Spice of Life? The Health Cost of Synthetic Cannabinoids and the Adverse Effects of Full Agonists

An animation symbolising the dreadful health toll of synthetic cannabinoids in the form of a cartoon Egyptian-style eye, reminiscent of the Spice logo, shedding black tears while the image background turns increasingly dark. Artwork: NaturPhilosophie What is Spice?

Synthetic cannabinoids were designed for recreational use. Many used them legally in an attempt to recreate the effects of organic cannabis, or to achieve similar psychoactive effects, until they were banned in May 2016.  But they promised more than they delivered.  Spice is one of them. 

Spice is a cannabis substitute made from a mix of herbs with the addition of lab-synthesised chemicals.

In 2012, 11% of American high school seniors were believed to have used synthetic marijuana in the past year according to a report published by the National Institute on Drug Abuse.  In 2010, this resulted in 11,406 hospital visits to Accidents and Emergency departments.  75% of those involved adolescents and young adults between ages 12 and 29.

Deaths linked to new psychoactive substances – formerly known as “legal highs” – have increased over the past five years, with 114 fatalities registered in England and Wales for 2015.

In the United Kingdom, these substances were banned in May 2016.

However, charities like DrugWise were quick to point out that the government ban had merely driven the market underground.


A photograph showing mylar packets of two different brands of synthetic cannabinoids: Spice and K2, once legally available in the United Kingdom.Synthetic Cannabinoids

Synthetic cannabinoids can be any of a number of different drugs, each one with different effects.

Spice and K2 are only two of them.  But Spice has actually been sold under more than 500 names, including Mojo, Scooby Snax, Black Mamba and Annihilation

These substances can be found in incense products most commonly used for smoking, and are legal in most, but not all, circumstances.  Their legality vary between different states and countries.

Some synthetic cannabinoids are as potent as, if not more potent, than THC, the main psychoactive chemical compound in cannabis.


Herbal Mixes

Herbal mixes have varying effects depending on the cannabinoids present in the mix and their amount.  Herbs listed on the packaging of Spice include Canavalia maritimaNymphaea caerulea, Scutellaria nana, Pedicularis densiflora, Leonotis leonurus, Zornia latifolia, Nelumbo nucifera, and Leonurus sibiricus.

Most synthetic cannabinoids sold legally will be packets of plant matter, sprayed with chemicals, such as JWH-018 or JWH-073 – both of which are analgesic chemicals that are full and partial agonists of the cannabinoid receptors, respectively.

According to Jeneen Interlandi’s The Paradox of Precision Medicine (2016), there is no way in which to describe general effects among all the different chemicals, because they all have different effects.

Each chemical will have different effects at different dosages.  Often, the drugs are crudely manufactured which make it impossible to know what chemicals the drugs contain or how much of any chemical one is absorbing.


The Endocannabinoid System and Associated Receptors

Two diagrams showing the endocannabinoid system in the human brain and body, and its various receptors.The Endo-Cannabinoid System is a group of endogenous cannabinoid receptors located in the mammalian brain and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors.

Known as “the body’s own cannabinoid system”, the ECS is involved in a variety of physiological processes including appetite, pain sensation, mood, and memory, and in mediating the psychoactive effects of cannabis.

Two primary endocannabinoid receptors have been identified:

  • CB1, first cloned in 1990

  • CB2, cloned in 1993.


The Cannabinoid Receptors and the Human Body


An infographic showing the endocannabinoid system inside the human brain and body, in particular the CB1 receptors. Source: Greengeo/Weebly.The CB1 cannabinoid receptor are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), Anandamide, as well as its mimetic phytocannabinoid, THC.

The CB2 cannabinoid receptor, is a G protein-coupled receptor from the cannabinoid receptor family that is encoded by the CNR2 gene in humans.

One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoidCBD.

2-AG and CBD are involved in the regulation of such crucial metabolic functions as:

  • appetite,

  • immune system and

  • pain management.


Relating to one particular case, psychiatrists have suggested that the lack of an antipsychotic chemical, similar to cannabidiol found in natural cannabis, may make synthetic cannabis more likely to induce psychosis than natural cannabis.

The consequences are quick addiction, fast-paced decline, and seemingly irreversible health consequences.


Don’t be Deceived…

Before the ban of “legal highs”, the marketing of synthetic cannabinoids was misleading and led consumers to expect that what they were purchasing was a product which mimics the effects of organically-grown (yet illegal) cannabis.


According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.

The brand “Spice” was released in 2004 by the now-dormant company The Psyche Deli in London, UK.  In 2006, the brand gained popularity.  According to the Financial Times, the assets of The Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007.


Unlike heroin, these drugs have been much more widely used.  When legal, they were quicker and easier to distribute, and they are harder to detect.

Kids started using them much younger than the “organic cannabis generation”.

Be that as it may…

Synthetic cannabinoids FAIL to produce the effects of cannabis.


Synthetic cannabinoids are not only generally more potent than natural marijuana, but they also act in very different ways.



Agonists and Antagonists

Two diagrams explaining the crucial functional and structural differences between a full agonist and a partial agonist. The captions read as follows. Full Agonist: The full agonist can induce a conformational change in the receptor leading to a maximal effect. The ability to induce changes in the receptor conformation leading to activation is a measure of the intrinsic activity. Partial agonist: Partial agonists can induce some degree of receptor activation but not of sufficient magnitude for a maximal response.An agonist is a chemical that binds to a receptor in the human body and activates the receptor to produce a biological response.  An agonist substance is capable of mimicking the physiological effect of a neurotransmitter by specifically interacting with its natural receptors.

  • Full agonist

The full agonist can induce a conformational change in the receptor leading to a maximal effect.  The ability to induce changes in the receptor conformation leading to activation is a measure of the intrinsic activity.

  • Partial agonist

Partial agonists can induce some degree of receptor activation but not of sufficient magnitude for a maximal response.


Whereas an agonist causes an action,

  • an antagonist blocks the action of the agonist and

  • an inverse agonist causes an action opposite to that of the agonist.


THC is a partial agonist.


When compared to the effects encountered through natural marijuana use, the more severe adverse effects are believed to stem from the fact that synthetic cannabinoids are full agonists to the cannabinoid receptors, compared to THC, which is only a partial agonist.


A chart showing the increased potency of a full agonist drug versus a partial agonist.More Problematic than MDMA: Synthetic Cannabinoids

Many of those who use it want to stop, but they find the withdrawal symptoms too intense. Users report waking up covered in sweat, as well as having stomach cramps, nausea, shaking, not being able to sleep, and violent rages.

Such difficulties actually sound like the symptoms experienced by people withdrawing from heroin!

It’s clear that the war on drugs has failed…


The new law banning legal highs may not help with this problem, however much it reduces the number of users by restricting access to the drug.  Those who are determined to use it will continue.

Driving it underground could render it even riskier and more likely to be tainted with other substances.

The main reason Spice has been more prevalent is that it is cheaper and much more potent than weed.  Those smoking it say afterwards they get no effect from smoking skunk.


Adverse effects

A drug overdose is often caused by the combination of two or more depressant drugs, although overdose is possible by consuming a large dose of one depressant drug.  It can also be caused by accidental or intentional inhalation or ingestion of certain volatile chemicals, such as Butanone (contained in plastic cement) or Isopropyl Alcohol.

Although most synthetic cannabinoids exhibit only the typical cannabinoid effects when used at appropriate doses, they are potent drugs capable of causing clinical intoxication and death, possibly due to CNS depression and hypothermia.


CNS Depression

The term ‘Central Nervous System depression’ refers to physiological depression of the central nervous system that can result in decreased rate of breathing, decreased heart rate, and loss of consciousness, possibly leading to coma or death.  CNS depression is specifically the result of inhibited brain activity.

CNS depression are metabolic disturbances such as hypoglycemia.  In the present case, we assume that the CNS depression has been caused by the use of depressant drugs, such as:

  • alcohol,

  • opioids,

  • barbiturates,

  • benzodiazepines,

  • general anesthetics,

  • and anticonvulsants, such as pregabalin used to treat epilepsy.


CNS depression is treated within a hospital setting by maintaining breathing and circulation. Individuals with reduced breathing may be given supplemental oxygen, while individuals who are not breathing can be ventilated with bag valve mask ventilation or by mechanical ventilation with a respirator.

Sympathomimetic drugs may be used to attempt to stimulate cardiac output in order to maintain circulation.  CNS depression caused by certain drugs may respond to treatment with an antidote.

Two antidotes have frequently been used in the hospital setting:

  • Naloxone is an opioid antagonist and reverses the central nervous depressive effects seen in opioid overdose.

  • Flumazenil has antagonistic and antidote properties to therapeutically used benzodiazapenes, through competitive inhibition.  Slow administration of Flumazenil can prevent a seizure.


A diagram showing the main symptoms of Hypothermia, including blueish lips, extreme thirst or dry mouth, rapid shallow breathing, chest pain, pale skin, cool clammy skin. Source: MtrosttotherescueHypothermia

Hypothermia is defined as a body core temperature below 35.0 °C (95.0 °F).  Symptoms depend on the temperature.

In mild hypothermia, there is shivering and mental confusion.

In moderate hypothermia, shivering stops and confusion increases.

In severe hypothermia, there may be ‘paradoxical undressing’, in which a person removes his or her clothing, as well as an increased risk of the heart stopping.

Hypothermia has two main types of causes.  It classically occurs from extreme exposure to the cold.  It may occur from any condition that decreases heat production or increases heat loss, including

  • alcohol intoxication,
  • hypoglycemia (low blood sugar),
  • anorexia, and
  • advanced age.


Vaping Liquid Synthetics

A photograph showing the World's very first e-Joint, designed by a Dutch company. Source: Mirror (2014)
The first e-joint designed by Dutch company. Source: Mirror (2014)

Today, vaping the liquid form of synthetic marijuana is a fast-rising trend, supported by the increasing popularity of e-cigarettes, vape pens and hookah pens – especially in high schools and universities.

The risks of vaping synthetic cannabinoid drugs may be greater than smoking them, for two main reasons:

  • new users have no idea what they are inhaling
  • liquids are easier to mix-and-match to create unique solutions in order to bring up unique mind-bending effects


In parts of the United States, where vaping liquid synthetic drugs has risen in popularity, a number of incidents involving liquid synthetic cannabinoids have been reported.  Although perhaps the most alarming new trend made possible by liquid forms of the drug is the mixing of different drugs to achieve a unique high – like boosting hash oil with a dose of liquid synthetic pot or psychedelic drugs, such as 2C-P.

For example, due to a rash of hospitalisations in Texas, several counties specifically outlawed Cloud 9, a popular liquid form of synthetic cannabinoid.  In Michigan, dozens of teens have been admitted to hospitals after overdosing on Hookah Relax and Cloud 9.

Spice does not show up on ordinary toxicology tests and some think it could be a hidden trigger in violent crimes where there are no signs of mental illness or other drug use.

If cannabis was legal, fewer would turn to these awful spice mixes to smoke.  But of course, that’s a fairly unrealistic policy.

Sometimes drug laws make drugs even more dangerous…