Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. Research is very scarce on the interactions involving cannabis & serotenergic psychedelics. Since they are in different classifications, there doesn’t seem to be as much cross-tolerance possibility as there would be with mushrooms and LSD for example. Nevertheless here an attempt to summarize the relevant research.


Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey

https://pubmed.ncbi.nlm.nih.gov/34734314/

published in Psychopharmacology Nov.2021 (involved 321 people)


Key takeaway/findings- “The simultaneous use of cannabis together with classic
serotonergic psychedelics (this includes LSD) was associated with more intense
psychedelic experience across a range of measures”
One article also looked at this study as well and stated “For example, people who mixed
their psychedelics with low doses of cannabis tended to obtain lower scores on both the
“fear” and “insanity” subscales than those who used no pot at all. However, the use of
high doses of cannabis appeared to enhance both of these unpleasant aspects.”
https://www.iflscience.com/brain/what-happens-mix-cannabis-psychedelics/


A comparison of LSD-25 with (−)-Δ9-trans-tetrahydrocannabinol (THC) and attempted cross tolerance between LSD and THC
https://link.springer.com/article/10.1007/BF00403684https://link.springer.com/article/10.1007/BF00403684
This is one of the oldest references from 1969 and the PDF is behind a paywall but the
summary says that “The objective effects of LSD and THC differed markedly. LSD
increased body temperature, systolic and diastolic blood pressure, lowered the threshold
for the knee-jerk, and dilated the pupils. THC had none of these effects but caused more
marked tachycardia than did LSD.” and that “Patients tolerant to LSD were not crosstolerant to THC, indicating that the mental effects of the two drugs are probably mediated by different mechanisms.” Sample size was small though on this one with only 8 subjects


Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through
Akt/mTOR pathway

https://www.nature.com/articles/s41386-018-0076-y

Neuropsychopharmacology 43, 2028–2035 (2018).
This study was from 2018 and was on animals so it is not entirely conclusive but it states, “In summary, the present study demonstrates that chronic THC exposure leads to the overactivation of a pro-hallucinogenic signaling pathway of 5-HT2AR through the regulation of Akt/mTOR pathway.” This study suggests that similar receptors are being affected, which underscores the need for caution if you are a heavy user of cannabis.
Also see this article in the Psychedelic Science Review, which focuses on the 5 HT2A receptors


Given there is very little established research specifically on the cross tolerance aspect, we can take a look at some firsthand accounts.


USER REPORTS
Here are a few reports from anonymous Reddit users
‘Weed & psychs are completely different from one another. Smoking before a trip like the day before wouldn’t affect ur trip, but lighting up during ur trip would surely have an affect (depending on how high your weed tolerance is too) ‘
‘Depends how much you smoke, and what your smoking. Weed will make everything more intense, including the hallucinations which I love. For me weed & lsd is the pure happiness, but that’s because I don’t overdo it, I know my sweet spot. Once you find your sweet spot you’ll never experience a bad
trip, trust me. Don’t be an idiot and smoke as much as you can to be “cool”. There’s nothing cool about a potentially life scarring trip. So just ease into it.’
‘Is mixing a bad idea? It is for many people; cannabis can potentiate lsd in powerful and
unpredictable ways and result in a bad trip.


Per Psychonautwiki:
Cannabis has an unexpectedly strong and somewhat unpredictable synergy with LSD,
strongly intensifying its sensory and cognitive effects. Caution is advised when using this
combination as it can significantly increase the chances of negative psychological effects
like anxiety, paranoia, confusion, panic attacks, and psychosis. Users are advised to start off with only a fraction of their usual cannabis dose and take long breaks between hits to avoid accidental over intake.’


For an informative page on LSD tolerance in general, please see this page
https://tripsitter.com/lsd/tolerance/


The key point there is that LSD tolerance develops quickly but also goes away quickly. Most tolerance is negligible after 3 days and definitely beyond a week. If you had been dosing more regularly then this could expand out to as long as 2 weeks however.
While it was long thought that LSD affected different receptors than the cannabinoids, there is some potential crossover in regards to the 5HT2A receptors. Users anecdotally report either enhanced effectiveness or negative outcomes when mixing both. It may be more accurate to say that there is definitely an interaction there to be very mindful of when using both, but cross-tolerance in the traditional sense is not a major concern. There is risk though and thus it would be wise to tread carefully.


We hope this exploration into issues related to tolerance between these substances is helpful and wish you safe journeys.

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