Is CBD a Placebo or Does It Work? What Does Research Show?

It's an important question to ask.

After all, placebo is involved in almost every medication or supplement that we take.

It's the powerful effect of expectations...the sheer strength of the brain.

We'll look at that more closely below but back to question.

Is the effect of CBD due to the placebo effect? Does it really do anything in the brain or body outside of placebo?

Let's get into it.

We'll cover these topics:

• A quick introduction to the placebo effect
• CBD's main effects in the body
• CBD versus placebo according to research
• CBD versus placebo for side effects
• Research on what dose for CBD to have real effects

Here we go!

A quick introduction to the placebo effect

The best studies incorporate two elements:

• Double-blind - the researchers do not who is receiving what
• Placebo controlled - a separate group of people receive a non-acting substance

The latter is critical!

We've read 100's of studies on CBD and without fail, you'll have three results.

• Control group - Receives nothing and has the least change
• Test group - Receives the substance and has the most change (if applicable)
• Placebo group - Receives a dummy substance and the effect lies somewhere in between the top two

Just how strong is the placebo effect?

A study looked at the placebo effect for migraines and found the following:

The researchers discovered that the placebo was 50% as effective as the real drug to reduce pain after a migraine attack.

https://www.health.harvard.edu/mental-health/the-power-of-the-placebo-effect

This effect is the result of a complex brain interaction involving various neurotransmitters such as endorphins (natural opioids) and dopamine (our reward circuit carrier).

We can now see this effect on brain scans:

According to a report published today in the Journal of Neuroscience, all of the participants who were told to expect medicine but got a placebo instead showed an increase in the activity of their endorphin system.

https://www.scientificamerican.com/article/brains-own-pain-relievers/

It's not just pain though as other studies have looked at seemingly immutable physical processes such as drops in respiration (breathing).

Pain, however, along with psychological stress, are both complex systems and very much under the sway of the placebo effect.

Another study worked with pain in athletes and gave one set morphine and another set, a salt solution. The results?

The results were remarkable: patients in both groups reported the same degree of pain relief.

http://sitn.hms.harvard.edu/flash/2016/just-sugar-pill-placebo-effect-real/

So the placebo effect is powerful...especially in areas that are the result of complex brain connections (pain, anxiety, depression, etc).

Before we jump into CBD's comparison with the placebo effect, let's first introduce what CBD is purported to do.

CBD's main effects in the body

We'll compare CBD with placebo below but if CBD is to work, what areas are most promising and how does it work?

First, we have to introduce the endocannabinoid system.

It's a check and balancing system that's tasked with managing other key systems:

• Endocrine system - hormones
• Immune system - inflammatory processes and cellular birth/death cycles
• Nervous system - neurotransmitters and the messengers of the brain and nerves

CBD works within this system alongside natural cannabinoids that we all have (2-AG and anandamide being the big ones).

There are key pathways that we have more research on:

• CBD works as a feedback mechanism for serotonin
• CBD has been shown to modulate (up or down) immune or inflammatory response
• CBD modulates both GABA and glycine, our main calming neurotransmitters
• CBD modulates opioid pathways
• CBD affects TRPV and PPAR plus many smaller pathways

One of our favorite NIH charts is here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345356/table/T1/

It shows the various effects.

The term "allosteric modulator" is very important. Many substances will increase or decrease a pathway.

This rarely works out long term as the ability to "overshoot" in critical brain pathways never feels good.

For example, benzos boost GABA activity in one direction.

This not only leads to side effects but also to tolerance where the brain starts to push back the other way.

CBD doesn't have this driving effect.

The best example of this is with cancerous cells:

• Healthy cell with low inflammation - CBD has no effect
• Healthycell with high inflammation - CBD reduces inflammation
• Cancerous or virally infected cell - CBD INCREASES inflammation

Read that back over...it's very telling.

The third effect doesn't make sense till you understand that the body naturally uses inflammation (oxidative stress actually) to kill wayward cells.

Three different results depending on the state of the cell or neuron.

Back to our main targets above.

CBD and Serotonin pathway

Serotonin is probably the biggest player.

It's a master regulator of brain function tied in with EVERY human behavior.

Downstream, it manages dopamine which is key for addiction and mental health.

Dopamine breaks down into norepinephrine...the adrenalin pathway.

Check out CBD and serotonin or CBD and dopamine.

This alone would be a coup but that's one effect albeit a powerful one.

Mental health. Gut health (serotonin is a big player there). Pain. Addiction. Stress response.

All are directly affected. Really check out the serotonin review above...it's fascinating!

CBD and Immune response

Then there's the new world of inflammation. It's tied into every health issues these days (mental and body).

CBD can have different results depending on the state such as the cancer example above.

After all, the immune system is tasked with maintaining healthy cells and neurons.

This directly ties into a slew of health issues from diabetes to pain to every mental health issues you can think of.

CBD has been shown to calm inflammatory responses including:

• Microglia (the sentinels of the immune system in the brain)
• Cytokines - the inflammatory agents of the immune system

Next up, a big one you may not know.

CBD and GABA/Glycine pathways

GABA is the "brake" pedal of the brain and nervous system. Glycine is a partner in crime there.

The opposing force is glutamate, our "gas" pedal.

The balance between these agents is critical for anxiety, depression, mental health, seizures, and pain.

Actually, glutamate is starting to show in all the new research. It's a major player when imbalanced.

Check out CBD and GABA or CBD and glutamate. It's a new dawn for mental health in terms of this pathway.

Then there's our "pain" pathway.

CBD and opioid pathway

We have to stop thinking of opioid pathways as being just for pain.

Yes, they are the primary actors for pain response (along with guidance from serotonin and glutamate).

When you get into the brain however, opioids wear many hats. This system is so complicated and varied that they're just starting to tease out how it's intertwined into everything.

Instead of thinking of opioids as strictly a pain suppressing mechanism, look at them as a way to move action. A positive (and sometimes negative - dynorphin) response which shapes behavior.

Check out CBD versus Tylenol to get into the pain side.

Finally, there's the stragglers.

PPAR. TRPV. GPR55. GPR18.

These various pathways have many effects throughout the body and brain. Check out GPR55 and anxiety as one example.

So...we've covered some of the targets and expected results of CBD.

Let's now see how much is CBD and how much is placebo.

CBD versus placebo according to research

We'll focus on CBD studies that incorporated placebo controls.

First, how CBD really came to fame. Epilepsy.

This is primarily a disease of glutamate/GABA imbalance. The gas pedal of the nervous system is left on with little (or exhausted) brake.

A double-blind, placebo study found the following for CBD treated patients:

Four of the epilepsy patients receiving CBD were “almost free of convulsive crisis” for the duration of the study. Three other patients receiving CBD had a partial reduction in seizures, and 1 subject had no response.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189631/

And for the placebo?:

Of the 7 patients receiving placebo, seizure frequency was unchanged in 6, and 1 had clear improvement in seizure control.

So out of 7 with CBD:

• 4 stopped convulsions completely.
• 3 had partial reductions
• 1 had no effect

For the 7 in the placebo group:

• 6 had no effect
• 1 had improvements (wow...placebo was powerful here)

Epilepsy has a clear biological and more specific pathway (glutamate) so you would expect less placebo effect there.

Let's move on.

Animal study for dementia with CBD versus placebo

A breed of mice has been genetically bred to develop dementia.

Researchers compared CBD versus placebo for plaque formation and resulting deterioration in social interaction:

CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.

This did not occur in the placebo group.

More importantly, they can drill down to the actual mechanisms involved:

Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment.

Those are both inflammatory markers and CBD reduced their levels to those of normal mice.

Check out CBD and neuroinflammation for more info.

• Placebo effect can't decrease inflammatory markers (at least in any study we've seen).
• Again, inflammation is tied to almost every health and mental health issue we come across.

Then there's addiction.

This may be one of CBD's greatest strengths (see CBD and addiction).

One example (of dozens) is for opioid withdrawal and the effects versus placebo:

Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues.

https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.18101191

More on that at our CBD and opioid addiction page.

Let's turn to some issues which are more nuanced and definitely under the sway of the placebo effect.

Anxiety is first stop.

This is a fascinating study. It looks at participant's response to fear...a key initial pathway for anxiety (and PTSD, psychosis, etc).

The results of a placebo controlled study:

These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.

https://pubmed.ncbi.nlm.nih.gov/23307069/

Let's explain since it's a bit technical.

Basically, CBD aided in the ability to forget bad memories and their emotional context.

It's called fear-extinction.

Check out CBD and anxiety for more info. We've written dozens of review on CBD and anxiety with no stone left unturned.

What about studies on actual anxiety?

Here's a placebo controlled study on social anxiety disorder (SAD).

The results:

SAD symptoms were measured at the beginning and end of the treatment period using the Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale. CBD significantly decreased anxiety measured by both scales.

The comparison of the placebo group and CBD?

CBD dropped the main score (FNE score) from 24.4 to 19.1
Placebo went from 23.5 to 23.3

Anxiety involves GABA (see CBD versus benzos), serotonin (CBD versus SSRIs), inflammation, and glutamate as key pathways. All of those are affected by CBD.

Let's go to the extreme...psychosis and schizophrenia.

A double-blind study compared CBD, placebo, and even a common anti-psychotic, amulsipride.

This is the best of both worlds..compare a placebo and another medication.

The results:

the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099166/

So...it had the benefits of amulsipride on schizophrenia symptoms but with the side effect profile of the placebo!

Amulsipride, like most antipsychotics, can have brutal side effects.

We're not surprised...they hammer dopamine down in the brain.

Dopamine, like serotonin, is so integrated throughout the brain that pushing it up or down in one direction is tricky.

Check out CBD and schizophrenia, CBD and bipolar, or CBD and paranoia as examples.

We could go on and on but hopefully, you see the pattern. You can check out any given issue to see more detail research at our A-Z list of CBD effects here.

Speaking of side effects, we can look at placebo effects to figure out CBD's side effect profile.

CBD versus placebo for side effects

You can give CBD to one group and placebo to another and then look at the reported side effects.

One note...we're only looking at CBD isolate, not the full spectrum that's being pushed by the market.

Read up on CBD isolate versus full spectrum but full spectrum may indeed have more side effects than CBD isolate especially for people with histamine (allergic) issues.

So..what does research show?

We saw how CBD at a very high dose (600-800mg) in the schizophrenia study above had the same side effect profile as the placebo group.

What about other studies?

There's a great review of CBD studies and side effects here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092763/

One study reported that side effects did not differ between the CBD and placebo groups after 8 weeks of follow-up [36], and another study reported a decrease of AEs 12 weeks after CBD initiation [38].

AE is adverse effects. Side effects. The key there is long term CBD use (see Can I take CBD long term?).

There's a huge review of many different studies versus placebo here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092763/

Another study looked at very high doses of CBD ( 1500mg) with the following conclusion:

CBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223703/

1500mg is very high. That study actually went up to 6000 mg! 6 grams.

So how much is shown to be effective?

Research on what dose for CBD to have real effects

Studies on neurogenesis show a peak effect at 300 mg per day. Check CBD and brain repair for more info.

Above 300 mg, that effect starts to go away.

The range of studies referenced in the links above generally show from 300-800 mg depending on the situation.

Sleep aid was shown at 160 mg.

Since so much of the mental health research points to this effect, 300 mg appears to be the long term dosage for affecting change beyond placebo.

Higher doses were used for acute issues (public speaking, panic attacks, psychosis, etc) but 300 mg is the long term target.

Generally, a good trial amount is around 40mg to see how you feel.

This brings up a good point...the type of CBD matters.

Best CBD for effects beyond placebo

First, there are basic requirements:

• Organically grown in the USA at FDA registered farms
• 3rd party tested
• CO2 processed
• No THC
• No Pesticides
• No Heavy Metals
• No Solvents
• No Bacteria
• No Mold

We actually test ours twice since our whole family uses it.

Next up is the question of CBD isolate versus full spectrum.

All the research above is based on CBD isolate.

Full spectrum introduces many different chemicals that have their own effects.

The biggest issue is that 40-60% of the population has histamine issues.

This gets worse as we get older and for women.

We see many people have side effects from full spectrum that go away with CBD isolate.

That's why we focus on isolate (and all the research).

Then there's the cost?

At 300 mg levels, the cost per mg of CBD is critical.

We purposely price our CBD oil at 2-3 cents per mg before discounts up to 30%.

It's the lowest priced, high-quality on the market since research is pointing to 300 mgs to be effective (and not just one more placebo effect).

Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.