diff --git a/changelog.d/14469.misc b/changelog.d/14469.misc
new file mode 100644
index 000000000000..a12a21e9aecb
--- /dev/null
+++ b/changelog.d/14469.misc
@@ -0,0 +1 @@
+Remove option to skip locking of tables when performing emulated upserts, to avoid a class of bugs in future.
diff --git a/synapse/storage/database.py b/synapse/storage/database.py
index a14b13aec83e..55bcb90001e9 100644
--- a/synapse/storage/database.py
+++ b/synapse/storage/database.py
@@ -1129,7 +1129,6 @@ async def simple_upsert(
         values: Dict[str, Any],
         insertion_values: Optional[Dict[str, Any]] = None,
         desc: str = "simple_upsert",
-        lock: bool = True,
     ) -> bool:
         """Insert a row with values + insertion_values; on conflict, update with values.
 
@@ -1154,21 +1153,12 @@ async def simple_upsert(
         requiring that a unique index exist on the column names used to detect a
         conflict (i.e. `keyvalues.keys()`).
 
-        If there is no such index, we can "emulate" an upsert with a SELECT followed
-        by either an INSERT or an UPDATE. This is unsafe: we cannot make the same
-        atomicity guarantees that a native upsert can and are very vulnerable to races
-        and crashes. Therefore if we wish to upsert without an appropriate unique index,
-        we must either:
-
-        1. Acquire a table-level lock before the emulated upsert (`lock=True`), or
-        2. VERY CAREFULLY ensure that we are the only thread and worker which will be
-           writing to this table, in which case we can proceed without a lock
-           (`lock=False`).
-
-        Generally speaking, you should use `lock=True`. If the table in question has a
-        unique index[*], this class will use a native upsert (which is atomic and so can
-        ignore the `lock` argument). Otherwise this class will use an emulated upsert,
-        in which case we want the safer option unless we been VERY CAREFUL.
+        If there is no such index yet[*], we can "emulate" an upsert with a SELECT
+        followed by either an INSERT or an UPDATE. This is unsafe unless *all* upserters
+        run at the SERIALIZABLE isolation level: we cannot make the same atomicity
+        guarantees that a native upsert can and are very vulnerable to races and
+        crashes. Therefore to upsert without an appropriate unique index, we acquire a
+        table-level lock before the emulated upsert.
 
         [*]: Some tables have unique indices added to them in the background. Those
              tables `T` are keys in the dictionary UNIQUE_INDEX_BACKGROUND_UPDATES,
@@ -1189,7 +1179,6 @@ async def simple_upsert(
             values: The nonunique columns and their new values
             insertion_values: additional key/values to use only when inserting
             desc: description of the transaction, for logging and metrics
-            lock: True to lock the table when doing the upsert.
         Returns:
             Returns True if a row was inserted or updated (i.e. if `values` is
             not empty then this always returns True)
@@ -1209,7 +1198,6 @@ async def simple_upsert(
                     keyvalues,
                     values,
                     insertion_values,
-                    lock=lock,
                     db_autocommit=autocommit,
                 )
             except self.engine.module.IntegrityError as e:
@@ -1232,7 +1220,6 @@ def simple_upsert_txn(
         values: Dict[str, Any],
         insertion_values: Optional[Dict[str, Any]] = None,
         where_clause: Optional[str] = None,
-        lock: bool = True,
     ) -> bool:
         """
         Pick the UPSERT method which works best on the platform. Either the
@@ -1245,8 +1232,6 @@ def simple_upsert_txn(
             values: The nonunique columns and their new values
             insertion_values: additional key/values to use only when inserting
             where_clause: An index predicate to apply to the upsert.
-            lock: True to lock the table when doing the upsert. Unused when performing
-                a native upsert.
         Returns:
             Returns True if a row was inserted or updated (i.e. if `values` is
             not empty then this always returns True)
@@ -1270,7 +1255,6 @@ def simple_upsert_txn(
                 values,
                 insertion_values=insertion_values,
                 where_clause=where_clause,
-                lock=lock,
             )
 
     def simple_upsert_txn_emulated(
@@ -1291,14 +1275,15 @@ def simple_upsert_txn_emulated(
             insertion_values: additional key/values to use only when inserting
             where_clause: An index predicate to apply to the upsert.
             lock: True to lock the table when doing the upsert.
+                Must not be False unless the table has already been locked.
         Returns:
             Returns True if a row was inserted or updated (i.e. if `values` is
             not empty then this always returns True)
         """
         insertion_values = insertion_values or {}
 
-        # We need to lock the table :(, unless we're *really* careful
         if lock:
+            # We need to lock the table :(
             self.engine.lock_table(txn, table)
 
         def _getwhere(key: str) -> str:
@@ -1406,7 +1391,6 @@ async def simple_upsert_many(
         value_names: Collection[str],
         value_values: Collection[Collection[Any]],
         desc: str,
-        lock: bool = True,
     ) -> None:
         """
         Upsert, many times.
@@ -1418,8 +1402,6 @@ async def simple_upsert_many(
             value_names: The value column names
             value_values: A list of each row's value column values.
                 Ignored if value_names is empty.
-            lock: True to lock the table when doing the upsert. Unused when performing
-                a native upsert.
         """
 
         # We can autocommit if it safe to upsert
@@ -1433,7 +1415,6 @@ async def simple_upsert_many(
             key_values,
             value_names,
             value_values,
-            lock=lock,
             db_autocommit=autocommit,
         )
 
@@ -1445,7 +1426,6 @@ def simple_upsert_many_txn(
         key_values: Collection[Iterable[Any]],
         value_names: Collection[str],
         value_values: Iterable[Iterable[Any]],
-        lock: bool = True,
     ) -> None:
         """
         Upsert, many times.
@@ -1457,8 +1437,6 @@ def simple_upsert_many_txn(
             value_names: The value column names
             value_values: A list of each row's value column values.
                 Ignored if value_names is empty.
-            lock: True to lock the table when doing the upsert. Unused when performing
-                a native upsert.
         """
         if table not in self._unsafe_to_upsert_tables:
             return self.simple_upsert_many_txn_native_upsert(
@@ -1466,7 +1444,12 @@ def simple_upsert_many_txn(
             )
         else:
             return self.simple_upsert_many_txn_emulated(
-                txn, table, key_names, key_values, value_names, value_values, lock=lock
+                txn,
+                table,
+                key_names,
+                key_values,
+                value_names,
+                value_values,
             )
 
     def simple_upsert_many_txn_emulated(
@@ -1477,7 +1460,6 @@ def simple_upsert_many_txn_emulated(
         key_values: Collection[Iterable[Any]],
         value_names: Collection[str],
         value_values: Iterable[Iterable[Any]],
-        lock: bool = True,
     ) -> None:
         """
         Upsert, many times, but without native UPSERT support or batching.
@@ -1489,18 +1471,16 @@ def simple_upsert_many_txn_emulated(
             value_names: The value column names
             value_values: A list of each row's value column values.
                 Ignored if value_names is empty.
-            lock: True to lock the table when doing the upsert.
         """
         # No value columns, therefore make a blank list so that the following
         # zip() works correctly.
         if not value_names:
             value_values = [() for x in range(len(key_values))]
 
-        if lock:
-            # Lock the table just once, to prevent it being done once per row.
-            # Note that, according to Postgres' documentation, once obtained,
-            # the lock is held for the remainder of the current transaction.
-            self.engine.lock_table(txn, "user_ips")
+        # Lock the table just once, to prevent it being done once per row.
+        # Note that, according to Postgres' documentation, once obtained,
+        # the lock is held for the remainder of the current transaction.
+        self.engine.lock_table(txn, "user_ips")
 
         for keyv, valv in zip(key_values, value_values):
             _keys = {x: y for x, y in zip(key_names, keyv)}
diff --git a/synapse/storage/databases/main/account_data.py b/synapse/storage/databases/main/account_data.py
index 282687ebce6e..07908c41d9ca 100644
--- a/synapse/storage/databases/main/account_data.py
+++ b/synapse/storage/databases/main/account_data.py
@@ -449,9 +449,6 @@ async def add_account_data_to_room(
         content_json = json_encoder.encode(content)
 
         async with self._account_data_id_gen.get_next() as next_id:
-            # no need to lock here as room_account_data has a unique constraint
-            # on (user_id, room_id, account_data_type) so simple_upsert will
-            # retry if there is a conflict.
             await self.db_pool.simple_upsert(
                 desc="add_room_account_data",
                 table="room_account_data",
@@ -461,7 +458,6 @@ async def add_account_data_to_room(
                     "account_data_type": account_data_type,
                 },
                 values={"stream_id": next_id, "content": content_json},
-                lock=False,
             )
 
             self._account_data_stream_cache.entity_has_changed(user_id, next_id)
@@ -517,15 +513,11 @@ def _add_account_data_for_user(
     ) -> None:
         content_json = json_encoder.encode(content)
 
-        # no need to lock here as account_data has a unique constraint on
-        # (user_id, account_data_type) so simple_upsert will retry if
-        # there is a conflict.
         self.db_pool.simple_upsert_txn(
             txn,
             table="account_data",
             keyvalues={"user_id": user_id, "account_data_type": account_data_type},
             values={"stream_id": next_id, "content": content_json},
-            lock=False,
         )
 
         # Ignored users get denormalized into a separate table as an optimisation.
diff --git a/synapse/storage/databases/main/appservice.py b/synapse/storage/databases/main/appservice.py
index 63046c052771..25da0c56c5d1 100644
--- a/synapse/storage/databases/main/appservice.py
+++ b/synapse/storage/databases/main/appservice.py
@@ -451,8 +451,6 @@ async def set_appservice_stream_type_pos(
             table="application_services_state",
             keyvalues={"as_id": service.id},
             values={f"{stream_type}_stream_id": pos},
-            # no need to lock when emulating upsert: as_id is a unique key
-            lock=False,
             desc="set_appservice_stream_type_pos",
         )
 
diff --git a/synapse/storage/databases/main/devices.py b/synapse/storage/databases/main/devices.py
index 05a193f889b7..534f7fc04a54 100644
--- a/synapse/storage/databases/main/devices.py
+++ b/synapse/storage/databases/main/devices.py
@@ -1744,9 +1744,6 @@ def _update_remote_device_list_cache_entry_txn(
                 table="device_lists_remote_cache",
                 keyvalues={"user_id": user_id, "device_id": device_id},
                 values={"content": json_encoder.encode(content)},
-                # we don't need to lock, because we assume we are the only thread
-                # updating this user's devices.
-                lock=False,
             )
 
         txn.call_after(self._get_cached_user_device.invalidate, (user_id, device_id))
@@ -1760,9 +1757,6 @@ def _update_remote_device_list_cache_entry_txn(
             table="device_lists_remote_extremeties",
             keyvalues={"user_id": user_id},
             values={"stream_id": stream_id},
-            # again, we can assume we are the only thread updating this user's
-            # extremity.
-            lock=False,
         )
 
     async def update_remote_device_list_cache(
@@ -1815,9 +1809,6 @@ def _update_remote_device_list_cache_txn(
             table="device_lists_remote_extremeties",
             keyvalues={"user_id": user_id},
             values={"stream_id": stream_id},
-            # we don't need to lock, because we can assume we are the only thread
-            # updating this user's extremity.
-            lock=False,
         )
 
     async def add_device_change_to_streams(
diff --git a/synapse/storage/databases/main/event_federation.py b/synapse/storage/databases/main/event_federation.py
index 309a4ba6643c..bbee02ab18f0 100644
--- a/synapse/storage/databases/main/event_federation.py
+++ b/synapse/storage/databases/main/event_federation.py
@@ -1686,7 +1686,6 @@ async def insert_insertion_extremity(self, event_id: str, room_id: str) -> None:
             },
             insertion_values={},
             desc="insert_insertion_extremity",
-            lock=False,
         )
 
     async def insert_received_event_to_staging(
diff --git a/synapse/storage/databases/main/pusher.py b/synapse/storage/databases/main/pusher.py
index fee37b9ce4f5..40fd781a6ab1 100644
--- a/synapse/storage/databases/main/pusher.py
+++ b/synapse/storage/databases/main/pusher.py
@@ -325,14 +325,11 @@ async def get_throttle_params_by_room(
     async def set_throttle_params(
         self, pusher_id: str, room_id: str, params: ThrottleParams
     ) -> None:
-        # no need to lock because `pusher_throttle` has a primary key on
-        # (pusher, room_id) so simple_upsert will retry
         await self.db_pool.simple_upsert(
             "pusher_throttle",
             {"pusher": pusher_id, "room_id": room_id},
             {"last_sent_ts": params.last_sent_ts, "throttle_ms": params.throttle_ms},
             desc="set_throttle_params",
-            lock=False,
         )
 
     async def _remove_deactivated_pushers(self, progress: dict, batch_size: int) -> int:
@@ -589,8 +586,6 @@ async def add_pusher(
         device_id: Optional[str] = None,
     ) -> None:
         async with self._pushers_id_gen.get_next() as stream_id:
-            # no need to lock because `pushers` has a unique key on
-            # (app_id, pushkey, user_name) so simple_upsert will retry
             await self.db_pool.simple_upsert(
                 table="pushers",
                 keyvalues={"app_id": app_id, "pushkey": pushkey, "user_name": user_id},
@@ -609,7 +604,6 @@ async def add_pusher(
                     "device_id": device_id,
                 },
                 desc="add_pusher",
-                lock=False,
             )
 
             user_has_pusher = self.get_if_user_has_pusher.cache.get_immediate(
diff --git a/synapse/storage/databases/main/room.py b/synapse/storage/databases/main/room.py
index 52ad947c6cfe..1309bfd374c3 100644
--- a/synapse/storage/databases/main/room.py
+++ b/synapse/storage/databases/main/room.py
@@ -1847,9 +1847,6 @@ async def upsert_room_on_join(
                 "creator": room_creator,
                 "has_auth_chain_index": has_auth_chain_index,
             },
-            # rooms has a unique constraint on room_id, so no need to lock when doing an
-            # emulated upsert.
-            lock=False,
         )
 
     async def store_partial_state_room(
@@ -1970,9 +1967,6 @@ async def maybe_store_room_on_outlier_membership(
                 "creator": "",
                 "has_auth_chain_index": has_auth_chain_index,
             },
-            # rooms has a unique constraint on room_id, so no need to lock when doing an
-            # emulated upsert.
-            lock=False,
         )
 
     async def set_room_is_public(self, room_id: str, is_public: bool) -> None:
diff --git a/synapse/storage/databases/main/room_batch.py b/synapse/storage/databases/main/room_batch.py
index 39e80f6f5b11..131f357d04d5 100644
--- a/synapse/storage/databases/main/room_batch.py
+++ b/synapse/storage/databases/main/room_batch.py
@@ -44,6 +44,4 @@ async def store_state_group_id_for_event_id(
             table="event_to_state_groups",
             keyvalues={"event_id": event_id},
             values={"state_group": state_group_id, "event_id": event_id},
-            # Unique constraint on event_id so we don't have to lock
-            lock=False,
         )
diff --git a/synapse/storage/databases/main/user_directory.py b/synapse/storage/databases/main/user_directory.py
index 698d6f7515a5..044435deab4e 100644
--- a/synapse/storage/databases/main/user_directory.py
+++ b/synapse/storage/databases/main/user_directory.py
@@ -481,7 +481,6 @@ def _update_profile_in_user_dir_txn(txn: LoggingTransaction) -> None:
                 table="user_directory",
                 keyvalues={"user_id": user_id},
                 values={"display_name": display_name, "avatar_url": avatar_url},
-                lock=False,  # We're only inserter
             )
 
             if isinstance(self.database_engine, PostgresEngine):
@@ -511,7 +510,6 @@ def _update_profile_in_user_dir_txn(txn: LoggingTransaction) -> None:
                     table="user_directory_search",
                     keyvalues={"user_id": user_id},
                     values={"value": value},
-                    lock=False,  # We're only inserter
                 )
             else:
                 # This should be unreachable.