We've noticed a big push lately in advertising and "articles" for ketamine and depression.
This is fascinating to us.
It's being described as a wonder cure and the buzz is definitely being pushed everywhere.
We'll dive into how ketamine works but the articles are missing one all-important piece…tolerance.
Tolerance is the gorilla in the room and it has to be addressed.
More importantly, there are ways to affect the same pathways but without tolerance.
We'll look at how CBD figures in here.
Let's get started…here are the topics:
- How ketamine works for depression and pain
- How CBD works for depression and pain
- Can you develop tolerance to ketamine
- Can you develop tolerance to CBD
- The all-powerful BDNF pathway and ways to support it
- How much CBD to match the benefits of ketamine
- What's the best CBD to take in order to replace ketamine
Let's get started.
How ketamine works for depression and pain
Ketamine's initial trigger is to boost the function of glutamate, our brain's "gas" pedal.
It does this by "antagonizing" NMDA receptors where glutamate plugs in. This allows more glutamate to be available.
Glutamate is a fickle beast and we have systems in play to keep it under control since it can be e toxic to cells/neurons if too strong.
That's the initial response but the real star is behind the curtain and that's BDNF.
Ketamine may increase glutamate levels and lead to synaptogenesis and elevated levels of brain-derived neurotrophic factor (BDNF).
BDNF is short for brain-derived neurotrophic factor…the brain's fertilizer!
We did a deep dive on how SSRIs really work (till tolerance kicks in) and lo and behold…it was BDNF pulling the strings.
Essentially, you can think of depression as a pulling away of neurons and brain connections. Atrophy.
Usually at the hands of:
- Stress (see stress and mental health)
- trauma (see trauma and mental health)
- Infection (see the immune system and mental health)
- loss of hormones (see estrogen and mental health)
Trauma is a big one…even early trauma or infection can trigger effects later in life.
BDNF is the counter to all these insults.
In fact, when BDNF was blocked, neurogenesis (brain repair) and antidepressant effects of SSRIs are blocked. See research on how SSRIs really work.
BDNF is your new best friend and we'll look at ways to boost it AND calm the insults.
It's one of the key reasons (along with stress) for relapse (see CBD and addiction).
So..what's the connection with ketamine?
We observed higher relative levels of BDNF 2 h and 24 h after ketamine compared to placebo.
That's it! This is why ketamine is given in hospital settings for suicidal situations.
See why BDNF needs to be your best friend?
So ketamine leads to hyperactivated glutamate pathways with the following effect:
Glutamate stimulates the production of BDNF in neurons, and BDNF promotes neurogenesis,.
Okay…we have that circuit…what about pain?
As for pain, remember that ketamine blocks the NMDA receptor and as a result:
Regarding pain, the NMDA receptor is involved in the amplification of pain signals, the development of central sensitization, and opioid tolerance.
Glutamate is a workhorse in the nervous system and as a result, a slew of downstream pathways (serotonin, opioid, etc) are also affected.
Remember…ketamine was originally prescribed as an anesthetic.
This all sounds too good to be true. The issue is tolerance and we'll look at that below.
For now, understand that glutamate is our primary lever with ketamine and as a result, many downstream players also come into play.
BDNF is THE trigger for depression effects.
Let's turn to CBD.
How CBD works for depression and pain
CBD works very differently.
It essentially supports a key pathway called the endocannabinoid system.
This system is tasked with balancing almost every important system in your body including:
- Nervous system - neurotransmitters like glutamate, GABA, serotonin, and more
- Immune system - inflammatory and repair pathways including BDNF
- Endocrine system - hormones like cortisol (stress) and steroidal hormones
- Opioid system - pain; both physical and psychological
The big star of this system is anandamide, our "bliss" molecule. It's a massive stress-response buffer essentially.
The key is that CBD doesn't just pump up anandamide-like activity (the way THC does). It supports it when low.
Like a feedback mechanism! It slows the enzyme (FAAH) that eats up anandamide.
THC imitates anandamide and that's why you can build tolerance to it long term. As well as have side effects.
We don't see tolerance, addiction, or psychoactive effects with CBD.
So…let's touch base on just a few pathways mentioned above.
- Serotonin - key stress response and mood manager
- GABA/Glutamate - excitability players
- BDNF - the star of the depression show!
- Anandamide (pain pathway)- key pain pathways (see endocannabinoid deficiency
Let's start with serotonin since that's the target of SSRIs (see CBD versus SSRIs).
CBD is an allosteric positive modulator for serotonin.
This means it supports serotonin WHEN LOW.
A study looked at CBD's effects hereafter serotonin was exhausted by physical pain (serotonin is a massive pain sensitivity manager):
repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
- Reduced pain (analgesia)
- Reduced anxiety (emotional pain is the same as physical pain to these systems)
- "Rescue" serotonin (5HT)
This is important…we don't want to pump serotonin up in one direction as that's just as bad as too little (see serotonin syndrome).
We have a whole review of CBD and serotonin here.
Then there's the all-powerful GABA/glutamate excitability balance.
This is literally the brake and gas pedal of the brain. Remember that ketamine causes hyperactivity of glutamate (gas pedal) which drives BDNF.
CBD actually works to balance it with the support of GABA (target of benzos).
Interestingly, it can have different effects in different brain areas depending on the state of the system.
A study looked at autism where glutamate/GABA is upside down in certain areas and found the following:
Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant.
This is fascinating! In people with autism, CBD dropped GABA in the prefrontal cortex exactly where those people needed less (so glutamate could be higher).
It's pushing back against cortisol (stress), histamine (allergy), and glutamate!
So…if glutamate isn't being spiked like with CBD, what about BDNF?
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex
We could probably drop the mic right there but we'll continue.
The Prefrontal cortex is the all-important locus of human thought and atrophy there is intimately tied to depression, anxiety, and a host of mental health issues.
See our review on neurogenesis (mindful meditation and exercise also help there) or our review on BDNF.
Serotonin is a big manager of pain sensitivity and too much glutamate can burn out pain receptors in the body.
What about the pain directly pathway?
This gets interesting!
The primary endocannabinoid in the nervous system is called anandamide. It's named after the Hindu goddess of bliss.
THC imitates and boosts activity too hard and for too long (hence tolerance with longer-term use).
Anandamide is the water on a fire when out of control (in this case, pain).
In fact, there are people (very few for good reason) who can't make the enzyme (FAAH) that breaks down anandamide.
They are unable to feel any pain. Zero. See our review here.
But…if we can nudge FAAH down, it will bring down pain sensitivity body-wide.
CBD also inhibits FAAH, which results in increased anandamide levels.
But not excessive like THC! We don't see the side effects (high, paranoia, etc).
There are other pathways involved with pain (COX2, PPAR, TRPV, etc) that are affected by CBD. We'll leave that to our CBD and pain review.
Now…let's turn to the really big difference.
Can you develop tolerance to ketamine?
First, a quick intro to the process of tolerance.
If a substance pushes a key pathway exclusively up or down (called agonist or antagonist) in the body, the body will start to push back.
Let's use THC as an example. It stimulates CB1 receptors similarly to anandamide.
One time and you may temporarily exhaust that activity (the hangover) but more regularly and the body will start to reduce your natural levels of CD1 activity and even numbers.
It takes a good 30 days after non-use for the DNA to turn on that makes those receptors.
The initial period is what we call "withdrawal" and it can be brutal because your "bliss" molecule is so low.
What about ketamine?
It started in animal studies:
Although the result of the initial injections confirmed a clear behavioral effect of ketamine injections in all monkeys, subsequent administrations showed that a tolerance eventually appeared in all monkeys.
Which continued on:
Sensitization occurs at short or long treatment intervals and at a broad range of doses, and, like other drugs of abuse, is enhanced in the presence of specific environmental cues (Heller and Trujillo 2007).
If we truly have tolerance, there should be a withdrawal from coming off of it (because our pathways are downregulated).
There's a list of withdrawal symptoms here:
Mainly psychological in nature.
Remember…we've been ramping up glutamate, the workhorse of the brain. You don't get more cog and wheel than glutamate.
Ketamine is actually an analog or a slightly different chemical version in the same family as PCP. Both work on NMDA receptors (glutamate) but ketamine is about 1/10th the strength.
This is tricky and it's why both are used (at higher doses) to study psychosis.
The bigger issue for us is excessive glutamate.
Glutamate is toxic when too high. It's like redlining a car engine…but to neurons!
More importantly, the NMDA receptor is key to brain plasticity…learning, changing, repair.
If we're slowly downregulating this activity from ketamine use, the withdrawal is going to be pronounced.
In experimental settings, acute sub-anesthetic doses of ketamine produce a reliable transient decrease in cognitive performance (Morgan & Curran, 2006).
There's a lot of interesting research on ketamine use in that report.
The key takeaway is that tolerance is a game-changer.
If you stay on a drug that causes tolerance, you're slowly going backwards. If you come off of it, you're now in freefall (natural levels are lower and drug effects are gone).
Tolerance is the most important medicine and drug term your doctor has never told you about!
Check out the book Never Enough, but Judith Grisel. Fabulous introduction.
What about CBD?
Can you develop tolerance to CBD?
CBD does not build tolerance, is not psychoactive, and is not addictive.
They also conclude from their survey, that none of the studies reported tolerance to CBD
If CBD has such powerful effects on key pathways (serotonin, GABA, inflammation, opioid, etc), how is it possible that it doesn't cause tolerance?
Let's introduce the endocannabinoid system.
It's a stress-response system that tries to balance other key systems:
- Nervous system - neurotransmitters like glutamate, GABA, serotonin, etc
- Immune system - inflammation and cellular birth/death cycles (BDNF fits in here)
- Endocrine system - hormones including cortisol (stress) and steroidal hormones
- Opioid system - pain; both physical and psychological.
CBD doesn't directly pump up these pathways but acts as an allosteric positive modulator.
Technically, this means a feedback mechanism!
For example, serotonin and GABA (the counter to glutamate), it supports when too low.
Our favorite example with cancer:
- Healthy cell or neuron with low inflammation - CBD has no effect
- Healthy cell or neuron with high inflammation - CBD reduces inflammation
- Precancerous or virally infected cell - CBD INCREASES inflammation
Three different results depending on the state of the INDIVIDUAL cell (surrounding cells were affected according to their state).
The net net…CBD does not cause tolerance, addiction, or psychoactive effects (like THC) since it doesn't just push these pathways in one direction.
Don't take our word for it:
Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD.
Let's turn to BDNF, our new best friend for depression and mental health.
The all-powerful BDNF pathway and ways to support it
As we noted above, BDNF was the surprise actor for depression with ketamine and CBD.
How can we boost this?
Ketamine does it (but with tolerance and side effects). CBD definitely does it in the brain areas most under assault (prefrontal cortex and hippocampus).
Exercise and mindful medication directly boost BDNF (see review here).
NAC can also support BDNF as does medicinal mushrooms (plus NGF, another brain fertilizer).
That's quite a line-up:
- Mindful meditation
Of course, the new research on psilocybin (magic mushrooms) is incredibly impressive. It will completely overturn mental health treatment over the next 5 years.
Psilocybin does not build tolerance!
Make sure to test and support steroidal hormones since estrogen and testosterone both drive serotonin and thus, BDNF. Vitamin D is critical as well (so many people are deficient).
There's also the question of reducing stress, inflammation, and damage that exhausts BDNF.
These above all work on that as well but we can add in:
- Berberine - gut inflammation which sets thermometer for the brain
- Vitamin D - calms inflammation
- Magnesium glycinate - powerful stress and inflammation calming agent
These are all safe options to look at. Speaking of safety.
Safety and side effects between CBD and ketamine
Night and day.
Remember, ketamine is a cousin of PCP at 1/10th the strength.
The side effect profile is pretty wild as a result.
A double-blind, placebo study looked at ketamine in subanesthetic levels on healthy individuals:
These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
For short term use in a study for depression:
Eight of these symptoms occurred in more than half of participants; these were feeling strange, weird, or bizarre; feeling spacey; feeling woozy or loopy; dissociation; floating; visual distortions; difficulty speaking; and numbness.
Long term?? We don't have great studies on that.
Our 2 cents…if tolerance is involved, they're not going to be great so you're probably not going to see them since ketamine is now squarely under the edifice of Pharma.
As for CBD, the side effects up to levels of 600-800 mgs are very mild. They've even tested up to 1gram and beyond.
A large review on multiple studies:
Regarding safety issues, most studies reported no AEs with acute administration and mild to moderate adverse effects with chronic administration. In comparison to other drugs, a better side effect profile was presented
Check out further research on CBD safety here.
Again, the tolerance piece is a deal-breaker.
Let's look at practical questions.
How much CBD to match the benefits of ketamine
We actually have some research on this if BDNF and neuroplasticity is our goal (which it is!).
300 mg is peak CBD per day for neurogenesis. After that level, it starts to go down but still benefits this pathway.
At the 6000 mg level, you could do ½ a dropper 3 times daily to reach this level.
Holding the CBD oil under your tongue for up to 60 seconds can boost availability and after means so the liver is busy.
Some effects are immediate (GABA, stress response, inflammation, etc) while the BDNF piece (via serotonin) takes about 2 weeks to kick in.
The type of CBD is also critical.
What's the best CBD to take in order to replace ketamine
First, basic requirements:
- From organically grown hemp in the USA at FDA registered farms
- CO2 cold-processed
- Third-party tested (easy to find)
- No THC (THC builds tolerance…just like ketamine)
- No solvents
- No heavy metals
- No pesticides
- No bacteria
- No mold
Our third party testing is available at the top of each page
Then there's full spectrum versus CBD isolate.
The research is all on CBD isolate (CBD by itself) yet most of the market is pushing full spectrum.
Here's the issue…40-60 of the population has histamine issues and that number goes up as we get older for women (as progesterone leaves the scene).
There are very different responses between CBD isolate (the research) and full spectrum as you can see from the product reviews.
If we're looking at depression, there's clearly a tie of calming brain inflammation and histamine is a part of the heightened immune response.
Then, there's the cost!
If peak neurogenesis is 300mg daily, the cost per mg of CBD is the critical piece.
We price our 6000mg bottles (½ a dropper is 100mg so perfect for 3 times daily with meals) at about 2-3 cents per mg of CBD before discounts up to 50%.
It's really important that people can afford this option.
Check out our full review on CBD and depression here.
Be well. Take care of each other. Take care of yourself!
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.