Today I was reading an article on cannabis dosing for beginners, which linked to an article covering something I had not given much thought to despite its increasing importance in the age of legalization. That topic was the interactions of cannabis with other substances.
If you’re using cannabis with other drugs (prescription or otherwise), it’s important to be aware of potential interactions that can occur so you know when it’s safe to light up and when it’s wise to wait. We’ll explore how cannabis interacts with four of the most common classes of drugs: opioids, stimulants, depressants, and hallucinogens.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
One of the most prominent lessons from the article is that it is more helpful to think of cannabis as a cornucopia of different compounds. Though tetrahydrocannabinol and cannabidiol are the well known headliners of the pack, there are but 2 of potentially hundreds of other cannabinoids present in any single batch of cannabis. And each of these cannabinoids tends to react differently with other medicinal compounds. For the sake of simplicity, the word medicinal in this case covers any and all drugs (from caffeine to cocaine, and beyond).
A big part of this is our internal endocannabinoid system.
Cannabis can interact in diverse ways with an incredibly wide variety of substances. One of the reasons is because our bodies are uniquely receptive to the effects of cannabis, courtesy of our endocannabinoid system (ECS).
“The ECS is a vast cellular communication system that intertwines all of our other body systems, and this means that cannabinoids often have overlapping effects with many prescription medications,” said Codi Peterson, PharmD, MS and Chief Science Officer at The Cannigma. “Cannabis is resoundingly safe compared to most prescription medications and even many herbs, but when combined with other substances it does carry some risks.”https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Not only are there multiple compounds within cannabis derivatives,they also tend to behave differently pharmacologically. Though science hasn’t even begun to scratch the surface in terms of cannabinoids, we already know that even THC and CBD are known to behave somewhat unexpectedly in the presence of other compounds.
Peterson also points out that the two major cannabinoids in cannabis, THC and CBD, interact with medications and substances in contrasting ways.
“THC’s drug-drug interactions are typically pharmacodynamic, meaning they change how [another] drug affects us. CBD’s drug interactions are typically pharmacokinetic, meaning they alter how other medication is broken down,” said Peterson.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Another aspect of cannabis that is mentioned is the presence of terpenes and their potential to interact with medications. Though that Avenue is likely many years away from exploration.
How does cannabis interact with stimulants?
Stimulants are substances that speed up the release of certain neurotransmitters such as dopamine, serotonin, and norepinephrine in our central nervous system.
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Stimulants can be prescription drugs (like Adderall for ADHD), legal substances like caffeine, or illegal compounds, like methamphetamine. Here are some common stimulants:
- Ritalin (amphetamine)
- Adderall (amphetamine)
- Concerta (amphetamine)
“Stimulants affect neurotransmitters in the brain to help improve wakefulness and focus,” said Peterson. “If we evaluate the systems in the brain that stimulants (and cannabis) act on, there is a clear overlap of the [endocannabinoid system]. Stimulants and THC can each increase heart rate, racing thoughts, and anxiety, and together, they can worsen these symptoms.”
Peterson explained that the effects of combining stimulants and cannabis depend more on the individual and the dose. For individuals with ADHD, for example, combining cannabis and prescription medication like Adderall, can produce different effects.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Certainly an interesting observation. But it does make sense when you think about it. If you get jittery and antsy with something like coffee alone, adding the potential paranoia and negative emotional experiences of cannabis on top of that likely isn’t going to make for a great experience. And this is just caffeine, the mildest of all stimulants.
Not to mention this potentially worrying side effect:
However, there may also be risks associated with teaming THC with stimulants used to treat ADHD in particular. In a 2015 study that explored the effects of combining THC and the active ingredient in Ritalin, methylphenidate, researchers found that the combination of substances increased the risk of cardiovascular strain, meaning extra stress was placed on the heart.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Something to take heed of if you already have been prediagnosed with heart problems or have high blood pressure.
Mixing cannabis and depressants
Depressants produce opposite effects to stimulants, helping to relax muscles, ease anxiety, and usher in feelings of calmness. High doses of depressants, however, can make individuals feel drowsy and disoriented, and can detrimentally affect coordination and concentration.
Some common depressants include:
- Valium (benzodiazepine)
- Xanax (benzodiazepine)
- Halcion (benzodiazepine)
- Klonopin (benzodiazepine)
Though I was aware of 5 of the substances on that list, Kava was new to me.
Kava kava (Piper methysticum) has been used as a ceremonial drink in the Pacific Islands for hundreds of years. Some people report its effects are similar to alcohol.
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In addition to its ceremonial uses, kava is best known for its relaxing qualities. Kava is said to elevate mood, well being, and contentment, and produce a feeling of relaxation. Several studies have found that kava may be useful in the treatment of anxiety, insomnia, and related nervous disorders.
However, there is serious concern that kava may cause liver damage. More than 30 cases of liver damage have been reported in Europe. However, researchers have not been able to confirm that kava is toxic to the liver. It is not clear whether kava itself causes liver damage, or whether taking kava in combination with other drugs or herbs is responsible. It is also not clear whether kava is dangerous at previously recommended doses, or only at higher doses. Some countries have taken kava off the market. It remains available in the United States. But the Food and Drug Administration (FDA) issued a consumer advisory in March 2002 regarding the “rare” but potential risk of liver failure associated with kava-containing products.https://www.mountsinai.org/health-library/herb/kava-kava
A ceremonial drink of the Pacific islands. That is why I have not heard of it.
Though its effects are compared to that of alcohol, there are clear differences. One being that it seems no one has yet clarified whether or not the compound is toxic to the liver. This caused its ban in Canada and many places in Europe, but not in the United States.
Either way, getting back to the original topic . . .
Depressants commonly work by increasing the activity of the GABA system, another type of neurotransmitter. When GABA activity speeds up, the central nervous system slows down.
“The GABA system serves as the essential ‘brake pedal’ in the brain,” explained Peterson. “Generally speaking, THC acts as a mild depressant, at least at larger doses. Combining depressants (like benzodiazepines) and THC carries an increased risk of sedation.”https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Here we have another new term. What is the GABA system? A complex part of the Central Nervous System.
Gamma-aminobutyric acid (GABA) is an amino acid that functions as the primary inhibitory neurotransmitter for the central nervous system (CNS). It functions to reduce neuronal excitability by inhibiting nerve transmission. GABAergic neurons are located when the hippocampus, thalamus, basal ganglia, hypothalamus, and brainstem. The balance between inhibitory neuronal transmission via GABA and excitatory neuronal transmission via glutamate is essential for proper cell membrane stability and neurologic function.
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Drugs that increase the amount of GABA are commonly used as anticonvulsants, sedatives, and anxiolytics. Due to the increase in GABA, CNS depression is a common adverse effect. Some GABA agonist has addiction potential, and use should be monitored closely. 
- GABAa receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine. Barbiturates include phenobarbital and sodium thiopental. Barbiturates are less frequently used due to the high addiction potential and lack of an antidote. Benzodiazepines have mainly replaced them. Benzodiazepines can treat anxiety, agitation, seizures, and muscle spasms. Only short-term use of benzodiazepine is encouraged. An overdose of benzodiazepines can be fatal due to respiratory depression, especially if concomitant use with alcohol and opioids. Flumazenil is the reversal agent for benzodiazepines. 
- GABAb receptor agonists: Baclofen, sodium oxybate (GHB), propofol. GABAb agonists increase CNS depression. Baclofen is typically used as a muscle relaxant to treat spasticity. GHB is approved for the treatment of narcolepsy. Severe CNS depression is common is GHB. Significant respiratory depression and obtundation are commonly seen. Propofol is used for induction and maintenance of general anesthesia. Adverse effects include hypotension, apnea, and involuntary body movements. 
- GABA analogs: Valproic acid, pregabalin, gabapentin. GABA analogs are used as anticonvulsants, sedatives, and anxiolytics. As with other medications that increase GABA, CNS depression is common in this class of drugs. Valproate is prescribed for the treatment of seizures and mood instability. Pregabalin is used for fibromyalgia, diabetic neuropathy, and postherpetic neuralgia. Gabapentin’s approved uses include postherpetic neuralgia and seizures. Off-label uses include diabetic neuropathy and fibromyalgia. 
Drugs that bind to but do not increase the amount of GABA are considered antagonists. Examples include picrotoxin or bicuculline methiodide. Both are mainly used for research. GABA antagonists are pro-convulsant and stimulants. ,https://www.ncbi.nlm.nih.gov/books/NBK526124/
That is a more detailed explanation of what is going on here, though they lost me at GABA Agonist.
Teaming THC and alcohol, however, produces an additional effect. “When consumed together, alcohol can enhance the effects of THC by allowing THC to enter the brain more easily,” explained Peterson.
“Even a single drink taken with a joint can lead to substantially more psychoactivity than either drug alone,” continued Peterson. “This combination does lead to more significant impairment, and research suggests the combination is frequently involved in traffic accidents, more so than cannabis alone or even alcohol alone.”https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
And THC isn’t alone in terms of interacting with depressants.
“We do know that CBD will interact with benzodiazepines by increasing their blood levels,” said Tishler. Thanks to its pharmacokinetic effect, as mentioned above, CBD can prevent the body from effectively breaking down benzodiazepines, a main class of depressants, which means elevated levels of the drug can stay and circulate in the body.
In one 2019 article, researchers highlighted that CBD taken with benzodiazepines could lead to an increased risk of side effects, such as drowsiness, dizziness and confusion. While these aren’t life threatening, taking both substances at the same time, particularly in high doses, is not recommended.
It’s worth noting that high levels of depressants in the blood can also lead to respiratory depression (slow, ineffective breathing). Tishler points out that this is not the case with all depressants, however, and does not appear to be the case when CBD is consumed with alcohol.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
So CBD + Alcohol likely comes with fairly limited risks. But be wary of CBD and other substances.
Good to know.
Can cannabis be a substitute for opioids?
Opioids work by interacting with opioid receptors in the body, which change the perception of pain in the brain and increase the threshold of pain in the spinal cord.
Some common opioids include:
Though one item on this list was unfamiliar (Tramadol), I was surprised to see 2 of the compounds. Robitussin and Imodium.
As it turns out, both are indeed opioids. This website (operated by the Oregon Alcohol and Drug Commission) does a good job not just outlining many of the different opioids we are familiar with or encounter in daily life but also outlining the difference between opioids and opiates. The former is the product of synthetic engineering, and the latter if the result of processing plant-derived opium.
Getting back to the original topic, we come to the opioid system.
Peterson explains that since the endocannabinoid system and our body’s own opioid system overlap, cannabis can reduce the dose of opioids needed to achieve pain control, thus reducing the risk of opioid overdose or addiction.
According to one study on monkeys, the combination of THC and opioids doesn’t appear to lead to significant cognitive problems, such as impulsivity (which can be a sign of impaired decision-making) or loss of memory. However, mixing THC and opioids may cause the user to feel extra sedated, or sleepy.
“As with any sedative, cannabis can increase the sedative effects of opioids,” said Peterson. “However, unlike opioids, cannabis does not affect the part of our brain responsible for controlling breathing. Despite the increased sedation, the combination is not believed to be more deadly than opioids alone.”https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
The opioid system?
The opioid system consists of three G protein-coupled receptors, mu-, delta-, and kappa, which are stimulated by a family of endogenous opioid peptides.4
mu-opioid receptors are a key molecular switch triggering brain reward systems and potentially initiating addictive behaviors. The lack of mu-receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. This receptor therefore mediates therapeutic (analgesia) and adverse (addiction) activities of morphine, suggesting that further development of morphine-like compounds may necessarily lead to addictive analgesics.
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The rewarding properties of both opioid, as well as non-opioid drugs of abuse (cannabinoids, ethanol and nicotine, natural reinforcers) are abolished in the mu-receptor knockout mice. Blocking the mu-receptor may build a valuable approach for the treatment for drug abuse.
Beyond the rewarding aspect of drug consumption, pharmacological studies have also suggested a role for this receptor in the maintenance of drug use, as well as craving and relapse. As a consequence, expanding our understanding of mu-receptor function should greatly help to further our knowledge of the general mechanisms that underlie addiction.https://www.sciencedaily.com/releases/2007/10/071014163647.htm
The human body certainly is a complex machine. And we’re just scratching the surface.
Cannabis may complement hallucinogens
Of the four major drug categories, we probably know the least about the consequences of mixing hallucinogens and cannabis.
Hallucinogens are a group of substances that ignite psychedelic effects, such as altering perception, mood, or thought processes. While many have their own specific mechanism of action, one mechanism that they all share is the activation of serotonin (5-HT2A) receptors.
Some common psychedelics include:
- Psilocybin (the active compound in magic mushrooms)
- Dextromethorphan (found in cough suppressants such as Dimetapp or Mucinex)
Now we come to the fun stuff. Though I have only ever used one item on the list by accident (my very first dose of cannabis was mixed with Salvia. Leftover in a 2L lung from a previous smoking session), I would likely only consider doing one item on this list (psilocybin). Maybe 2 (Mescaline). The rest I am either not in the correct headspace for (LSD, DMT), or their potential for adulteration or ill health effects scares me (Ketamine, MDMA).
As for salvia and cough medicine, it’s hardly worth bothering when cannabis is legal in Canada. Edibles taste a whole lot better than something that may make me throw up.
THC can also be considered a hallucinogen when taken in high doses. Peterson points out that there’s some overlap in how psychedelics and cannabis work on the body. However, he also acknowledges that the interactions of cannabis and psychedelics may boil down to a question of dose and individual tolerance.
“The serotonin system (activated by psychedelics) is directly connected with the endocannabinoid system,” said Peterson. “Many consumers report enhanced psychoactivity with the combination, but others have reported it helps to mellow out the tripping experience. Using too much of either substance can be overwhelming.”
Peterson emphasizes that the most important thing to remember is that even if the combination of both feels intense, the safety profile of psychedelics and cannabis are very good and unlikely to cause major issues.
“There’s little data at all for mixing hallucinogens with cannabis, but years of common experience has not shown any overt problems,” added Tishler.
Of the little data that does exist, recent research shows that mixing psychedelics and cannabis can enhance the mystical, awe-inspiring experiences that sometimes accompany psychedelic trips. Combining psychedelics with low doses of weed also appeared to reduce the chances of experiencing a bad trip, while high doses elevated feelings of both fear and “insanity” (the term used in the study).https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
So aside from temporarily losing your mind, mixing hallucinogens can be a relatively risk-free experience. Though I will not say this about Ketamine, which is shown to have medical risks (particularly with prolonged use).
How does cannabis interact with prescription medications and other substances?
Beyond these four major classes of drugs, there are other medications and compounds with which cannabis can interact.
“Of the cannabinoids that we know about, thankfully THC doesn’t interact much,” said Tishler.
“CBD, on the other hand, interacts with a wide range of common medications, even over the counter meds.”
Examples of such medications include blood thinners like Warfarin and Clopidogrel; common heart medications like Amiodarone; immunosuppressive medications used for transplant patients like Tacrolimus, and antihistamines like Loratadine (also known as Claritin). There are even lists available detailing such interactions.
CBD inhibits the metabolic pathway used by these drugs, similar to other natural compounds like grapefruit or St. John’s Wort. When this pathway is suppressed, medications take longer to be metabolized or broken down by the body, so levels of the drug can accumulate and circulate in the blood for longer.
This in turn increases the likelihood of side effects, so if you’re thinking about using CBD, or cannabis in general, and you’re taking a prescription medication, it’s vital to chat with your doctor first.https://www.leafly.ca/news/health/how-does-cannabis-interact-with-other-drugs
Interesting. Though I hate the taste of grapefruit, I have always wondered why doctors often told people to avoid them while on certain medications. Now I know.
In closing, if you take nothing else from reading this, do not assume that just because THC and (particularly) CBD have a reasonably benign reputation when used in combination or on their own, they will be similarly benign when mixed with other substances.
Ask a medical expert and do your research.