are the only official cannabinoids to be classified as such. Nonetheless, several studies have shown the medicinal benefits of CBD, and other cannabinoids, on several conditions that involve the CNS, such as epilepsy, Parkinson’s, and Alzheimer’s disease; with the potential to not produce any psychotropic effects.

Indeed, CBD can cross the blood-brain barrier and can directly affect the CNS which can induce changes in mood, without having the intoxicating effects like THC as well as the obvious cognitive alterations or withdrawal effects.

This is where researchers can be misled.  They identify CBD, among others, as a non-psychoactive cannabinoid, due to the lack in production of “intoxicating effects”, even though they are clearly mood-altering substances.

Understanding cannabinoids’ effects on the CNS

Industrial cannabis (hemp) has been used for textile to manufacture rope and clothing, however this material contained very little amounts of THC.  However, some specific cannabis strains can also contain high levels of THC, ranging from approximately 3% to 20%.  Moreover, there have already been over 150 other cannabinoids identified in the plant.  Other cannabinoids of interest including cannabinol (CBD), cannabinol (CBN), and cannabigerol (CBG) largely lack the ability to activate all cannabinoid receptors but are biologically active.

When the endocannabinoid system (ECS) was discovered, there was very minimal knowledge on the subject, along with cannabinoid pharmacology, which was accompanied by the controversy regarding the use of cannabis for its medicinal properties and its capability for abuse and dependence. Owing to all the research conducted during recent years, today we are able to describe the key substances present in cannabis, along with most of their biological properties and mechanisms of action through the endocannabinoid system, such as the ability to mediate modulation of immune function within the nervous system.[1]

Endocannabinoid receptors

The endocannabinoid system (ECS) is composed of cannabinoid receptors, endogenous cannabinoids (endocannabinoids) and enzymes which synthesize and degrade the endocannabinoids. The two best-known cannabinoid receptors are CB1 and CB2, both of which are G protein-coupled receptors (GPCRs).[2]

GPCRs mediate most physiological responses to hormones, neurotransmitters, and environmental stimulants, and so have great potential as therapeutic targets for a broad spectrum of diseases. [3]

Tetrahydrocannabinol (THC) is known as the main psychoactive compound in cannabis and it produces the majority of its medicinal effects by interacting with CB1 and CB2 receptors. Both receptors have seven transmembrane domains, coupled to G-inhibitory proteins, and are linked to signalling cascades that may regulate intracellular calcium levels, involving adenylyl cyclase and cAMP, mitogen-activated protein (MAP) kinase.

CB1 is expressed throughout the nervous system as well as in other organ systems. The interaction with this receptor plays a role in regulating pain, stress responses, energy regulation, lipogenesis, and immune function. Moreover, studies have shown how this receptor is predominantly responsible for the psychotropic effects of THC.

On the other hand, CB2 is mainly associated with the immune functions and is expressed on immune cells, including microglial cells within the nervous system, but its presence in the central nervous system (CNS) is much lower than that of CB1.

However, cannabinoids can also bind to other receptors suggesting the existence of additional cannabinoid receptors or even other binding sites. Another cannabinoid receptor is GPR55. GPR55 is dose-dependently activated by THC (as an agonist in low doses and antagonist in higher doses) and deactivated by CBD (antagonist), certain synthetic cannabinoids, and by endogenous cannabinoids, such as Anandamide (AEA) and 2- arachidonoylglycerol (2-AG). Unlike CB1 and CB2, GPR55 receptors are not activated by the synthetic cannabinoid receptor agonist WIN 55212–2 and increase intracellular calcium levels upon activation.

Endogenous cannabinoids

The discovery of the cannabinoid receptors, which mediate the actions of phytocannabinoids, has led to the research of the endogenous ligands that bind these receptors. Several studies have found that Anandamide and 2-AG are the primary endogenous ligands that bind with CB1 and CB2. One these studies shows that Anandamide (AEA) can bind to a cannabinoid receptor acting as a brain constituent, providing further evidence that anandamide is an ‘endogenous cannabimimetic’. The euphoric effects produced during the study were also parallel those caused by psychotropic cannabinoids, such as THC.[4]

AEA and 2-AG are rapidly hydrolysed by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), their respective chief degradative enzymes.  However, there are also other enzymes that play a role in endocannabinoid metabolism. MAGL hydrolysis of 2-AG also represents an important pathway in the production of free arachidonic acid in the brain, which can suggest a role in neuro-inflammation. Inhibitors of FAAH and MAGL as well as genetically modified mice that lack these enzymes were used to elucidate endocannabinoid function, and as a test of their potential as therapeutic agents.

CB1 Receptor

CB1 receptors are expressed in the hippocampus, mesolimbic dopamine areas (ventral tegmental area and nucleus accumbens), cingulate cortex, prefrontal cortex, and cerebellum. Moreover, they have also been identified in the mitochondria, where they may exert effects on memory formation. The wide distribution of this receptor may help to explain the diverse effects in manipulating the endocannabinoid signalling system.

As mentioned before, CB1  receptors are G-coupled receptors, and represent the most prominent G-coupled receptors in human CNS. G-coupled proteins downregulate cyclic adenosine monophosphate (cAMP). CB1 agonism also activates the mitogen-activated protein (MAP) kinase intracellular signalling pathways.

For example, CB1 receptors, acting on presynaptic neurons, may inhibit GABA release but also glutamate levels, with the following modulation and regulation of excitatory processes.

At the very beginning, it was thought that CB1 was only expressed in the brain, but later it was found in the CNS and in smaller amounts in peripheral organs. Its distribution corresponds to the behavioural effects of cannabis:

  • Pleasure,
  • Anxiety,
  • Fear,
  • Panic,
  • Learning and memory,
  • Thinking,
  • Concentration,
  • Movement,
  • Coordination,
  • Increased appetite, and
  • Sensory and time perception.

In short, given the widespread distribution in the brain, as well as among different cell types, CB1 receptors mediate diverse effects. They are responsible for maintaining a delicate balance between neuronal inhibition and excitation, especially in dopaminergic transmission which can suggest that this is where psychotropic effects are mainly produced. [5]

Knowing their distribution and cellular location may allow us to find out where these receptors are involved in potential neurological and psychiatric disorders in order to potentially find a target for pharmacotherapy.

The fact that the CB1  receptor is located on presynaptic terminals of both GABA and glutamatergic neurons has tremendous implications for therapeutic use for phytocannabinoids and endocannabinoids.

Psychotropic Cannabinoids

There is evidence that delta-9-THC can produce psychological changes in human subjects similar to those experienced recreationally with cannabis. However, the naturally occurring delta 8 tetrahydrocannabinol (delta-8-THC) has been shown to be only slightly less potent. It can also potentially contribute to little cannabis-induced ‘highs’ since it is only present in relatively small amounts. In addition, at high doses, the oral administration of cannabinol (CBN) was not producing psychical alterations, but when CBN was injected intravenously, it was found to induce the cannabis-like ‘high’ psychotropic effects.

On the other hand, cannabidiol (CBD) has been found to be psychically inactive when administered both orally and intravenously, even at doses well above those at which delta-9-THC is known to produce its psychotropic effects.

In an experiment, results showed that several of the cannabinoids were able to produce behavioural changes in rhesus monkeys, squirrel monkeys or dogs. This data is consistent with those obtained from human psychopharmacological studies. The results showed that other cannabinoids, such as delta-8-THC and CBN, were all less potent than delta-9-THC and that CBD was psychically inactive.

CBN was reported to elicit no behavioural effects in rhesus monkeys but did produce delta-9-THC-like behavioural changes in squirrel monkeys and dogs. As in the human studies, it was markedly less potent (about 10 times less potent) than delta-9-THC in both tests.

Psychotropic reactions produced by these cannabinoids are very varied, being much influenced by the behaviour of the group, and they can include:

  • It is believed to follow stimulation of the limbic system reward pathways causing release of dopamine from the nucleus accumbens.
  • Giggling or laughter,
  • Visual perception change,
  • Size distance of objects are distorted,
  • Disappearance of perception of time which can lead to a sense of timelessness,
  • Impaired short-term memory and selective attention; the beginning of a sentence may be forgotten before it is finished,
  • User can get easily distracted,
  • Impaired psychological tests such as mental arithmetic, digit-symbol substitution, and pursuit meter tests,
  • Effects may be accompanied by feelings of deep insight and truth,
  • Memory defects may persist for weeks after abstinence,
  • Impaired memory can lead to a less effective concentration,
  • Produce an insensitivity to danger or the consequences of actions. A striking phenomenon is the intermittent wavelike nature of these effects which affects mood, visual impressions, time sense, spatial sense, and other functions.[6]

Nonetheless, the results of the experiments conducted with cannabis can be particularly difficult to interpret. There are three main reasons for this:

  • First, cannabis contains a number of compounds, both cannabinoid and non-cannabinoid, having different pharmacological properties.
  • Second, the chemical composition of cannabis is not always the same. It is affected by heat when smoked and by storage and also depends on the geographical origin of the plant material.
  • Third, and maybe most important, there is evidence that the effects of delta-9-THC can be intensified or attenuated by CBN, CBD and other constituents of cannabis.[7]

Cannabinoids’ synergy: how some cannabinoids may inhibit psychotropic effects

Most cannabinoid-base drugs available under medical prescriptions are THC derivatives, suggested for anorexia and emesis associated with chemotherapy. As a result of systematic activation of the CB1 receptor, the accompanying side effects always include cardiovascular dysfunction, digestion failure, neurological disorders, and the potential for addiction. We can see the success of Sativex in this case. The goal of the research on cannabinoids is to fully explore their promising therapeutic potentials without these adverse psychotropic effects.

Firstly, phytocannabinoids may block the undesired psychotropic effects of compounds targeting CB1 receptor. Although the exact mechanism of how a 1:1 ration of CBD to THC enables Sativex to be well-tolerated by patients is not clear, the addition of CBD certainly contributes to the prevention of the associated side effects.

Secondly, phytocannabinoids alone possess great potential as drug targets. Excluding THC, most of the phytocannabinoids identified so far are non-psychotropic, making them a safer choice and a viable option for drug screening. There have already been encouraging results reported on their therapeutic potential in various diseases.

Thirdly, allosteric modulators designed to modify the effect of CB1 receptor agonists/antagonists may be beneficial in minimizing the side effects. Research has progressed significantly towards this direction in the past few years, with several synthetic or natural compounds characterized as CB1 receptor allosteric ligands. Briefly, CBD may act as an inverse agonist and as a negative allosteric modulator, showing the ability CBD has to counteract or minimise the psychotropic effects of THC, produced through CB1 receptors.

As the main mediator of psychoactive effect of THC, CB1 has garnered tremendous interest over the years. Its widespread expression and versatile functions not only support its promising potential as a drug target for various diseases, but also make the undesired side effects almost inevitable. This complication drives researchers to dedicate more investigations on CB2 and other phytocannabinoids and cannabinoids.[8]

Conclusion about cannabinoids’ psychoactive and psychotropic Effects

In conclusion, it should be known that many cannabinoids are psychoactive, but not all of them produce psychotropic effects. This is why THC is differentiated as it is a psychoactive cannabinoid producing psychotropic effects, by altering the sensorial perception and motor abilities.  It is also known that the CB1 receptor mediates these psychotropic effects, which leads researchers to further investigate other receptors’ roles regarding psychotropic effects as well as other cannabinoids and phytocannabinoids with the ability to inhibit these adverse reactions.

[1] Cabral, G. A., et alt. (2015). Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. Journal of Neuroimmune Pharmacology, 10(2), 193–203. doi:10.1007/s11481-015-9615-z

[2] Mackie K (2007). Understanding cannabinoid psychoactivity with mouse genetic models. PLoS Biol 5(10): e280. doi:10.1371/journal.pbio.0050280

[3] Rosenbaum, D. M., et alt. (2009). The structure and function of G-protein-coupled receptors. Nature, 459(7245), 356–363. https://doi.org/10.1038/nature08144

[4] Fride, E., & Mechoulam, R. (1993). Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. European Journal of Pharmacology, 231(2), 313–314. doi:10.1016/0014-2999(93)90468-w

[5] Atkinson, D. L., & Abbott, J. K. (2018). Cannabinoids and the Brain: The Effects of Endogenous and Exogenous Cannabinoids on Brain Systems and Function. The Complex Connection Between Cannabis and Schizophrenia, 37–74. doi:10.1016/b978-0-12-804791-0.00003-3

[6] Haydock, S. (2012). Drug dependence. Clinical Pharmacology, 136–159. doi:10.1016/b978-0-7020-4084-9.00050-1

[7] Zou, S., & Kumar, U. (2018). Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International journal of molecular sciences, 19(3), 833. https://doi.org/10.3390/ijms19030833

[8] Zou, S., & Kumar, U. (2018). Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International journal of molecular sciences, 19(3), 833. https://doi.org/10.3390/ijms19030833